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Natural Immunity and HIV

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

It's focus is on individuals who have been repeatedly exposed to HIV but remain seronegative. Several different genetic and immunological mechanisms have already been discovered that can account for their apparent resistance to infection.   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).   

Gene Shearer, a pioneer in the study of HIV exposed seronegative individuals 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.  

By 1981 we had come to understand that infection and disease are not synonymous terms.  But it almost 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 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 (2) 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.   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 journalists.

This is the headline of a story in the New York Times in 1991 which will give some idea 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 the relatively little experience that had then accumulated, we could only be at a stage of establishing a record.   There was no firmly established record at that time when 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. 

The constant behind the scenes pressure exerted on David Imagawa noted by the New York Times seems 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 that had no place for prolonged seronegative infection.  This account is illustrated in the very familiar diagram of the typical course of HIV infection that appeared in the 1990s.

Thumbnail image for hivaids_9_fig-5.gif

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 new 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 foundation 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  "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 surely have been seen between repeated isolates. This is because HIV, when it is in the form of DNA, remains unchanged.  Sequence variations between different virus isolations may have been reported somewhere.

But in another report of prolonged carriage of HIV DNA in seronegative individuals, sequences remained constant (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 was the fear it might have raised 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 the continued absence of antibodies in some individuals exposed to HIV.   It seems to be just taken for granted that these individuals are resistant to infection.  

We are told:

Approximately 15% of HIV exposed seronegative individuals repeatedly resist infection, a phenomenon that has been observed in all investigated HIV‐exposed cohorts. 

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.

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 an individual would  not be resistant to infection, but for probably a variety of reasons connected both with the virus, as well as the host, 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 infections.    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 response, ensuring that cells expressing HIV antigens are killed, as is the case with EBV infected B lymphocytes.

HIV infection, like other chronic viral infections can progress in different ways.  If we had been more open to this, rather than trying to discourage work that did not conform to the early preconceptions about the course of HIV disease  there may have been greater interest and funding into research that investigates the various factors that influence how the disease progresses. 

This is a slightly changed and shortened version of something I posted elsewhere and contains material written last year. HIV infection in seronegative individuals.    




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

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



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



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

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

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


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Comments on Joseph Sonnabend, MD's blog entry "Natural Immunity and HIV"

This is encouraging. I find there is little to no support for those who are in Poz/Neg relationships as to help support the emotional factors involved with the threat of cross-infection.

Thank you for posting this article. It is a step in the right direction of FULLY understanding all the aspects of this epidemic. As stated in the end of the blog, it is to bad this was not a leading thought process in the beginning of this epidemic. It might have lead to better understanding the mechanics of the virus and host interaction and possibly lead to a cure/vaccine sooner.


Hi thank you very much for this article.

I too have wondered about the seemingly loose threads in HIV research. There are several reports of unusual HIV infections and observations regarding testing, but none of these reports seem to be followed up by new research, but are not rebutted either, so it's hard to know what to think of it.

Another example of this is the studies showing delayed seroconversion after needle-stick injuries in health care workers. This setting has the benefit that one knows exactly the day of exposure and the affected individuals were intensively tested often over long periods.
At least one report found that in some cases, it took more than a year after exposure for seroconversion to happen. I've heard someone trying to explain this by the insensitive HIV antibody tests in use at the time. However, this argument doesn't stand up to scrutiny, because these workers were not only screened for HIV antibodies but also for p24 antigen and HIV RNA, for which they were negative too. The samples were even sent to the CDC for additional analysis. What seemed to happen in these cases was that after a long period of absolutely no detectable sign of HIV infection, suddenly there was a burst in viremia, often accompanied by symptoms associated with primary HIV infection. This was followed by HIV seroconversion shortly after. In other words, it was not the production of the antibodies that was the delayed - it was the onset of viremia! I believe this might be a case of the patient havingly only one or a few latently infected T-cells (or even another type of cell). These cells have have the HIV virus in their genome but for some reason, perhaps because the particular T-cells are not activated, there's no production of virus proteins and thus no viremia or antibodies. At some point something happens that activate these cells, thereby kicking off the production of virions. From this point on the infection follows the classical course that would usually have happened a few weeks after the exposure.

Finally, I find your idea of a secondary disease triggering primary HIV very interesting. I agree that it could explain the symptoms associated with primary HIV. I have often wondered why there's such a high degree of variability in the reported symptoms. It seems almost any symptom can occur. My own theory has been that at least some of the symptoms are not a result of HIV itself but rather (re)activation of other latent infections as a result of the dramatic weakening of the immune system seen during primary HIV infection, where many patients seem to reach AIDS-like CD4 counts temporarily.

This could at least explain the variability in symptoms and can also explain why not everyone gets symptoms. I suspect some of the symptoms, like fever, swollen nodes and perhaps sore throat, might be "core HIV" symptoms brought on by HIV itself, whereas many of the others (rash, mouth sores, genital ulcers etc.) might be due to activations.

Finally: to all the worried well out there, don't be afraid that you can't trust you HIV negativ tests. In all likelihood your negative test represent that you don't have HIV. If you are still worried, focus that worry on the other (probably much bigger) risks in your live. You can always get tested again if you experience symptoms or feel sick, but don't freak out. Regarding the health care worker study, keep in mind one can never be absolutely sure that the workers involved didn't get infected by some later, after their needle-stick injury. However, in at least one case a phylogenetic analysis indicated that the person did get infected from the needlestick.

Interesting and promising!

I'm not a scientist and I've only begin educating myself on this disease a couple weeks ago. The more I read, the more questions I have .. I'm sure all of us experience this. They are still calling this a "new" disease? True, it's not as old as measles and the common cold, but 28 years?

I so wish this theory would have been focused on and studied more. We very well might have found our vaccine or cure by now. Oh well, I give credit to the pioneers of this theory and applaud all the hard-working scientist' today who are doing their best help understand and to help defeat this virus once and for all.

Okay ... now a question I have that I can't seem to find an answer to or anything remotely close to an answer.

Strains of the virus. Not really HIV-1 and HIV-2 in that sense but more like how after an infection the patient will take a test to see what kind of antivrals will fail or work based on the virus type in their body.

They say 1 in 3 people do not know they are infected because they have no symptoms while 2 of 3 experience mild / moderate symptoms and lastly, most of those infected say they get the worst flu of their life. Most of the people I've heard talk about their acute infection and seroconversion have stated they experienced the worst illness ever.

Here is my question: Can it be possible that symptoms of an acute infection can be based off a certain type of strain their infected parnter pass on to them? Example: Poz partner contracted the vius and became VERY ill during seroconversion 6 weeks after infection, thus, he passes the virus onto his un-infected and again, 6 weeks after exposure the newly infected becomes gravely ill.

While someone with a different strain experienced no symptoms and any person me infects may not experience symptoms. Thus, the 1:3 ratio.

It might explain certain dates of serconversion as well as symptom severity. My hypothesis is very basic and not too scientific and I apologize, I'm not a scientist. Rather, someone who is tired of seeing people suffer over something so natural. It's even extended into the innocent children. It breaks my heart.

Thank you for your comment.
Perhaps one reason why there seem to be loose threads in HIV research is that we were presented with a description of HIV disease at the end of the 1980s, only 5 years after HIV was discovered. This description, illustrated in the very familiar graphic I reproduced could not have been based on extensive observations, yet it was eagerly accepted seemingly without question.
When observations were made that were inconsistent with the model they often were either ignored or as in the case of David Imagawa, aggressively rejected. This preference for theoretical constructs rather than empirical evidence is quite odd in a society where scientists pride themselves in their respect for evidence. Maybe not, as noted by Oliver Wendell Holmes in 1860:
"The truth is that medicine, professedly founded on observation, is as sensitive to outside influences, political, religious, philosophical, imaginative, as is the barometer to the changes of atmospheric density”

Your theory that some of the symptoms of the seroconversion illness result from activation of other infections seems perfectly reasonable, and if these add substantially to immune activation at that time, might determine a more rapid progression of HIV disease. There is a reciprocal relationship between HIV and herpes viruses, particularly CMV and EBV, which can mutually enhance each other in a positive feedback interaction. So both your idea and what I proposed could exist.
There could be some seroconversions that are triggered by another infection and I’m reminded of very early evidence of EBV reactivation preceding HIV seroconversion. Here is another example of an observation that did not fit with the model and was simply ignored.
I hope your wise words to the worried well will be heeded. Certainty is an unrealistic expectation but we can recognize relative risk, and in this regard a negative test is a great reassurance.

James, thanks for your comment.
Why do only some people experience an illness of varying severity when they seroconvert?
As you suggest one reason may be that, as with many pathogenic microorganisms, there are HIV strains with greater or lesser virulence or replicative competence. But this would only be one factor which determines if a primary illness occurs at all and if it does how severe it will be.
The size of the infecting dose of virus and how it’s introduced into the body will have an influence. Host factors will also play a role; these may be genetic and immunologic, conferring relative degrees of resistance. Concomitant infections may also have an effect on the initial response to infection.
The primary illness is associated with the appearance of HIV in the blood stream, which in turn is a reflection of the extent of HIV replication. So the primary illness will be affected by all those factors, both related to HIV and the host that can influence HIV replication.
The proportion of infected people who experience an illness at seroconversion can only be estimated very roughly. The illness can be mild and forgotten; it can also resemble other mononucleosis like viral illnesses. It’s even possible that occasionally the illness was indeed mononucleosis like illness caused by another virus which then activated HIV that had been present as proviral HIV DNA in the host genome.

I have really wondered about the claims that some people have completely asymptomatic infection. I've seen some surveys suggestion that symptoms occur in 90% and other surveys suggesting 50%. Intuitively, it is hard to understand how an infection with HIV could occur without any symptoms at all, especially given the very severe symptoms some people get! As Joseph points out, many factors could affect the initial phases of infection. One explanation could be people who have very slow initial replication of virus (due to either viral or host factors) meaning that the acute phase takes place more slowly and is thus "diluted by time" leading to fewer symptoms. It would enable the body to get the virus under the control with antibodies (and CD8+ cells) when the replication was at a lower level than if the initial replication had been fast. Before HAART some studies suggested disease progression was faster for people with severe ARS symptoms.

This again goes back to Joseph's original complaint about how people view HIV infection as having just "one couse" instead of being open to different courses even if they may be rarer than the standard course.
For other viruses, asymptomatic infection and silent carriers are not uncommon. You can get infected by hepatitis and not get any symptoms at all for instance, whereas other people might get severe jaundice.
There are clearly host factors at play - some people tend to get relatively high fevers even from mild infections like the common cold, whereas others only run fevers with more serious infections like the flu. Some get sick (with fevers etc.) from a vaccine whereas others don't (in that case the agent is the same, so this difference must definitely be caused by host factors).

Then there's also the subjective component. One person's "I feel sick" maybe another persons "I'm not feeling totally on top, I will just take a nap at lunch". Some symptoms may be subtle and not noticeable in the lighter courses - a swollen lymph node could easily be overlooked.

Then there's the problem Joseph points out about recall. Some people are not even sure when they were infected so that may cause confusion in recalling ARS (for instance if they were infected way longer back and by a different encounter than they think). Other people may have plainly forgotten they were sick or may not even have thought they had symptoms (i.e. relating to the subjective component).

So all in all there are biological reasons why people's acute courses may vary (and at least theoretically not cause any symptoms at all), and there are practical reasons why symptoms might be forgotten even when they occur. How much of each explanation contributes to the "asymptomatic" cases are not known.

To someone who is sexually active, getting symptoms that resemble ARS might be a good reason for getting an HIV test taken (at the appropriate time) and taking care not to infect other people (after all, if you have symptoms, you could have another disease that you could also infect with!) However, it wouldn't be wise, for many reasons, to conclude you are definitely HIV negative, just because you didn't have symptoms of ARS.

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This page contains a single entry by Joseph Sonnabend published on October 19, 2010 10:21 AM.

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