Comments and discussion on issues in as well as on contemporary AIDS issues
RSS icon Home icon
  • Interferon in AIDS: Too Much of a Good Thing

    Posted on May 12th, 2011 admin No comments

    Interferon and AIDS:  Too much of a good thing

    This discovery of interferon in AIDS

    AIDS was first recognized in 1981.  Interferon was found in the blood streams of people with AIDS later that same year, making it one of the earliest of the significant AIDS associated immunologic abnormalities to be noted.    Large amounts of interferon were found that were present for very prolonged periods, a situation noted before only in auto-immune diseases like lupus.

    The interesting story of how interferon came to be discovered in people with AIDS so early in the epidemic illustrates at least one way in which science can progress;  it also demonstrates a way in which scientific progress can be retarded.

    The production of interferon following viral infections is part of the innate immune response that is the immediate first line of defence against viral infections.   Interferon has potent antiviral activity against a broad range of viruses.  It also has widespread effects on the immune system as well as effects on other organ systems.  Some of these effects are harmful if prolonged, so there are mechanisms for turning off the interferon response after a few days as other antiviral mechanisms come into play.

    HIV and disease causing SIV infections differ from most viral infections in that the production of interferon is not turned off; it continues to be produced, sometimes at very high levels.  The prolonged presence of interferon contributes to the disease process and is a factor in the loss of CD 4 cells.

    The sustained activation of both innate and adaptive immune responses is now understood to be at the heart of AIDS pathogenesis.

    Interferon continues to be produced, sometimes in large amounts, in HIV infected individuals.  In untreated HIV disease we have the unusual situation where increasing amounts of interferon are associated with increased HIV replication.

    Interferon can’t be exerting much of an antiviral effect in HIV infected individuals, but this did not deter investigators from injecting yet more of it into people with AIDS early in the epidemic.

    This is even more puzzling as by 1983 we had evidence that interferon was able to suppress CD4 lymphocyte proliferation.  Long before this we knew that treatment with interferon was associated with low white blood cell counts, and a low white blood count is characteristic of advance HIV disease.

    But if interferon was of no use against HIV it has been spectacularly successful against Hepatitis C, curing many people of this infection.  It also may still have a place in treating some people whose Kaposi’s sarcoma is unresponsive to antiretroviral drugs, possibly through its ability to inhibit angiogenesis, which is the process of new blood vessel growth.

    Although there were lots of reasons to consider that prolonged exposure to high levels of interferon might have something to do with this newly recognized illness even in 1981, serious work on this possibility was delayed for many years.  The zeal to administer yet more interferon to treat AIDS is surely part of the reason for this neglect.

    The inexplicable enthusiasm to treat AIDS with interferon resulted in no benefit to patients; it probably accelerated the disease process in some.

    It also had the unfortunate effect of delaying research into interferon’s role in the pathogenesis of HIV disease.

    It’s only in the past ten years that we have gained some information on how prolonged exposure to interferon can contribute to the loss of CD 4 lymphocytes.

    Finding interferon in people with AIDS

    This is how we came to find interferon in people with AIDS so early in the epidemic.

    Early in 1981 I had referred one of my patients to Dr Joyce Wallace.  A biopsy taken of lesions seen in his stomach indicated that these were Kaposi’s sarcoma.   Joyce called to tell me that she had contacted the National Cancer Institute to help identify experts in New York City who were familiar with Kaposi’s sarcoma  because this was the first time she was confronted with this diagnosis (the first time for me as well).   She had been told that over twenty gay men had been diagnosed with Kaposi’s sarcoma and that Dr Alvin Friedman Kien at NYU was treating a number of them.  I knew Alvin through my association with Jan Vilcek, a long-time colleague in the field of interferon research.  Alvin is a dermatologist but also worked in the NYU lab that Jan headed.

    I immediately called Jan who confirmed that Alvin was treating a number of gay men with Kaposi’s sarcoma. Jan very kindly allowed me to work in his lab.  I then arranged my time so that I worked in the virology lab in the mornings and saw my patients in the afternoon.

    I was one of several scientists who thought it likely that cytomegalovirus (CMV) played a role in this newly recognized disease so initially my lab work centered on this virus.

    In the early months of the epidemic Alvin had sent blood samples to Pablo Rubenstein at the New York blood center for HLA typing.   HLA refers to the human leukocyte antigen system which allows the immune system to differentiate foreign antigens from self-antigens. It’s important in organ transplantation, where a match in HLA antigens between recipient and donor can prevent organ rejection.

    HLA typing is important in investigating a newly recognized disease as there is an association of certain HLA types with some diseases, even some infectious diseases.

    A serologic method was then used for HLA typing.  It depended on the attachment of HLA specific antibodies to HLA antigens on the surface of leukocytes.

    HLA typing of our first patients with Kaposi’s sarcoma proved to be difficult because the patient’s own antibodies were already coating the   surface of their leukocytes, interfering with the test.

    At the same time I had come across a preprint of a paper reporting an important observation by Jan Vilcek.  The CD3 antigen is present on the surface of T cells.  Jan had reported that an antibody against the CD3 antigen was a powerful inducer of gamma interferon.

    As I read this report it occurred to me that Pablo Rubenstein’s observation that antibodies were attached to our patient’s leukocytes could mean that these blood cells were secreting gamma interferon, which we might be able to detect in their sera.

    I discussed this possibility with Jan and Alvin and we immediately set out to test the sera of Alvin’s patients.  This idea was to bear fruit, but not what we had expected.    Rather than gamma interferon, large amounts of alpha interferon were found.

    Jan Vilcek has also described this event, which can be seen by clicking here.

    Maybe what’s important is to have a reasonable idea that can be tested, not that the idea need be correct.  In fact much later, using more sensitive tests gamma interferon was eventually found in AIDS sera.

    Robert Friedman is a colleague from the early days of interferon research, with whom I had published work on the mechanism of interferon’s antiviral action.  He was – and still is ,chairman of the pathology department at the Uniformed Services University of the Health Sciences in Bethesda.  He, Jan and I have been colleagues since the 1960s when Alick Isaacs, a discoverer of interferon was still alive.   We joined forces to study the association of interferon with AIDS.

    Our extended findings including data obtained at both Jan Vilcek’s and Bob Friedman’s lab was published in the Journal of Infectious diseases in 1982.

    Since there were so many names, it was left to me to decide their order, and I chose that they be listed alphabetically. Thus Gene DeStefano became lead author. He was a technician in Jan’s lab and I believe he went on to become a dentist.  This is the title.

    Acid-Labile Human Leukocyte Interferon in Homosexual Men with Kaposi’s Sarcoma and Lymphadenopathy

    E. DeStefanoR. M. FriedmanA. E. Friedman-KienJ. J. GoedertD. Henriksen,O. T. PrebleJ.Sonnabend* and J.Vilček (1)

    This early discovery prompted a pretty obvious question:  could the sustained presence of interferon have anything to do with the pathogenesis of this newly recognized disease?  From what was then known about the effects of interferon it was a question that certainly needed to be explored.

    Although interferon had been discovered in 1957 through its antiviral properties, by the 1970s it was already known that it had widespread effects on the immune system.

    In the first few years of the epidemic I was in a position  to begin to begin to explore the possibility that interferon played a role in this newly recognized disease.

    I was able to obtain interferon assays on sera from my patients at Robert Friedman’s lab.   Further interferon tests were done by Mathide Krim, then head of the interferon lab at Memorial Sloan Kettering cancer center.

    I also was able to obtain quite extensive immunological tests on my patients through my collaboration with David Purtilo at the University of Nebraska in Omaha.    As a result I had (and still have) a small database of my own and so was able to produce further evidence for the association of high interferon levels with low CD4 counts, as well as some other associations with interferon. (2).

    The numbers of patients was not huge but the following graphic shows that 7 people with over 50 units of interferon/ml had under 50 CD4s, 12 people with 10-49  units had under 500 CD4s while 17 people without interferon had about 700.

    There are several other interesting correlations.  Interferon levels correlate with IgA levels and not surprisingly there is an inverse correlation between CD4 counts  and IgA levels.

    This was a CRIA presentation in the 1990s from the days when I was the medical director, but the data had first been presented in 1986.

    Being familiar with the adverse immunological effects of prolonged exposure to interferon I was puzzled by the attempts to conduct trials of alpha interferon to treat AIDS.  This is very different to the benefits of interferon in treating Hepatitis C and some cases of Kaposi’s sarcoma.

    The zeal to use interferon as a treatment for HIV disease created a strange situation concerning a molecule called beta-2 microglobulin (beta 2M).

    In the early  years of the epidemic various markers were sought that could act as prognostic indicators.   It was soon found that a raised beta 2M level in the serum of patients was an adverse prognostic indicator.   High levels were indicative of a poor prognosis.   But interferon is the major stimulus for the synthesis and release of beta 2M, something that was known in the 1970s.

    In fact the adverse prognostic significance of serum interferon had already been reported early in the epidemic.

    A 1991 paper by a noted AIDS researcher, reported studies undertaken to evaluate the hypothesis that elevated beta 2M levels were associated with the production of interferon.   But this association had been well known for about 20 years!

    Beta 2M levels can be elevated in certain conditions where interferon is not detectable. But even before the onset of the epidemic we knew that when interferon levels are elevated we expect to see increases in beta 2M.   Nonetheless this particular paper was noteworthy in that it discussed this association.   Few others papers dealing with beta-2M  during those years made any mention of it, thus avoiding the following question.   If elevated beta-2M levels indicated an adverse prognosis should we not be concerned that administering interferon will result in yet further increases in beta-2M?

    This of course doesn’t mean that beta-2M mediated any pathogenic effects, but it simply prompts a question.  Of course we now know that interferon mediates some of the pathological effects of HIV disease, and beta-2M can properly be regarded as a surrogate marker for interferon.

    How is it possible to explain why in a disease characterised by low CD 4 lymphocyte counts and the presence of large amounts of interferon, it was thought that injecting yet more interferon could possibly be of help?

    Dr Fauci and other investigators tried to explain the paradox of administering interferon to people who already had huge amounts of it in their blood stream by claiming that the endogenous interferon was different.   The difference referred to was that the AIDS associated interferon could be partially inactivated by acid, whereas the administered interferon was resistant to acid (3).

    But we knew that AIDS associated interferon was neutralized by monoclonal antibodies against administered interferon, meaning that the molecules were identical, and the interferon in patients’ blood had the antiviral activity expected of alpha interferon when tested in cell cultures.  It certainly was responsible for the beta 2M.

    In fact the sensitivity to acid is not a property of the interferon molecule but is conferred by other components.  Interferon from patients that is partially purified loses its sensitivity to acid.

    This explanation which cannot stand up to even the most cursory scrutiny was apparently good enough for community writers on AIDS treatment.

    I repeatedly tried to bring attention to the probable contribution of interferon to pathogenesis without success.  I received no response to a letter that can be seen by clicking   here.

    In 1990 I was able to organize a meeting to bring basic researchers and clinicians together to discuss the role of interferon in pathogenesis and in treatment.

    The meeting was very well attended, but I have no idea if it accelerated interest in interferon’s role in pathogenesis.

    I probably angered a number of investigators when I tried – with the help of Michael Callen and Richard Berkowitz to inform people of the risks of receiving very high doses of interferon in clinical trials. We felt that information about interferon should be included in the consent form.  We even went to the lengths of taking out a paid advertisement in the New York Native to inform people about potential problems associated with receiving high dose interferon. This can be seen here. Richard Berkowitz has posted the complete ad on his website,



    It’s now more difficult to undertake studies that can investigate correlations between endogenous interferon levels and various immunological abnormalities.  It would have to be done on material stored before AZT was introduced or on individuals not receiving antiretroviral drugs.

    The reason for this is that antiviral therapy promptly removes interferon from the circulation.  This is something that the group I worked with at Roosevelt hospital, including Elena Klein and Michael Lange found shortly after AZT was introduced.  We had access to sera from clinical trials of AZT.  In one of these trials AZT was administered for a week on alternate weeks.

    We found that interferon promptly disappeared during the week on AZT, only to reappear just as promptly when AZT was discontinued.

    Another report studying sera from the same trial looked at the effect of intermittent AZT therapy on beta 2M.  The same saw tooth response of beta 2M was unsurprisingly seen, but my recollection is that the word interferon was not mentioned.

    Undoubtedly researchers today are looking at the significance of this almost immediate turning on and off of the interferon response in pin pointing the mechanism of its induction.

    With continuous AZT therapy interferon remains suppressed for about 5 weeks and then reappears and increases steadily.  Interestingly HIV as measured by p24 antigen  reappears many weeks after interferon

    One interesting implication of the effect of AZT (and other antiretroviral drugs) on endogenous interferon levels relates to hepatitis C.  It’s been noted that in coinfected individuals starting anti HIV drugs, sometimes there is an increase in liver enzymes as well as an increase in hepatitis C RNA.  It’s possible that in some individuals, hepatitis C is controlled to some extent by endogenous interferon, and flares up when interferon is removed by the anti HIV drugs.  Some researchers have commented on this although I don’t know it this possibility has actually been studied.  There are also other reasons why liver enzymes can increase on starting anti HIV drugs.

    We presented these results at a meeting I organized in New York in 1990.

    The innate immune response is a first line of defence against infection coming into play within hours.  Secretion of interferon is an important part of this response which also includes the inflammatory response.  Innate immune responses are immediate attempts to localize and overcome infections.  These beneficial responses last for a brief period because they become harmful if prolonged.  There are mechanisms that turn them off.  But in HIV infection and in pathogenic SIV infections innate immune responses are not turned off.  Persistent immune activation involving the adaptive immune system as well is at the heart of HIV disease pathogenesis.

    Several important research questions that I’m sure are being pursued are:   Why is the interferon response not turned off in HIV disease?  Why does the innate immune response continue to be activated?   What are the mechanisms that normally turn off interferon production and why are they not working?

    The precise role of interferon in contributing to CD4 loss remains to be worked out, although several mechanisms by which this can occur have been elucidated.

    But for years there was almost no work on identifying what induced such high levels of interferon and on determining which cell produced it.   It took over twenty years since interferon was first identified in AIDS sera for work to be undertaken to identify the ways in which it contributes to pathogenesis. There is still much to be learned, and hopefully the findings can be translated into new therapeutic possibilities.

    The reasons why the role of interferon in pathogenesis has been neglected for so long are undoubtedly multiple and complex. But one reason for this neglect was surely the early enthusiasm to administer it as treatment.

    But many years have been  lost by the neglect of a critical line of research the importance of which was evident in the same year that AIDS first came to attention.

    I have chosen these three references from a growing literature to illustrate what we are beginning to learn about interferon’s role in the pathogenesis of HIV disease.

    1. Herbeuval JP, Shearer GM.  HIV-1 immunopathogenesis: How good interferon Turns Bad.Clinical Immunology (2007); 123920:121-128
    2. Boasso A,Hardy AW et al.  HIV-1 induced Type 1 interferon and Tryptophan Catabolism Drive T Cell Dysfunction Despite Phenotypic Activation. PLoS ONE  (2008); 3(8): e2961
    3. Stoddart CA, Keir ME et al.  IFN-α-induced upregulation of CCR5 leads to expanded HIV tropism in vivo, PLoS pathogens (2010); 6(2) e1000766



    Some immunologic parameters in homosexual patients with Kaposi’s sarcoma (KS) or unexplained lymphadenopathy resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with SLE have an unusual acid-labile form of human leukocyte interferon (HuIFN-α) in their serum. Sera from 91 homosexual men were tested for the presence of HuIFN. Of 27 patients with KS, 17 had significant titers of HuIFN in their serum. Ten of 35 patients with lymphadenopathy and three of four patients with other clinical symptoms also had circulating HuIFN. In contrast, only two of 25 apparently healthy subjects had serum HuIFN. All 32 samples of HuIFN had antiviral activity on resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with bovine cells, a characteristic of HuIFN-α, and all of 14 representative samples tested were neutralized by antibody to HuIFN-α. In addition, the HuIFN-α in six of eight representative patients was inactivated at pH 2 and therefore appears to Some immunologic parameters in homosexual patients with Kaposi’s sarcoma (KS) or unexplained lymphadenopathy be similar to the HuIFN-α found in patients with SLE. These findings suggest that an autoimmune disorder may underly lymphadenopathy and KS in homosexual men.


    Sonnabend J., Saadoun S., Griersen H., Krim M., Purtilo D.  Association of serum interferon with hematologic and immunologic parameters in homosexual men with AIDS and at risk for AIDS in New York City.

    2nd International Conference on AIDS Paris 1986.  Abstract 100

    There were several other interesting associations including a positive correlation between IgA and interferon, so needless to say, there is an inverse correlation between CD4 counts and IgA.   In the early days I used easily obtainable IgA measurements as an unproven  prognostic indicator.



    I found a transcript of a meeting in New York where Dr Fauci answered questions posed people with AIDS and their advocates, where he explains this.

    You can see this at the very end of another article I wrote about interferon and AIDS in 2009 that contains some of the same material in this blog.

  • HIV exposed individuals who are seronegative.

    Posted on October 18th, 2010 admin No comments

    A current supplement to the Journal of Infectious Diseases is devoted to natural immunity to HIV infection.

    It contains several articles dealing with individuals who have been repeatedly exposed to HIV and remain seronegative. They are apparently able to resist infection and do not develop antibodies against HIV.   Several different genetic and immunological mechanisms have already been discovered that can account for this phenomenon.   The best known may be the inherited absence of a particular cell surface molecule that HIV needs in order to infect a cell, as a result of a genetic mutation (CCR5delta32).   But this is far from the only basis for the apparent resistance of some individuals to HIV infection.

    Gene Shearer is a pioneer in the study of HIV exposed seronegative individuals who published some of the earliest reports on this phenomenon.  In this journal supplement he with Mario Clerici estimate that about 10 – 15 % of individuals repeatedly exposed to HIV remain uninfected.       They note that in the first years of the epidemic “little attention was given to the chance observation that mucosal [or] parenteral exposure to human immunodeficiency virus type 1 (HIV) would not consistently induce infection, and none to the possibility that such putative non-infectious exposures might induce protective immunity “.

    I can’t recall that there ever was an assumption that mucosal or parenteral exposure to HIV would  consistently induce infection.   This would have accorded HIV the probably unique ability among infectious agents to infect 100% of those exposed to it.      However I certainly recall that in the earliest years after HIV was discovered it was assumed that infection would invariably lead to disease.  HIV infection it was claimed was like a Mack truck with nothing but time standing in the way of its inevitable progression to disease.  This too would have made HIV infection almost unique among infectious diseases.  Rabies may be the only infectious disease where 100% of infected (and unvaccinated) individuals become ill, although I believe some exceptions have been described.

    The rapid acceptance of the assumption that HIV infection always leads to disease was quite remarkable at that time, as there could not yet have been sufficient observations to justify ascribing such an unusual property to HIV infection.    Yet this view was so firmly held by the HIV research leadership that it was left to AIDS activists to alert them in the 1990s(1)  to the fact that there were indeed individuals who appeared not to have progressive disease, or whose disease progressed very slowly.

    We had come to understand that infection and disease are not synonymous terms, but remarkably it seemed that this important lesson learned at least a century ago had somehow been ignored by some of those producing a detailed picture of the course of HIV infection at a time when so little was known about it.

    These words were written by Rene Dubos, a great microbiologist, in Man Adapting published in 1966.

    “…….This approach requires that the determinants of infection be separated conceptually from the determinants of disease; its objective will be to understand and control the processes responsible for converting infection into overt disease”

    That there is a distinction between infection and disease is something I learned as a medical student in Johannesburg in the 1950s which I in turn tried to pass on when I taught medical students in New York in the late 1960s until 1977.    Even in the first years of the epidemic I sent copies of Man Adapting to several individuals involved in the early response as I was discovering with surprise that some concepts that I thought were firmly established in our understanding of infectious diseases seemed all too frequently  to have been forgotten.

    Rene Dubos, was associated with the Rockefeller University in New York for 50 years.  He was a truly towering figure; his writings helped move us beyond the oversimplification that is the germ theory of disease.  While recognizing that the doctrine of specific etiology – as represented by the germ theory of disease was “the most powerful single force in the development of medicine”, he also wrote that “there is now increasing awareness that it fails to provide a complete account of most disease problems as they naturally occur”.

    Rene Dubos died in 1982, one year after AIDS was first recognized.  The “now” in the above quotation refers to a period before 1966, when “Man Adapting” was published.  The increasing awareness of the limitations of the doctrine of specific etiology had apparently dissipated by 1981, at least in the medical response to AIDS.   At that time, genetic factors, socio- economic factors, behavioral factors, the effect of concurrent infections, or anything else were not going to slow the Mack truck.  By 1990, only six years after HIV had been discovered we were also told that, except for a period of 3 to 6 months after infection, called the window period, tests for HIV antibodies could not fail to detect infection.

    But reality cannot be held at bay indefinitely, and to the surprise of some there did indeed appear to be individuals who were HIV infected but were able to control the infection to varying degrees, as well as those who were infected for prolonged periods but had no detectable antibodies.    However when the first reports of these phenomena appeared, the authors were subjected to a torrent of outraged criticism, much of it abusive.

    David Imigawa and The Window Period.

    In 1989 David Imagawa, reported that in 31 of 133 HIV antibody negative individuals it was possible to detect the presence of the virus for periods longer than 6 months.  In 27 of these individuals, HIV continued to be detected for up to 36 months despite remaining HIV antibody negative (2).   This publication in the New England Journal of Medicine resulted in a furious response culminating in a letter to the New England Journal of medicine from David Imagawa and Roger Detels that almost appeared to be a retraction but certainly was not.

    David Imagawa and his colleagues were subjected to hostile and  baseless criticism, not only from leading researchers but also from science writers.

    This is the headline of a story in the New York Times in 1991 which will give an indication of the kind of response the report received.

    THE DOCTOR’S WORLD; Researchers in Furor Over AIDS Say They Can’t Reproduce Results.

    This is how the article starts:

    “THE scientists who came up with one of the most shocking scientific findings about AIDS — one that set off alarms concerning the safety of the blood supply and about the state of mind of people at risk — now cannot reproduce their own results. But they still have not said clearly that their finding was incorrect”.

    It includes this statement:

    “Even this confusing letter would not have appeared without constant pressure behind the scenes from officials of the National Institutes of Health who paid for the original research and who were determined to try to straighten the record”.

    But how secure was the record from which David Imagawa and Roger Detels had strayed?

    In 1989, only 5 years after the discovery of HIV, with relatively little experience accumulated by that time, we could only be at a stage of establishing a record.   Activists had yet to alert officials that long term non progressors really existed.

    Whatever attributes science possesses that distinguishes it from more metaphysical pursuits surely one is a requirement to as best as we can describe phenomena as they are, rather than as we might wish to see them,  so the constant behind the scenes pressure exerted on David Imagawa sounds more like demands made on an apostate to recant.

    David Imagawa’s observations were in fact correct. Similar observations have been made by others.

    Sadly he did not live to experience the vindication of his pioneering studies.  He died of a heart attack shortly after the New york Times article appeared.

    A fairly detailed account of the course of HIV infection had been constructed only 5 to 6 years after the discovery of HIV, essentially that illustrated in this very familiar diagram.

    The rapid acceptance in those early years  that there  even was  a typical course of HIV infection is particularly odd as not only was the disease newly recognized, we then had no precedents of human retroviral diseases (apart from HTLV-1 associated disease);  the techniques used to study the disease were themselves new. The ability to identify T lymphocyte subsets with monoclonal antibodies is about as old as the HIV epidemic. So we had no idea at that time of the variation in T subset numbers in health and disease. Other immunological and virological techniques were, and continue to be introduced.

    At that time, only 5 to 6 years after the discovery of HIV there could not have been a solid enough empirical basis to justify the confident assertion, in the case of sexually transmitted HIV that there could not be situations where integrated HIV DNA is carried for prolonged periods without seroconversion.  Unlike infections acquired by blood or blood products, the time of initial infection can rarely be known.  The infecting dose of virus in the case of sexual transmission could be even orders of magnitude less than that when infection is acquired by blood transfusion.

    How then to account for the persistence of recoverable virus for up to 36 months in the absence of seroconversion?

    In the original New England Journal of Medicine publication David Imagawa and his colleagues raised the possibility of a “silent” HIV infection, suggesting that HIV in the form of proviral DNA integrated into the genome could persist without production of HIV virions.   This is a perfectly reasonable suggestion.  But in their subsequent letter, they changed their minds and ascribed their finding to the ability of the men to overcome the infection. Because of continued high risk activity virus was repeatedly detectable.   In a more recent article Roger Detels expands on this explanation, noting:  “The fact that we isolated HIV ONLY from those men who continued their high-risk exposure suggested that transient infection and clearance of HIV was the more likely explanation”.

    Of course this may be the explanation.  If so, HIV sequences should have been consistent on repeated isolations, whereas if infections were transient, variations would likely  have been seen with repeated isolates.

    But it was not the explanation in another report of HIV DNA in two antibody negative individuals (3).   In the abstract of this paper the authors note:  (ES refers to exposed seronegative individuals)

    “Some individuals remain inexplicably seronegative and lack evidence for human immunodeficiency virus type 1 (HIV-1) infection by conventional serologic or virologic testing despite repeated high-risk virus exposures. Here, we examined 10 exposed seronegative (ES) individuals exhibiting HIV-1-specificcytotoxicity for the presence of HIV-1. We discovered HIV-1 DNA in resting CD4(+) T cells (mean, 0.05 + /- 0.01 copies per million cells) at multiple visits spanning 69 to 130 weeks in two ES individuals at levels that were on average 10(4)-to 10(6)-fold lower than those of other HIV-1-infected populations reported. Sequences of HIV-1 envelope and gag genes remained markedly homogeneous, indicating little to undetectable virus replication. These results provide the evidence ……… suggesting that extraordinary control of infection can occur. The two HIV- infected ES individuals remained healthy and were not superinfected with other HIV-1strains despite continued high-risk sexual exposures to multiple HIV-infected partners. Understanding the mechanisms that confer diminished replicative capacity of HIV-1 in these hosts is paramount to developing strategies for protection against and control of HIV-1 infection”.

    At the heart of the furious response to David Imagawa’s observation is the fear it raises about the safety of the blood supply and the peace of mind of those testing HIV negative.  Roger Detels in the article linked to above makes these comments:

    “We were presented with an ethical dilemma — should we publish knowing that there was a possibility that the publication would create panic, or should we not publish to prevent the panic? “

    As far as the blood supply is concerned, the most reliable data on the window period were derived from observations on transfusion related infections, and antibody tests have been  hugely effective in ensuring the safety of the blood supply  (even without additional tests reducing the risk to less than 1 in 1,000,000).   So the New York Times article and others like it were quite unjustified in raising fears for the safety of transfused blood based on observations made on sexual transmission.

    As far as the peace of mind of individuals testing negative is concerned, if there should be those who are able to maintain HIV in latency in the form of proviral DNA, that is never fully expressed, it’s entirely possible that in some of these individuals, HIV has had an immunizing effect rather than causing productive infection.

    It appears that to this day the reluctance to even consider HIV seronegative infection persists.

    Returning to the supplement of the Journal of Infectious Diseases dealing with natural immunity to HIV, the possibility of stable HIV infections that remain unexpressed is not considered at all as at least one explanation for persistent seronega   tivity  of some individuals exposed to HIV.   It seems to be just taken for granted that these individuals are resistant to infection.  But how can it be known that all of these seronegative individuals exposed to HIV have resisted infection?   Some may carry HIV in the form of unexpressed proviral DNA.   Even if this is not detected in cells circulating in the blood stream this does not mean a great deal as only a tiny minority of CD4 + cells circulate, and the DNA containing HIV may be in cells without the CD4 receptor.

    Over a year ago I wrote about HIV infection in seronegative individuals.     There I outlined one possible consequence of HIV infection.  Retroviral replication requires prior integration of the viral genome into that of the host cell in the form of proviral DNA which must be activated before new virions can be made.  Under certain conditions it’s possible that the process may stop at integration or be aborted after a very limited expression of viral gene products.  No virus is produced so there will be no antibodies as these are made in response to viral proteins. If there had been very limited expression of viral gene products this might induce cell mediated immune responses, as has often been reported in HIV seronegative individuals.  This may be sufficient to kill HIV infected cells that start to express HIV antigens on their surface, and with each incipient burst of replication the immune response might be further primed.

    EBV is a virus that remains latent in B lymphocytes rather than T lymphocytes. Virtually all adults carry this virus and remain in good health although EBV can be lethal under certain circumstances.   Much is understood of the elaborate mechanisms that maintain this virus in latency.   EBV is very different to HIV, it’s a double stranded DNA virus, huge in comparison with HIV – with a genome of 172 Kbp compared to HIV’s of less than 10.  Unlike HIV its replication does not require integration into the host genome.   Despite these differences, if HIV can be maintained in latency we might expect that analogous mechanisms operate, and provide a helpful model.

    If HIV can be carried in a stable integrated form as proviral DNA, that is not expressed at all or only partially and intermittently expressed, then this may be the basis for the apparent resistance of some ESNs.  Such individuals are not resistant to infection, but for probably a variety of reasons connected both with the virus, as well as host factors, the infection is aborted at the stage of integration.

    We know some of the signals that can activate HIV DNA to start the process of making new viral particles.  Some cytokines are potent activators of HIV and can also appear during the course of other.    In the absence of sustained activating signals and with a small infecting dose of virus abortive but persistent infection might occur.  If there is very limited viral replication this may be sufficient to induce a cell mediated immune respons

    It would be extremely difficult to identify such individuals as cells carrying HIV DNA may not be in the circulation.

    Since it’s not too practical to study biopsy specimens, HIV genome detection techniques applied to tissues from a large number of unselected autopsies may just surprise us.

    (The following is adapted from the previous post)

    A model representing the course of HIV infection shown in the above illustration was constructed before sufficient evidence was available to justify it.  It really had a very limited empirical basis at that time; moreover it seemed to utterly ignore what we knew of other chronic viral diseases.  For example, hepatitis B and hepatitis C can both have very variable courses.  These can range from clearing the infection, running a fulminant course ending fatally,  to the establishment of a chronic active state which may progress at varying rates.  If we were to construct a model of the course of HIV disease less than 10 years  after the virus was discovered, why  did we not consider the precedents of other chronic viral diseases?   Thus we might have then included the real possibility that some exposures may result in infections that are cleared, as well as a situation where disease does not progress.    The picture shown above – and presented in every text on HIV disease may indeed represent the most common course of HIV infection. But even this is not known.

    HIV infection, like other chronic viral infections can progress in different ways. If we were more open to this there may have been greater interest and funding into research that investigates the various factors that influence how the disease progresses. This has obvious therapeutic implications  –  for example as proinflammatory cytokines promote HIV replication, the control of endemic infections in some areas where they are highly prevalent is absolutely relevant to the control of HIV infection.  Steps as simple as the provision of sanitation and clean water may well have an impact on the control of HIV infection in some geographical areas.  Had we not been so tied to the notion of  a fixed course of HIV infection, we might have placed importance on the individualization of therapy, not only considering a fixed CD4 count as a signal to start therapy, but also considering each individuals rate of disease progression.

    HIV disease is in this sense like every other infectious disease, the course of which to a greater or lesser extent can be influenced by many different factors, including host factors, factors related to the pathogen, the particular variant , the size of the infecting dose, the route of infection amongst many others.

    I have often wondered why there has been such resistance to not only the reasonable idea, but also to actual evidence that HIV disease does not necessarily take the course shown above.


    “Gonsalves recalls a meeting with Anthony Fauci, MD, head of the National Institute of Allergy and Infectious Diseases, in the early 1990s. He and fellow activist Mark Harrington, along with a New York City physician named Joseph Sonnabend, explained to Fauci that Sonnabend had a small group of patients with HIV who didn’t seem to have disease progression. They wanted Fauci to explore this phenomenon—and it was the MACS that took up the question.

    Phair says he and other MACS researchers confirmed the existence of these nonprogressors ….”

    Imagawa, D.T., M.H. Lee. S.M Wolinsky. et al.  Human immunod eficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods. New England Journal of Medicine 1989 320:1458-1462.


    Persistence of extraordinarily low levels of genetically homogeneous human immunodeficiency virus type 1 in exposed seronegative individuals.

    Journal of virology, {J-Virol}, Jun 2003, vol. 77, no. 11, p. 6108-16,


  • HIV disease and Positive feedback: An additional comment.

    Posted on August 31st, 2010 admin No comments

    HIV Disease and Positive Feedback.  An additional comment.

    A previous post focussed on the positive feedback interaction between HIV replication and immune activation.   HIV replication and immune activation reciprocally enhance each other.

    While HIV infection is an essential cause of the immune activation that’s characteristic of HIV disease, there are other factors that also contribute to it.   In that post as well as in the blog I write on the POZ magazine website, I described some of these additional factors that can add to immune activation.   As noted, viruses of the herpesvirus family, cytomegalovirus (CMV) in particular are the most important of these worldwide, while in parts of Africa certain endemic infections may be of great significance in contributing to immune activation.

    Since sustained immune activation, involving both innate and adaptive immunity is at the heart of the pathogenesis of HIV disease an understanding of how it is perpetuated is critical.

    Evidence for activation of innate immunity was noted in 1981, the year that AIDS was first reported, in the detection of large amounts of alpha interferon in the circulation of patients.  We even knew then that interferon alpha and gamma could  induce an enzyme, indole 2,3-dioxygenase  (IDO),  (IDO was known to be responsible for the inhibition of toxoplasma gondii by depletion of  tryptophan  in cells treated with gamma interferon) but we did not know then that this enzyme could contribute to the loss of T lymphocytes.   Another observation of historical interest is that even before AIDS was first reported in 1981, interferon was known to preferentially inhibit CD4 lymphocyte proliferation in mixed lymphocyte culture.

    Since immune activation and its effects, including  inflammation, are harmful if sustained,   there are mechanisms that can  dampen it.

    But in HIV disease, immune activation persists with continued deleterious consequences.

    The reason I’m revisiting this now is that there is a question that continues to be bothersome.

    HIV disease is not the only infection associated with long standing immune activation.

    Several endemic infections in Africa are also associated with sustained immune activation, certainly not all – some even have a dampening effect on immune responses. TB is another example of an infection associated with chronic immune activation.   In none of these conditions is there such a profound loss of CD4 lymphocytes as in HIV disease.  While individuals with active pulmonary  TB have been reported to have lower CD4 counts than healthy individuals, the numbers were well above 500.

    Is the difference between sustained immune activation associated with HIV and that associated with other chronic infections in HIV negative individuals a matter of degree – is it a quantitative difference?

    Could the  mechanisms that dampen and check  immune activation be impaired in HIV disease?   These mechanisms include the secretion of cytokines that have anti-inflammatory properties, such as IL-10, IL-13, and  TGF-beta, among others.  Specialized immune system cells can also dampen immune activation.  Tregs, a subset of T lymphocytes, have such a dampening effect.   Although there are conflicting reports on the relationship of Tregs to HIV disease, it is known that HIV targets some of  these particular T lymphocytes.

    This graphic comes from a previous post.

    In the diagram,  disease progression is represented by a circular  clockwise movement propelled by a positive feedback interaction between HIV replication and immune activation.   It can be accelerated by infections that contribute to immune activation, CMV in particular, but probably also  some endemic infections in parts of Africa.   CMV probably also has a positive feedback association with HIV in that it is more likely to be driven out of latency in the setting of HIV infection, and active CMV infections can enhance HIV replication by several mechanisms including their contribution to immune activation.   Some endemic infections probably also have analogous reciprocal interactions with HIV.    The influences that can slow the cycle are those mechanisms that dampen immune activation.   They include the effects of  Tregs, a subset of T cells with regulatory functions that  dampen immune responses, and the effects of cytokines with anti-inflammatory properties.

    In graphic terms, the speed of the clockwise circular movement will be the balance of forces that speed it up and those that slow it down.

    HIV disease progression is represented as moving clockwise in a circle, reinforced by sources of immune activation other than HIV and retarded by Tregs and other mechanisms that dampen immune responses.  Tregs  act as brakes, but HIV can directly make the brakes less effective.

    Could critical differences between HIV disease and other infectious causes of long standing immune activation where CD4 numbers are relatively preserved, be  the preferential targeting of Tregs by HIV and a different pattern of cytokine secretion?

    I wonder if this revised representation of HIV disease lends itself to a more formal modelling process.

    In this particular model a disease process is represented by a circular motion in a clockwise direction, with forces that both propel and retard it.  Some predictions can be made.

    The degree of immune activation at the time of HIV seroconversion would favour more rapid HIV disease progression.  The set point – the level from which CD4 lymphocytes decline following an acute HIV infection, would be lower, and the subsequent  rate of CD4 decline higher when HIV infection occurs in a person where there already is a higher degree of immune activation, compared to an individual where this is not the case.  There already is  some evidence in support of this possibility.

    It’s well established that HIV disease progresses more rapidly with increasing age.  Could an explanation for this be that immune activation increases with age – indeed, it’s been suggested that immune activation  contributes to the aging process.

    HIV disease progresses more rapidly in individuals with active TB.  CMV viremia was noted to carry an adverse prognostic significance in HIV disease very early in the epidemic.  There are but two  examples, but there are many more of  of a more rapid course of HIV disease in the setting of other  infections caused by bacteria, protozoa, viruses and helminthes.  Some are referred to in a previous post.

    Are Treg numbers at seroconversion and for a period immediately afterwards  related to subsequent disease progression?

    Could treatment with anti CMV agents during acute HIV infection retard subsequent disease progression?

    There already  is some evidence that treatment of HIV during acute infection might slow the subsequent course of HIV disease.

    The utility of any model of a disease process lies in its ability to provide a common explanation for disparate observations as well as to make predictions that can be tested by an analysis of available data or by experimentation.

    Viewing HIV disease as a process with a positive feedback interaction between HIV replication and immune activation with forces that both enhance and retard this interconnection,  provides a useful descriptive framework as well as testable predictions.

  • AIDS Pathogenesis: HIV disease has characteristics of positive feedback systems

    Posted on April 2nd, 2010 admin No comments

    There is a similar and slightly extended version of this post on the blog I have on the POZ website. It’s in two parts:

    Part 1

    Part 2

    HIV infection and many other infections caused by a wide variety of microorganisms have a mutually enhancing relationship that is characteristic of positive feedback systems.

    Although the reciprocal enhancing effects of HIV and other infections have been frequently described since the late 1980s, it is useful to explicitly recognize these as positive feedback systems as this highlights the implications they have for treatment of individuals and for control of the epidemic.  Explicitly recognizing the positive feedback characteristic of HIV disease also provides a way of looking at pathogenesis that can suggest further studies, both clinical and laboratory, that might advance our understanding of mechanisms of disease acquisition.

    This is an illustration of positive feedback.    A stimulates B which in turn stimulates A. In this way the effects of A and B are increased.

    The infections associated with the immunological disorders of HIV disease are generally, but not solely, caused by microorganisms that replicate within cells.     Many of the organisms that cause these infections survive in healthy people without causing disease, prevented from doing so by a competent immune system.   When the immune system fails these infectious agents start to divide.   They may then cause disease.  An additional effect of some of these active infections is to accelerate the replication of HIV.  Several mechanisms are responsible for this effect, which can then result in further immunological deterioration.

    In addition, co-infection with many of the pathogens that also affect individuals with intact immune systems can also promote HIV replication.

    Not all co- infections result in a more rapid progression of HIV disease.  Many have no effect and a few have even been reported to cause a temporary improvement of HIV disease.    This may be the case with measles, scrub typhus and a form of transfusion associated hepatitis.   But more often, when an effect of a co-infection has been noted, it has been to promote HIV disease progression.

    Different co-infections can therefore affect the course of HIV disease in different ways.  Some may have no impact on the course of HIV disease; a few may possibly cause a temporary amelioration.   Those that are able to accelerate it are highly prevalent in HIV infected individuals.

    Worldwide, viruses of the herpes family are probably the most important of the co-infections that interact with HIV in a mutually enhancing fashion. .    Virtually all adults are infected with some of these viruses that usually exist in a latent or dormant state.  They are readily activated in the setting of HIV infection and then promote further HIV replication by a number of different mechanisms.

    In developing nations a range of different endemic infections, depending on geography, may be just as important; many can also accelerate HIV disease progression.  Conversely, HIV infection can promote progression of some  endemic infections.

    Several different mechanisms have been uncovered that can explain the effects of co-infections on promoting HIV replication.    With such a wide range of infections, the precise ways in which each do this will vary in detail.

    However there is one characteristic possessed by all HIV potentiating infections.  This is their ability to add to the immune activation that is a feature of progressive HIV disease.

    By now I think it is generally accepted that chronic immune activation not only results from HIV infection but is a major contributor to the pathogenesis of HIV disease.   A state of sustained high level immune activation is the basis of the chronic inflammation and immunologic deterioration characteristic of progressive   HIV disease.

    But what exactly is immune activation?

    Immune activation refers to those changes that take place in the immune system when exposed to an infectious agent that allow it to eliminate or control the infection.  Essentially, the immune system is activated from a resting state to fight an infection.   Generally this process will last for days until the infection is overcome, and usually but not always, is followed by a lifelong immunity to the infectious agent.

    However in progressive HIV disease the immune system continues to be activated at a high level and it is this sustained immune activation that eventually results in disease.   An activated state of the immune system is characterized by differentiation of precursor immune system cells.  Differentiation is the process by which these cells develop specialized functions.   Examples of cells that have acquired specialized functions are those that produce specific antibodies, or those with the ability to kill other cells infected with specific microorganisms.   Proliferation of immune system cells is an important characteristic of an activated state.  This is usually a short-term response subsiding with control of the infection that stimulated it.  But in progressive HIV disease, proliferation is sustained, probably with episodic cycles of further accelerations, and this continued proliferation contributes to the loss of immune system cells.

    These cellular changes, differentiation and proliferation, are associated with the secretion of a variety of cytokines.  Cytokines are molecules that can change the behaviour of cells by binding to specific receptors on their surfaces, for example, causing them to divide.  Once released, cytokines not only attach to receptors on other cells but can also come back and attach to the receptors on the cell that produced it.

    The cytokines that are released   have widespread effects.  Importantly, they include those that are associated with inflammatory changes, – the pro-inflammatory cytokines.    With respect to positive feedback, pro-inflammatory cytokines including IL-6 and TNF alpha are able to accelerate HIV replication.

    A part of the immune system, the innate immune system, responds immediately to infection by recognizing molecular patterns common to different organisms.  The more familiar adaptive immune system responds to specific characteristics unique to each organism.

    The innate immune system is also activated in untreated HIV infection.   Interestingly effects of activation of innate immunity were recognized very early in the epidemic, even before HIV was discovered, and so are among the earliest recognized AIDS related immunological abnormalities.  Activated innate immunity is responsible for the large amounts of alpha interferon in the circulation of people with untreated HIV/AIDS, first noted in 1981, the year this disease first came to our attention[i].   At that time the origin of this endogenous interferon was not known.   For a period, elevated levels of beta 2- microglobulin were regarded as an adverse prognostic marker.  This molecule can be regarded as a surrogate marker for interferon.   The association of interferon with abnormalities characteristic of this disease – including low CD4 numbers was also reported in the first 2-3 years of the epidemic[ii].   Over twenty years later mechanisms have been discovered that can explain the participation of interferon in the disease process[iii].

    Interferon appearing in the circulation in untreated HIV disease may even be the first marker of immune activation noted, although not recognized as such when first observed

    The changes that occur on activation of the immune system are associated with many other markers that can be measured.    Different molecules appear on the surface of activated cells.  These can be detected and measured, as can the cytokines associated with immune activation.

    These measurements can tell us the extent of immune activation.   Importantly, the degree of immune activation parallels the rate of HIV disease progression.

    Although it is now accepted that the consequences of continued activation and proliferation of immune system cells contribute to the loss of CD4 cells and the development of disease, the precise way it does so is not yet known, although there  are a number of different mechanisms  that could account for it.  The   associated inflammation also has adverse effects beyond the immune system.   For more detailed information on these mechanisms there are references to two reviews at the end of this article[iv].

    Sustained immune activation is therefore at the heart of HIV/AIDS pathogenesis.   It is the sustained nature of the activated state that is critical.  Short lived states of immune activation are of course beneficial allowing us to recover from infections.  But in progressive HIV disease the process continues at variable rates.   Understanding what causes continued immune activation is central to an understanding of the pathogenesis of HIV disease.

    What causes Immune activation?

    While infection with HIV may start the process, other causes of immune activation are almost certainly also necessary to keep it going.

    The following all contribute:

    1:            The immune response to HIV itself.   This includes both innate and adaptive immune responses.  As noted above, adaptive responses are the familiar specific antibody and cell mediated responses that provide generally lifelong immunity to specific infectious agents.  Innate responses depend on recognition of molecular patterns common to several organisms.

    Some suggest that HIV contributes directly to immune activation through binding of some of its proteins to immune system cells.

    2:            Microbial products that can penetrate into the intestinal wall as a result of damage caused by HIV.  These microbial products then activate immune system cells.

    3:            Other infections.

    Some like active herpesvirus infections or the more traditional opportunistic infections can be seen as indirect effects of HIV infection.

    Others are infections that can cause disease in people with intact immune systems like the endemic infections in developing nations. Some of these can be more severe in the setting of HIV infection.

    Infections that can accelerate HIV replication include those caused by bacteria, viruses, protozoa and helminths.

    Those that promote HIV disease progression can  usefully be  described in three categories.

    A:            Herpes virus infections.   These are probably the most important worldwide.  Virtually 100% of adults are infected with some of them.     They represent infections that are more often latent, but are  readily activated  in HIV infected individuals.

    B:            Endemic infections caused by a variety of different microorganisms than promote HIV disease progression and HIV replication.   These are important in developing nations.

    C:            Other infections.  These include the opportunistic infections, as well as those that can affect people with intact immune systems.  TB may be the most important.  HIV infected individuals are much more susceptible to active TB infections than those who are HIV uninfected.  HIV transcriptional activity and viral loads have been noted to be higher in people with active TB.

    Here is a little more detail about these three classes of infection:

    A:  Herpesviruses.

    There are eight members of the herpesvirus family that can infect humans.   Herpes simplex virus types 1 and 2 (HSV-1, HSV-2) are perhaps the most familiar.  Cytomegalovirus (CMV) and the Epstein-Barr virus (EBV) infect close to 100% of adults.   Varicella-Zoster virus (VZV) causes chicken pox on initial infection and shingles when reactivated. Of the three remaining human herpes viruses HHV-6, HHV-7, and HHV-8, the last is associated with Kaposi’s sarcoma.

    With all of the herpes viruses, once infected, individuals carry them for the rest of their lives, usually in a dormant or inactive state.  All can be periodically reactivated with or without symptoms.

    Humans and herpes viruses have co-existed for evolutionary periods and are well adapted to each other.   The immune system generally maintains these viruses in a latent sate so that they cause no harm.  Reactivation does occur periodically but is generally limited.  Virtually 100% of adults will carry some viruses of the herpesvirus family, usually in a dormant or latent state.

    The impaired immunity characteristic of HIV disease however results in reactivation of herpes virus infections. In progressive HIV disease these viruses become active and through a variety of mechanisms, including their contribution to immune activation, promote the replication of HIV.    Cytomegalovirus (CMV) may be the most important of the herpesviruses that promote HIV disease progression.  It can be part of a positive feedback system in its interactions with HIV.

    HIV → latent herpes infections  →active herpes infections → HIV

    It is not only through their contributions to immune activation that herpes viruses promote HIV replication.   In addition to the pro-inflammatory cytokines that have this effect, herpes virus gene products can directly activate HIV if a cell is infected with both viruses.  This process, called transactivation works both ways; HIV can also activate herpes viruses.

    In addition herpes infections cause a receptor (Fc) to appear on cell surfaces that allows HIV to enter it.  In this way cells that do not possess CD4 molecules can become infected with HIV.   Active CMV infections can also exert a mildly immunosuppressive effect.

    Herpesviruses, particularly CMV are singled out because they probably play a significant role in the pathogenesis of HIV disease.  CMV infections are so common that it is hard to find HIV infected individuals who are free from it so that they can be compared to those who are not.   But as early as 1991 this was done with HIV infected haemophiliac patients, when it was noted that those also infected with CMV had a much more rapid progression of their HIV disease[v].

    That CMV may play a role was suggested by many very early in the epidemic.  A multifactorial model for the development of this disease published in 1983 before HIV was discovered suggested a major role for CMV and EBV[vi].    The considerable evidence for a role for herpesviruses, particularly for CMV, did not disappear with the discovery of HIV.   The interactions of CMV and other herpes viruses with HIV that have been discovered may now explain their role.

    Large studies on the effects of acyclovir on the course of HIV infection have provided compelling evidence that active infection with these viruses can be regarded as part of the disease process for most HIV infected individuals.    Investigators focussed on HSV-2 undoubtedly because it is the most common cause of genital ulcers.   The dose of acyclovir used would also have suppressed  HSV-1, which is even more prevalent than HSV-2 and may be more sensitive to acyclovir.  HIV viral loads and the rate of HIV disease progression were reduced in individuals receiving acyclovir compared to those receiving placebo.  Although genital ulcer recurrences were suppressed by acyclovir, the drug had no effect on the transmission of HIV.

    The effects of acyclovir on HIV probably resulted from suppression of active herpes infection.  This is entirely consistent with a model that places HIV and herpesviruses in a positive feedback relationship.

    EBV and CMV are much more resistant to acyclovir than HSV-1 and 2.   But it cannot be excluded that this drug did not have some effect in also diminishing reactivations of CMV and EBV.   If samples from the trial have been stored appropriately, this can be looked at.  EBV reactivation patterns are easily recognized, CMV virus isolation is possible and even detection and quantification of activated T lymphocytes would tell us something.

    B:  Endemic infections:

    These are singled out because of their high prevalence in some parts of the developing world.

    These infections affect significant proportions of the population, they tend to be chronic and persist in the absence of treatment.    The specific infections will depend on geography and many are transmitted by insects.   Many of these can also accelerate   HIV disease progression, and some also progress more rapidly in the setting of HIV infection[vii].

    C:   Other infections:

    On an individual level, some episodic infections can promote HIV replication.   An acute febrile illness may increase HIV viral loads, but this is a transient effect lasting for the duration of the infection.

    Most of the serious opportunistic infections occur late in the course of HIV disease, and may promote even further disease progression.

    TB deserves special consideration because of its high prevalence in HIV infection.  Susceptibility to TB is increased even at higher CD4 levels. Active TB can then promote further HIV replication thus becoming a partner with HIV in a positive feedback interaction[viii].

    A role for immune activation in a positive feedback system:

    One way to look at the process of disease acquisition in HIV infection assigns a central role to immune activation.

    Immune activation not only results from HIV infection, it can also promote further replication of HIV.

    HIV replicates more efficiently in activated immune system cells.  Secondly, the pro-inflammatory cytokines that are associated with an activated immune system   can directly stimulate HIV replication.   Progressive HIV disease and immune activation are therefore components of a positive feedback system in this way.

    HIV disease → Immune activation → HIV disease → Immune activation

    The process starts with HIV infection, and is promoted by other infections , some of which are activated by HIV infection.

    Whatever is driving immune activation is driving HIV disease.

    The following diagram illustrates this.

    Looking at the course of HIV infection in this way has a number of implications.


    In the above diagram the course of HIV disease is represented by a self perpetuating cycle proceeding in a clockwise direction.

    In addition to the elements that have positive effects in driving the process, there will also be those that retard the cycle.  Two influences that will slow the cycle are the residual immunological control of HIV  infection, and those mechanisms that dampen immune activation.  Amongst the latter are the effects of a  subset of Tregs,  T cells with regulatory function, and the secretion of anti-inflammatory cytokines.    Since sustained immune activation is harmful, there are mechanisms that can dampen it.     This is illustrated in the next diagram (edited from an earlier version ) which focuses for simplicity on those infections that add to immune activation and on processes that dampen it.    Of course there are other mitigating factors, for example, genetic factors conferring varying degrees of resistance resulting from receptor polymorphism.

    In the diagram, the connection of HIV with CMV and other herpes viruses is probably constant and indicated by a red arrow.   The connection of HIV with endemic and associated infections is indicated by a blue dotted line, because HIV infection does not increase susceptibility to all of them, nor does it accelerate the progression of all.

    [October 5,2010:  This illustration is one  redrawn  for a later post.  The added text is HERE.

    The positive feedback cycle starts with HIV infection.  At least some of the determinants of the rate of disease progression may be found in the conditions that exist at the time of initial infection that promote or retard the cycle.

    There is evidence that the degree of immune activation at the time of seroconversion predicts future disease progression.[ix] [x] It may also be an important determinant of what is called the set point.  This is the point following initial infection with HIV, from which CD4 numbers decline.

    The degree of immune activation at seroconversion thus influences the starting CD4 level; the rate of subsequent decline is influenced by the degree of immune activation  in a system where once started, conditions can exist where  immune activation increases with falling CD4 numbers, in a self perpetuating and accelerating fashion.   Whatever the outcome, it will be the balance of positive and negative influences.

    In the earliest years there were reports of EBV reactivation preceding HIV seroconversion[xi].

    I have not seen any follow up of this interesting report.   It at least suggests that there might even be   situations in which active herpes infections could sometimes promote seroconversion.  They certainly produce signals that can activate HIV transcription from proviral DNA.

    Treatment and prevention.

    The role of immune activation in driving HIV disease is generally accepted now.   There are sources of immune activation other than HIV and some of these can be controlled.

    Attempts to identify and control additional sources of immune activation may be critical in the fight against HIV/AIDS.

    Perhaps the most significant benefit in this respect concerns the developing world, where there are so many additional sources of immune activation. Even ascariasis, infestation with the common intestinal round worm is associated with significant immune activation.   Worldwide prevalence is estimated to be about one billion, with 173 million in sub-Saharan Africa.

    Many highly prevalent endemic infections can promote HIV replication.  Controlling these are perfectly appropriate targets in the fight against HIV/AIDS, and of course this would independently improve the lives of millions of individuals.

    Measures to control endemic infections include traditional public health interventions, such as the provision of sanitation and clean water and the control of insect vectors. Effective drugs are sometimes inexpensive.  Peter Hotez has written an article entitled “Africa’s 32 cent solution to AIDS”.[xii] This refers to the price of Praziquantel , effective in treating  schistosomiasis as a single dose.

    The lives of impoverished populations are ravaged and shortened by these infections. Many of these infections also interact with HIV to compound the devastation they cause.  Poverty, multiple endemic infections and HIV are intimately intertwined and in many instances reciprocally affect each other.

    Recent and ongoing studies will probably lead to the routine use of drugs that are effective against herpes virus infections.       Trials of valacyclovir to reduce HIV viral loads are in progress. Given the ubiquitous nature of herpes infections, the use of acyclovir as adjunctive therapy might be warranted even in the absence of recurrent herpetic ulcers.  Valacyclovir unfortunately is not yet available as a generic medication.

    Unfortunately EBV and CMV are much more resistant to these drugs.   The development of agents less toxic than valgancyclovir is important.   Valgancyclovir has already been shown to reduce immune activation in HIV infected individuals as measured by a reduction in activated CD8 lymphocytes.

    In summary it is useful to explicitly recognize the positive feedback interactions between HIV and other infections that can promote its replication, some of which are in turn promoted by HIV.    Control of the AIDS epidemic in Africa must include measures to prevent and treat multiple endemic infections that affect hundreds of millions of individuals.

    [i] This is of particular interest to me as I was involved in the discovery of large amounts of interferon in the circulation of people with HIV/AIDS in 1981, the year the disease was a first described.

    [ii] Fig 1 shows CD4 counts in relation to serum interferon  . Presented 1986 at the 2nd international aids conference in Paris.


    [iv] Immune activation and inflammation in HIV-1 infection:  causes and consequences.

    V.Appay and D. Sauce

    J.Pathol. 2008; 214: 231-241

    (This is an important  review)

    HIV immunopathogenesis and strategies for intervention.

    M. Cadogan and A Dalgleish

    Lancet Infectious diseases. 2008: 8: 675-84



    [vii] Endemic infections in Africa have everything to do with HIV/AIDS: