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  • 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, Richardberkowitz.com

    .

    .

    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

    (1)

    Abstract

    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.

    (2)

    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.

    .

    (3)

    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.

    http://aidsperspective.net/blog/?p=118

  • 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.

    Pathogenesis.

    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.

    http://aidsperspective.net/articles/Interferon_Vilcek.pdf

    http://aidsperspective.net/blog/?p=118

    [ii] http://aidsperspective.net/articles/Interferon-AZT-1991.pdf Fig 1 shows CD4 counts in relation to serum interferon  . Presented 1986 at the 2nd international aids conference in Paris.

    [iii] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491901/

    [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

    [v] http://www3.interscience.wiley.com/journal/119316871/abstract?CRETRY=1&SRETRY=0

    [vi] http://aidsperspective.net/articles/NYAS.pdf

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

    http://aidsperspective.net/blog/?p=403

    [viii]

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1905977/

    http://www.ncbi.nlm.nih.gov/pubmed/14551885?ordinalpos=1&itool=PPMCLayout.PPMCAppController.PPMCArticlePage.PPMCPubmedRA&linkpos=4

    http://www.ncbi.nlm.nih.gov/pubmed/12416451?ordinalpos=1&itool=PPMCLayout.PPMCAppController.PPMCArticlePage.PPMCPubmedRA&linkpos=5

    [ix] http://jvi.asm.org/cgi/content/full/81/16/8838?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=fig&searchid=1&FIRSTINDEX=1440&resourcetype=HWFIG

    [x]

    http://bloodjournal.hematologylibrary.org/cgi/content/full/104/4/942

    [xi]

    http://www3.interscience.wiley.com/journal/119342256/abstract?CRETRY=1&SRETRY=0

    [xii] http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0000430

  • HIV disease and alpha interferon

    Posted on March 21st, 2009 admin No comments

    I had intended to continue writing about individualization of treatment for HIV infection with an emphasis on the variability of the natural history of HIV disease. Instead, I will make an historical digression. I’ll do this from time to time. An account of the diverse AIDS related issues with which I have been involved since 1981 (and even before the epidemic was first recognized) is on my web site aidsperspective.net. I’m slowly adding content. This should speed up; a lucky circumstance has provided me with access to professional web advice. I have until now had to rely on “how to” articles to get the site going. Surprised that at 76 I have got this far. At the outset I had said that one purpose of this blog was to bring attention to the web site, and that is one reason for this short introduction.

    This post is concerned with the connection between alpha interferon and AIDS. I should say connections; there are many.

    Today, most people will probably only be aware of interferon in connection with the treatment of hepatitis C in HIV infected and uninfected individuals. The benefit conferred by interferon treatment to many people with Hepatitis C, even those co infected with HIV is tremendous. The FDA first approved interferon alpha for the treatment of hepatitis C in 1991.

    There are many connections between interferon and AIDS; the first of these became evident in 1981, the year the epidemic was recognized.

    People with AIDS produce large amounts of interferon themselves. The sustained production of large amounts of interferon by untreated HIV infected people with more advanced disease is not only a part of the disease, but the most compelling evidence suggests that its various actions contribute to producing some of the abnormalities associated with it. But, paradoxically, in the early years of the epidemic more was injected into patients in attempts to treat the underlying disease. (There is an important difference between this and treating Kaposi’s sarcoma or Hepatitis C in coinfected people with interferon).

    That interferon can be seen as both contributing to the disease and also as a means of treating it makes for a confusing but interesting story [1]

    It will be helpful to start with a very brief description of the interferon system.

    The interferons – there are several types, are a family of proteins produced by vertebrates. They are cytokines, the name given to polypeptide or protein molecules produced by cells which act as signals that can influence their behavior, and that of other cells distant from the producing cell. In acting at sites distant from where they are produced, cytokines are akin to hormones.

    All the interferons share some common properties, and it is easier to write about interferon in the singular. Interferon is best known for its broad antiviral effect. It is produced by cells in response to viral infections, and circulates to render other cells resistant to infection, thereby playing a central role in recovery.

    Most viruses are sensitive to interferon and it was once hoped that interferon might prove to be a broad spectrum antiviral agent, similar to broad spectrum antibiotics that act against bacteria. There was great difficulty in purifying interferon for human use but in 1980 recombinant DNA technology permitted the manufacture of large amounts of pure interferon by inserting the gene for interferon into bacteria or yeast. Apart from its antiviral effect, interferon has numerous other effects, particularly on the function of the immune system. It can inhibit the growth of certain cancers, and has an inhibitory effect on new blood vessel formation. It therefore has been effective in the treatment of AIDS related Kaposi’s sarcoma. Unfortunately its clinical utility is more limited than originally hoped. Its greatest success is in the treatment of hepatitis C. Here are some brief reviews:

    http://pathmicro.med.sc.edu/mhunt/interferon.htm

    http://www.isicr.org/pdf/IFNprimer_ISICRApril_2006.pdf

    To return to interferon and its connections with HIV:

    This paradoxical situation – in which interferon is seen at the same time to be harmful and helpful, has given rise to some peculiar interpretations. Research directions have been influenced; on balance the desire to treat HIV disease itself with interferon (as opposed to treating Kaposi’s sarcoma and Hepatitis C in coinfected individuals) has probably inhibited research into its role in pathogenesis. It is notable that the overproduction of alpha interferon, a striking abnormality in people with AIDS, known since 1981, was barely studied, let alone discussed, in the first years of the epidemic.

    This strange story of a substance seen by some to be harmful, and by others to be beneficial in the same circumstances, is best told in the light of my own experiences in both fields; in AIDS and in interferon.

    The two areas that have occupied my professional life have been the laboratory study of the mechanism of interferon’s antiviral action, and clinical work in HIV disease, providing direct medical care to a very large number of HIV infected people as well as conducting clinical and laboratory research on this disease.

    In the strangest of circumstances these two fields came together as early as 1981. In that year, AIDS was first recognized, although I and others had already noted early manifestations of what was to be called AIDS among our patients.

    The first information I received concerning the occurrence of Kaposi’s sarcoma in several gay men in New York City came from Dr Joyce Wallace. She had received a biopsy report of a diagnosis of Kaposi’s sarcoma in one of our patients. Joyce had called the National Cancer Institute to ask if there was a physician in New York who was familiar with what was then a very rare condition. She had been told that there were – I think at that time, about 20 men with this condition in New York who were under the care of Dr Alvin Friedman-Kien.

    This was quite astounding. Unsurprisingly, I did not immediately connect this with what I had been seeing in my own practice, – enlarged lymph nodes, enlarged spleens, low white blood cell counts, low blood platelets among other abnormalities.

    Jan Vilcek, who was head of the virology lab at NYU is an old friend and interferon colleague, and I knew Alvin, because he also worked in Jan’s laboratory. So I immediately called to obtain more information about this remarkable news.

    Given my training and experience as a microbiologist and the nature of my practice, there was no question that I needed to contribute to the response.

    So, in 1981, I also started to work in the virology laboratory at NYU.

    I divided my time. Mornings were spent in the lab, and patients seen in the afternoons.

    My work in the lab was initially focussed on cytomegalovirus (CMV) as there was evidence that many gay men at risk for this new disease were actively infected with this ubiquitous virus and excreting it at rates higher than noted in others. There also was literature at that time suggesting that CMV was involved in the development of non AIDS related Kaposi’s sarcoma (an idea that was not to hold up).

    Once in the lab a strange circumstance brought interferon back into my life in connection with this new disease.

    I read a preprint of a paper of Jan Vilcek’s where he described the ability of an antibody to lymphocytes – specifically anti CD3, to induce the synthesis of gamma interferon. Because of other observations that were made on our first patients, I had the idea that we would find gamma interferon in the circulation of patients with AIDS. This incident has been recorded and published by Jan Vilcek and an extract of the article can be seen by clicking here.

    This is just the relevant part from a longer article, appearing in the annual “Interferon” series published by Academic Press and edited by Ion Gresser.

    It explains how we came to look for interferon in the blood of people with AIDS. Alvin Friedman-Kien provided sera from his patients, and Jan Vilcek provided just about everything else. Gene De Stefano, who is the lead author on the paper we finally published,[2] was a student working in Jan’s lab. The author’s names are in alphabetical order, as this seemed the best way to deal with the matter of precedence, as so many collaborators had become involved. I had sent sera to Robert Friedman in Bethesda, another old friend and interferon colleague, and we joined forces in pursuing this work.

    As Jan Vilcek’s account describes, my idea proved to be wrong, the interferon we found was not gamma interferon, but alpha interferon.

    Many years later gamma interferon was detected in the circulation of people with AIDS.

    This was the first of many connections between interferon and AIDS, a connection made in the first year of the epidemic.

    It immediately suggested that the sustained presence of large amounts of interferon in the circulation might be contributing to pathogenesis, and that there was an autoimmune component to AIDS. Apart from AIDS, at that time the only other situation in which there was the sustained presence of large amounts of interferon was in auto immune diseases such as lupus. Also, as individuals with various diseases, including Hepatitis C were treated with interferon, auto immune complications were noted among them.

    Since I will be critical of some aspects of AIDS research in relationship to interferon it is very important that, before I get into this, I make the following point very clearly.

    Interferon has been of inestimable value to people infected with Hepatitis C, including those coinfected with HIV. Interferon in combination with ribavirin has been able to cure many individuals of Hepatitis C infection. It has thus been life saving, as the consequences of Hepatitis C infections can include liver cirrhosis and liver cancer. It is probably the case that interferon’s greatest clinical triumph has been in the treatment of hepatitis C. At one time it was also the only available treatment for Hepatitis B.

    So, to emphasize the point, interferon for the treatment of hepatitis C in HIV infected individuals can be life saving. It may be useful in some instances of Kaposi’s sarcoma unresponsive to antiretroviral drugs.

    But I believe it has absolutely no place in the treatment of HIV disease itself. There are early reports of benefits conferred by interferon treatment [3] but there is also a great deal of persuasive evidence that long term treatment is hazardous[4]. (This article contains numerous references supporting a role in pathogenesis for interferon).

    So this is an illustration of the Jekyll and Hyde view of interferon. Does it mediate some of the pathological features of HIV disease, or should we use it to ameliorate these features?

    On balance, I believe the evidence supports the view that overproduction of alpha interferon contributes to the manifestations of HIV disease. In specific instances, particularly in Hepatitis C in coinfected individuals and in some cases of AIDS related Kaposi’s sarcoma, the benefits of interferon most definitely outweigh the risks. This is particularly true in people with higher CD4 counts.

    Nonetheless overproduction of interferon is a feature of AIDS. But It took many years for work to be done to identify the interferon producing cell. This was achieved by Frederick Siegal in 1999.

    Quite early in the epidemic, AIDS was described as a disease characterized by a dysregulation of cytokine production. Interferon is a cytokine, in fact the very first to have been described, but it rarely appeared in the list of cytokine abnormalities associated with AIDS.

    Here are some of the biological effects of interferon that resemble features characteristic of HIV disease:

    Interferon inhibits the development of white blood cells and platelet and red blood cell precursors. It causes fevers. It stimulates the production of a molecule called beta2microglobulin, which was used as an adverse prognostic marker in AIDS. It affects lipid metabolism and can cause an increase in serum triglycerides, observed in AIDS patients before the era of HAART. It modulates the activity of B cells, which make antibodies, and B cells are overactive in AIDS.

    But perhaps of greatest interest is the ability of Interferon α to selectively inhibit the proliferation of the CD4 lymphocyte subset, a finding that was published as early as 1983.[5]It also has a slight stimulatory effect on CD8 lymphocytes.

    This is the “dark and sinister” side to interferon.

    Given these effects of interferon it is hard to understand what the researchers hoped to achieve by injecting yet more of into people who were already full of it.

    Two reasons were given for administering interferon. Firstly interferon has antiviral properties. This rationale was resistant to the obvious problem that despite large amounts of interferon in the circulation, HIV continued to replicate. Indeed, as the disease progressed and viral production increased, so did the levels of interferon.

    The second reason given was that cells taken from people with AIDS could not be stimulated to produce interferon in the test tube. This was an early finding of Dr Siegal.

    The inability of cells from people with advanced HIV disease to make interferon in the test tube is actually exactly what is to be expected. It has been known for many years that when cells are exposed to large amounts of interferon for long periods, they cannot be stimulated to make interferon. They are in what is called a refractory state. The authors describing the inability of patient’s cells to make interferon seemed to not consider this, and so the strange idea that the inability to make interferon was an intrinsic abnormality in AIDS was advanced as a reason to administer interferon.

    The inability to induce interferon production in cells derived from people with AIDS is indeed strange as the circulation from which they are removed is full of it. The interferon must come from somewhere. It is possible that it comes from cells in solid tissue. The reason for suggesting this is that membrane fragments from HIV infected cells are excellent inducers of interferon. This suggests that in the body, interferon may be made by cells that are in apposition to HIV infected cells in solid tissue.

    This may be more difficult to study now. AZT promptly removes interferon from the circulation, and this is probably true for all effective antiretroviral drugs.

    The prompt removal of interferon by antiretroviral treatment must make one wonder if this is at least part of the reason for the benefits of treatment. Inhibition of HIV replication, associated with the loss of circulating interferon definitely suggests that HIV is responsible for the high levels of interferon.

    In this connection here are some results that we observed:

    aidsinf-12

    The solid line represents HIV levels, and the dotted line interferon levels. These two individuals, A and B were treated with AZT for one week at weekly intervals. Both interferon and HIV levels promptly decline when on AZT and just as quickly go up when AZT is removed.


    aids-inf-2

    These three people started AZT at time 0. Both HIV (p24) and interferon rapidly decline.


    aids-inf-3

    These are individuals on continuous AZT therapy. Interferon rapidly declines in all, but returns at varying times despite continued treatment with AZT. Is it possible that the transient and variable duration of benefit experienced, coincides with the period when interferon is absent?


    aids-inf4


    This is one person on continuous AZT treatment. Interferon starts to return and rise before 18 weeks. P24 only returns after 33 weeks. However this does not necessarily mean that interferon returns to the circulation before HIV. P24 measurements are not that sensitive and if PCR had been used HIV may have been detectable much earlier.

    This is turning out to be a long post, and I will just make a few more points and end it.

    When cells are exposed to interferon for prolonged periods several changes are noted in addition to their diminished capacity to make interferon when stimulated to do so. The antiviral action of interferon depends on the attachment of interferon to a specific cell receptor. The number of interferon receptors is reduced in cells taken from patients with AIDS, most probably as a result of exposure to endogenous interferon, and this may partly explain the diminished antiviral effect of interferon in advanced disease. This finding also has implications about possibly diminished effects of added interferon

    From the point of view of interferon’s antiviral action only, it might seem advantageous for interferon to always be present. But there are active mechanisms to turn off its production, usually after a matter of days, which supports the view that prolonged exposure to interferon can be detrimental. Its many actions – other than its antiviral action are in fact deleterious. Apart from untreated HIV disease, lupus, an autoimmune disease is also associated with the sustained production of interferon α. There are studies in this disease on the mechanisms that sustain interferon production that may also have relevance to HIV disease. In HIV disease, it may of course be the persistence of HIV, but the opportunity to do study this has probably been lost as antiretroviral treatments remove interferon from the circulation.

    When the question was asked, why add more interferon to people who already had lots of it, the answer was that the interferon already in the patient, (the endogenous interferon), was different to that to be injected. The basis for this claim of difference was that endogenous alpha interferon was unstable in acid, unlike conventional interferon.

    But endogenous alpha interferon did everything that conventional interferon did – most importantly it had the same antiviral properties. Further, there was evidence that the acid instability was not an intrinsic property of the interferon molecule[6].

    The neglect in pursuing a possible role in pathogenesis of high levels of circulating interferon was connected with a desire to use it to treat people with AIDS. This was a strange initiative. Apart from Kaposi’s sarcoma and hepatitis C it helped nobody in the long term and subjected people to extremely unpleasant side effects. Considering what interferon can do, one must wonder what effect it might have had on disease progression in the longer term.

    Here is an extract from a transcript of a meeting in New York City that Dr Fauci attended to answer questions. This is the response to a question about administering interferon to people who already had more than enough of it in their circulation:

    Fauci:

    No. I think that acid-labile alpha interferon is an abnormal form of alpha interferon that really doesn’t have the same effects as the kind of interferon we’ve been infusing. It’s almost as though it’s two different drugs. It’s very confusing, because that’s been in the literature and in the paper a lot. It really is different. It’s different. It isn’t the same. There are some similarities, obviously, because it’s the same type of species of an agent, but there are some differences. Whether or not it’s doing harm or good, we don’t know, because there’s so many other things going on ………………………

    Fouratt:…….

    You said there are differences, and then you went on. But I didn’t hear what the differences were between the two.

    Fauci:

    Yeah. In vitro effects. Joe, you look like you had a question about that.

    Sonnabend:

    I’m not aware that there are any biological differences between acid-labile interferon and conventional interferon. Acid-labile interferon is neutralized by antibodies to conventional interferon. There’s been a recent report that, as you know, in lupus, a similar interferon appears, and there’s quite some conjecture that indeed it may play a role in pathogenesis. More recently, from Jan Vilcek’s lab, there’s been a demonstration that the acid lability may be due to another protein that sticks to it. If that’s so in lupus, my guess is that there’s no reason to think it’s different in AIDS. As far as I know the biological properties of acid- labile interferon are identical to those of –

    Fauci:

    Yeah, well –

    The other argument for using treatment with interferon was that cells from AIDS patients could not make interferon. As noted, the problem with this justification is that the people from whom these cells were taken were full of interferon, which had to come from somewhere. So if the cells taken from the patients were unable to be stimulated to make interferon, other cells are actually overproducing it.

    There are still some attempts to treat HIV infection (as opposed to hepatitis C and Kaposi’s sarcoma) with interferon. It is possible that a place may eventually be found for its use, but this would almost surely be on temporary basis and in those who do not already have interferon in their circulation.

    The presentation made in 1991 from which the figures in this post were taken can be seen by clicking HERE; there are a few contemporary annotations.


    [1] “For, like the character of Dr Jekyll and Mr Hyde, interferon , while possessing great virtues, has a dark and sinister side” Susan Krown, in “Interferon 7” 1986 Academic press p 185-211

    [2] DeStefano-E, Friedman-R-M, Friedman-Kien-A-E, Goedert-J-J, Henriksen-D, Preble-O-T, Sonnabend-J-A, Vilcek-J

    Acid-labile human leukocyte interferon in homosexual men with Kaposi’s sarcoma and lymphadenopathy. The Journal of infectious diseases, {J-Infect-Dis}, Oct 1982, vol. 146, no. 4, p. 451-9, ISSN: 0022-1899.

    Abstract

    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-alpha) 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 Hu IFN had antiviral activity on bovine cells, a characteristic of HuIFN-alpha, and all of 14 representative samples tested were neutralized by antibody to HuIFN-alpha. In addition, the HuIFN-alpha in six of eight representative patients was inactivated at pH 2 and therefore appears to be similar to the HuIFN-alpha found in patients with SLE. These findings suggest that an autoimmune disorder may underly lymphadenopathy and KS in homosexual men.

    [3] Marroni M., Gresele P., Landonio A. et al. Interferon-alpha is effective in the treatment of HIV-1-related, severe, zidovudine resistant thrombocytopenia. A prospective, placebo-controlled, double-blind trial. Ann Intern Med 1994; 121(6): 423–429.

    Skillman D. R., Malone J. L., Decker C. F. et al. Phase I trial of interferon alfa-n3 in early-stage human immunodeficiency virus type 1 disease: evidence for drug safety, tolerance, and antiviral activity. J Infect Dis 1996; 173(5): 1107–1114.

    Rivero J., Fraga M., Cancio I., Cuervo J., Lopez-Saura P. Long term treatment with recombinant interferon alpha-2b prolongs survival of asymptomatic HIV-infected individuals. Biotherapy 1997; 10(2): 107–113.

    Mauss S., Klinker H., Ulmer A., et al. Response to treatment of chronic hepatitis C with interferon alpha in patients with HIV-1 is associated with higher CD4+ cell count. Infection 1998; 26(1):16–19.

    [4] Yabrov,A. It is hazardous to treat HIV patients with interferon-a

    Medical Hypotheses (2000) 54(1), 131–136

    [5] Selective effects of alpha interferon on human T-lymphocyte subsets during mixed lymphocyte cultures.

    Scandinavian journal of immunology, {Scand-J-Immunol}, Jun 1983, vol. 17, no. 6, p. 559-67, ISSN: 0300-9475.

    Hokland-M, Hokland-P, Heron-I, Schlossman-S-F.

    Abstract

    Mixed lymphocyte reaction (MLR) cultures of human lymphocyte subsets with or without the addition of physiological doses of human alpha interferon (IFN-alpha) were compared with respect to surface marker phenotypes and proliferative capacities of the responder cells. A selective depression on the T4 (inducer) T-cell subset could be demonstrated as a sequence of events: decreased fluorescence intensity of the T4 inducer cells (day 2 of culture), decreased percentages of T4 cells as demonstrated by cell cytofluorometry (days 3-6 of culture) , and decreased 3H-thymidine incorporation of purified T4 cells and decreased numbers of T4 cells harvested from IFN MLRs (days 5-6 of culture). In contrast, it was shown that the T8 (cytotoxic/suppressor) subset in MLRs was either not affected or slightly stimulated by the addition of IFN. The depression of the T4 cells by IFN was accompanied by a decrease in the number of activated T cells expressing Ia antigens. On the other hand, IFN MLRs contained greater numbers of cells expressing the T10 differentiation antigen. In experiments with purified T-cell subsets the IFN effect was exerted directly on the T4 cells and not mediated by either T8 suppressor cells or monocytes. These findings are discussed in relation to other immunoregulatory effects of IFN-alpha.

    [6] Endogenous “acid labile” interferon is neutralized by monoclonal antibodies against conventional “acid stable” interferon. The amount of interferon in a preparation was measured by observing how much the interferon containing sample could be diluted before it lost antiviral activity. Samples from patients contained antiviral molecules other than alpha interferon, and those that synergized with alpha interferon to increase its effects. Gamma interferon and TNF would be examples. These are destroyed by acid – not the interferon.