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  • 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.

    1:

    http://www.poz.com/articles/hiv_macs_anniversary_401_16589.shtml

    “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 ….”
    2:

    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.

    3:

    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,

    Zhu-TuofuCorey-LawrenceHwangbo-YonLee-Jean-MLearn-Gerald-HMullins-James-IMcElrath-M-Juliana.

  • HIV Infection in HIV Antibody Negative Individuals

    Posted on April 1st, 2009 admin 2 comments
    • HIV infection in HIV antibody negative individuals

    There is another post on this topic: HIV infection in individuals who are HIV antibody negative:

    The possibility that there are individuals who are infected with HIV but who are negative on the test for HIV antibodies has always been theoretically possible. Considerable evidence has accumulated for many years that there are indeed such individuals. Despite the importance of this phenomenon, it receives relatively little comment.

    It sometimes seemed to me ever since I first tried to discuss this possibility in the mid 1980s that there was a wilful discouragement of any discussion of this topic.

    In 1989 David Imagawa reported that that 31 of 133 HIV antibody negative men showed the presence of HIV.

    In 27 of them this persisted for 36 months despite remaining seronegative  [1]. This resulted in a vigorous response culminating in what almost looked like a retraction by the authors. At that time many unsuccessful attempts to replicate these results were reported, and the findings of David Imagawa were generally presented as due to technical errors, such as incorrect specimen labelling. In view of many subsequent findings, the likelihood is that David Imagawa and his colleagues were correct. The furious response to Imagawa’s paper is an indication of how non rational considerations can influence the progress of science. This is of course nothing new.

    Curiously in a recent book, Imagawa’s findings are included in a list of what are stated to be errors and controversies in the HIV/AIDS epidemic that impeded scientific progress [2]

    What in fact impeded progress was a rigid adherence to what was only a hypothetical, not an empirical model of the course of HIV infection.

    David Imagawa died shortly after this controversy, and sadly did not live to see that his initial conclusions were absolutely consistent with what has been learned of the complexity and diversity of individual responses to HIV infection.

    I certainly experienced considerable resistance and disbelief when I raised the possibility of silent HIV infections. In the late 1980s I took part in a NPR program, and was quite abruptly dismissed by another scientist (I have forgotten who) when I raised the absolutely reasonable theoretical possibility of persistent latent infections in antibody negative individuals.

    Apart from very few exceptions there was an almost complete lack of interest in HIV seronegative, but infected individuals, by science writers; there was no shortage of community commentators who also seemed to be oblivious or uncaring of this phenomenon.

    To be sure there were occasional reports of seronegative but infected individuals. Gus Cairns, a UK journalist wrote about this in the UK magazine, Positive nation. I wrote something about this as a result of an interview with him in 2000, which he published. I have scanned the article. I was unable to make a perfect copy, but a legible version can be seen by clicking HERE.

    In the US reports confirming the existence of seronegative infected people continued to receive very little comment; what little there was was generally quite hostile..

    Today this issue was again brought to my attention by an article I saw reporting the presence of HIV proteins and HIV RNA in cervical biopsies from women who were persistently HIV seronegative , at least for the duration of the study which was one year [3]. They did not have antibodies to HIV despite being infected; of course it is possible that they are in an unusually long “window period” and will eventually seroconvert.  If we use “window period” in this sense then we  can speak of a distribution of window periods of different lengths, including an indefinite one.

    I expect that, as is usual this report will provoke little or absolutely no interest.

    But it is enormously interesting; (just one of many questions: can these women infect their male partners?)

    Seeing this article is the reason why I decided to make this issue the subject of this post.

    It was no great surprise when evidence appeared that there were some individuals who were HIV infected but remained negative on the HIV antibody test. It must be said that there were probably more papers in the early years in which silent HIV infections in HIV antibody negative individuals was not observed.

    In another approach, reports started to appear that HIV antibody negative individuals had T lymphocyte responses to HIV which means that they were exposed to the virus, not necessarily that they were infected – although that is quite a real possibility. Some early papers, before 2000, including those showing T cell responses can be seen by clicking HERE . There was quite an extensive literature at that time, but most, as mentioned reported that there was no such thing as a silent antibody negative infection, apart from the short window period following infection.

    Why has the possibility of prolonged latency always been theoretically possible?

    As part of its life cycle HIV is turned into DNA and is then incorporated into the host genome. In infected cells it effectively becomes part of our genetic material. Once inserted into human DNA, it must be activated to start the process of making new virus particles. Cellular signals that start the process of activating HIV DNA include cytokines, which are messenger molecules produced and released by cells, which can then act on other cells to evoke a variety of responses. Amongst these HIV activating cytokines are those that are called proinflammatory cytokines.  These appear during the course of many different infections.  Once HIV DNA is activated, and at least some of its proteins made, these then mediate further activation.

    There are some other factors that can activate HIV DNA.

    Alloantigens are antigens expressed on foreign cells. When these antigens are in contact with a cell containing integrated HIV DNA, activation occurs; HIV DNA is transcribed and new viral particles made. In earlier days HIV was isolated from infected lymphocytes in this way. Latently infected lymphocytes were induced to produce HIV by culturing them together with lymphocytes from an uninfected donor.

    It is the nature of HIV infection that it is frequently acquired in situations which involve exposure to foreign cells (to alloantigens). This may be exposure to semen in sexual transmission, or blood cells in the case of infection by shared needles, or by blood transfusion.

    Herpes viruses have the ability to activate HIV if a cell is infected with both viruses. I suppose this must happen but I imagine doubly infected cells may not be found  too frequently. Of course active herpetic infections in non HIV infected cells may be associated with the production of pro inflammatory cytokines, which circulate and can activate HIV DNA in a cell at a distance.

    There is absolutely no reason not to expect that in some circumstances incorporation of HIV DNA into human DNA will result in a state of stable integration. This means that HIV DNA remains in the genome, it is not activated, and no virus is produced. Since antibodies are made as a response to viral proteins, and as none are made, the HIV antibody test will be negative.

    So it was no surprise when such individuals were again reported in 1999 [4]. These individuals remained in good health and were reported to be antibody negative as long as they were observed [5].

    We cannot know if these individuals may seroconvert (or maybe already have), but what is established is that stable integration of HIV DNA without seroconversion can occur. In such individuals limited expression of HIV can occur, at least sufficient to induce, if not antibodies, a cellular immune response.

    The presence of such cellular immune responses in HIV antibody negative individuals is further evidence consistent with HIV DNA persistence, but in itself does not indicate this.

    Demonstration of cell mediated immunity to HIV:

    Apart from the identification of antibodies, specific immunity to HIV can also be detected by a much more elaborate test that measures cellular immunity rather than immunity determined by detecting specific anti HIV antibodies. In this case what is measured is the ability of lymphocytes to recognize HIV. They will do so only if they have been exposed to the virus, which would obviously be the case if they were taken from an infected individual.

    The detection of such lymphocyte responses in the mid 1990s was one of the first indications that there may be infected people who don’t make antibodies. Other interpretations are that the infection was overcome, or that that the individual was infected with defective virus.

    Gene Shearer was I believe the first to report this phenomenon. HIV antibody negative sexual partners of HIV positive people, as well as individuals who had occupational contact with HIV were among those showing these responses.

    It is unknown how widespread this phenomenon of silent HIV infection is. It may be exceedingly rare. It is also unknown if this condition of stable integration is really just a prolonged “window” period that always follows all HIV infections.

    But it is entirely possible that there are individuals in whom the ability to control HIV is such that they will remain healthy and HIV negative.

    A number of different  outcomes of HIV infection are possible:

    Some of the factors that influence this:


    Host genetic factors.

    Size of the inoculum – the amount of infecting virus.

    Route of infection

    The particular virus strain.

    The presence of associated systemic infections.

    these provide signals activating HIV proviral DNA. In the case of some tropical infections there may be cytokines (IL 10) that blunt immune responses.

    Sexually transmitted infections with genital ulcers.

    Double infection of a cell with HIV and herpes viruses – probably an unusual occurrence.

    Exposure to alloantigens; a theoretical possibility.

    These are some of the known influences.

    Maybe the most common outcome is a productive infection where viral DNA is activated within a few weeks.

    But this scenario is also possible:

    Infection is followed by insertion of HIV DNA into cellular nuclear DNA. Possibly with small inoculums, and in the absence of strong or sustained activation signals, the proviral DNA remains silent. This has been observed.

    Or this one:

    There is a limited burst of viral production, not sufficient to elicit an antibody response but enough to induce a cell mediated response with the generation of lymphocytes that recognize HIV antigens and can kill HIV infected cells. HIV seronegative individuals with such specific lymphocyte responses have certainly been observed. In this case if there is an incipient burst of HIV production, the producing cells are promptly killed. Each time this happens the cellular immune response is primed and strengthened. Such a mechanism has been well studied in EBV infections. This common virus is totally unlike HIV, but it does similar things. It remains present in B lymphocytes rather than T lymphocytes for life. The mechanism of persistence is quite different – EBV is not a retrovirus. But the majority of individuals carry this virus – which in rare situations can have lethal effects, in their B lymphocytes for life. We have evolved many mechanisms to keep this virus in check. The ability of some types of lymphocytes to kill EBV infected cells which start to make virus is well understood. Similar mechanisms must exist for HIV – but obviously for most, are insufficiently effective. But in those with very limited HIV production these killer lymphocytes may actually be what allows such rare fortunate individuals to remain HIV seronegative.

    With this outcome, one can view the infection as actually having an immunizing effect.

    If there were not yet enough reason to study the phenomenon of persistently seronegative HIV infection, this is an important one. What are the circumstances that produce this outcome?

    So, for many reasons individuals who are seronegative but have lymphocyte responses to HIV are of great interest.

    Yet another scenario is one of stable integration, but where some HIV proteins, but not complete virus, are produced. Maybe the women referred to whose cervical biopsies contained HIV antigens might be in this category. This is a strange situation as antigens were detected but these women apparently did not develop antibodies.

    Another very early observation that can be explained by the prior presence of integrated HIV  DNA that is only activated by a subsequent non HIV  infection is the finding that  episodes  of EBV reactivation may precede HIV seroconversion. [6].  This raises the possibility that at least some illnesses associated with primary HIV infection are nothing of the sort. They instead may represent rather non specific viral infections that activate already present integrated HIV DNA, and thus  followed by HIV seroconversion. This is a completely plausible scenario. Of course self reported sexual histories may sometimes  not be too reliable, but nontheless, I well recall an older gay male patient of mine who told me that he had had no sexual contact for years, he had several negative HIV tests over a period of a few years, and then tested positive.  I wondered  then if he may possibly have been infected years before, that he carried latent HIV DNA and this was subsequently activated by some febrile illness. I know this is only an anecdote, and that individuals can be guarded about their sexual histories.  I wonder if others have had similar experiences?

    I think around 1996  a description of the course of infection was produced. Everyone interested in this disease will have seen this picture: Here it is again:

    hivaids_9_fig-53

    This may represent a typical course of infection.  But HIV disease is probably so variable in the course it can take that there may well not be such a thing as a typical infection.

    This depiction does however give the impression that there is,  and discourages an appreciation of the probably  immense variations in the course of  HIV disease.  The notion of a “standard” course of HIV disease has  had implications for treatment.  Recommendations are made that take no account of  individual  rates of disease progression;  a one size fits all approach has been adopted.

    The  rapid acceptance that there is a typical – or an  average  course of HIV infection is particularly odd as not only is the disease new – we have no precedents of human retroviral diseases (apart from HTLV-1 associated disease);  the techniques used to study the disease are 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 then of the variation in T subset numbers in health and disease. Other immunological and virological techniques were, and continue to be introduced as the epidemic is proceeding.

    A model was constructed before sufficient evidence was available to justify it.  It really had no empirical basis; 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 only about  12 to 15 years after the disease was first seen, why on earth did we not consider the precedents of other chronic viral diseases?   Thus we might have  included the real possibility that some exposures may result in infections that may be cleared , as well as the now demonstrated situation where silent antibody negative infections occur.    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.

    In conclusion, the study of prolonged HIV seronegativity in infected people is important. Some reasons are:

    1. There are obvious implications for vaccine development.

    2. Seroprevalence may significantly underestimate the prevalence of HIV infection.

    3. Understanding the phenomenon will advance our understanding of the pathogenesis of this disease, which in turn will open new therapeutic approaches.

    4. There are instances of infected people remaining seronegative and in good health.

    [1]

    Imagawa, D.T., M.H. Lee. S.M Wolinsky. et al..

    Human immunod­eficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods.

    New England Journal of Medicine 1989 320:1458-1462.

    [2]

    Scientific Errors and Controversies in the U.S. HIV/AIDS Epidemic: How They Slowed Advances and Were Resolved

    By Scott D. Holmberg

    Published by Greenwood Publishing Group, 2008

    [3]

    Human Immunodeficiency Virus (HIV) Antigens and RNA in HIV-Seronegative Women with Cervical Intraepithelial Neoplasia
    Jayasri Basu, Seymour L. Romney, Ruth H. Angeletti, Sten H. Vermund, Edward Nieves, Anna S. Kadish, Magdy S. Mikhail, and George A. Orr

    The publisher of this journal kindly sends me the contents of each issue as I started this journal around 1983 and was its first editor, seeing it through its first two volumes. It was then simply called AIDS Research.

    [4]

    Zhu T, Corey L, Akridge R, Change Y, Feng F, Kim J, Alef C, Mcelroy J, Mullins J, Mcelrath J.

    Evidence for HIV-1 latent infection in exposed seronegative individuals.

    Abstract No.8, 6th Conference on Retroviruses and Opportunistic Infections. Chicago. 1999.

    [5]

    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,

    Zhu-Tuofu, Corey-Lawrence, Hwangbo-Yon, Lee-Jean-M, Learn-Gerald-H, Mullins-James-I, McElrath-M-Juliana.

    Abstract

    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-specific cytotoxicity 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 for HIV-1 infection in ES individuals below the detection limit of standard assays, suggesting that extraordinary control of infection can occur. The two HIV- infected ES individuals remained healthy and were not superinfected with other HIV-1 strains 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.

    [6]
    Schattner, A, Hanuka N, Sarov B, Sarov I, Handzel Z, Bentwich Z.

    Sequential serological studies of homosexual men with and without HIV infection. Epstein-Barr virus activation preceding and following HIV seroconversion.

    Clin Exp Immunol 1991; 85: 209-13.