Posted on May 12th, 2011 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
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.
- Herbeuval JP, Shearer GM. HIV-1 immunopathogenesis: How good interferon Turns Bad.Clinical Immunology (2007); 123920:121-128
- 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
- Stoddart CA, Keir ME et al. IFN-α-induced upregulation of CCR5 leads to expanded HIV tropism in vivo, PLoS pathogens (2010); 6(2) e1000766
Some immunologic parameters in homosexual patients with Kaposi’s sarcoma (KS) or unexplained lymphadenopathy resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with SLE have an unusual acid-labile form of human leukocyte interferon (HuIFN-α) in their serum. Sera from 91 homosexual men were tested for the presence of HuIFN. Of 27 patients with KS, 17 had significant titers of HuIFN in their serum. Ten of 35 patients with lymphadenopathy and three of four patients with other clinical symptoms also had circulating HuIFN. In contrast, only two of 25 apparently healthy subjects had serum HuIFN. All 32 samples of HuIFN had antiviral activity on resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with bovine cells, a characteristic of HuIFN-α, and all of 14 representative samples tested were neutralized by antibody to HuIFN-α. In addition, the HuIFN-α in six of eight representative patients was inactivated at pH 2 and therefore appears to Some immunologic parameters in homosexual patients with Kaposi’s sarcoma (KS) or unexplained lymphadenopathy be similar to the HuIFN-α found in patients with SLE. These findings suggest that an autoimmune disorder may underly lymphadenopathy and KS in homosexual men.
Sonnabend J., Saadoun S., Griersen H., Krim M., Purtilo D. Association of serum interferon with hematologic and immunologic parameters in homosexual men with AIDS and at risk for AIDS in New York City.
2nd International Conference on AIDS Paris 1986. Abstract 100
There were several other interesting associations including a positive correlation between IgA and interferon, so needless to say, there is an inverse correlation between CD4 counts and IgA. In the early days I used easily obtainable IgA measurements as an unproven prognostic indicator.
I found a transcript of a meeting in New York where Dr Fauci answered questions posed people with AIDS and their advocates, where he explains this.
You can see this at the very end of another article I wrote about interferon and AIDS in 2009 that contains some of the same material in this blog.
Posted on August 31st, 2010 No comments
HIV Disease and Positive Feedback. An additional comment.
A previous post focussed on the positive feedback interaction between HIV replication and immune activation. HIV replication and immune activation reciprocally enhance each other.
While HIV infection is an essential cause of the immune activation that’s characteristic of HIV disease, there are other factors that also contribute to it. In that post as well as in the blog I write on the POZ magazine website, I described some of these additional factors that can add to immune activation. As noted, viruses of the herpesvirus family, cytomegalovirus (CMV) in particular are the most important of these worldwide, while in parts of Africa certain endemic infections may be of great significance in contributing to immune activation.
Since sustained immune activation, involving both innate and adaptive immunity is at the heart of the pathogenesis of HIV disease an understanding of how it is perpetuated is critical.
Evidence for activation of innate immunity was noted in 1981, the year that AIDS was first reported, in the detection of large amounts of alpha interferon in the circulation of patients. We even knew then that interferon alpha and gamma could induce an enzyme, indole 2,3-dioxygenase (IDO), (IDO was known to be responsible for the inhibition of toxoplasma gondii by depletion of tryptophan in cells treated with gamma interferon) but we did not know then that this enzyme could contribute to the loss of T lymphocytes. Another observation of historical interest is that even before AIDS was first reported in 1981, interferon was known to preferentially inhibit CD4 lymphocyte proliferation in mixed lymphocyte culture.
Since immune activation and its effects, including inflammation, are harmful if sustained, there are mechanisms that can dampen it.
But in HIV disease, immune activation persists with continued deleterious consequences.
The reason I’m revisiting this now is that there is a question that continues to be bothersome.
HIV disease is not the only infection associated with long standing immune activation.
Several endemic infections in Africa are also associated with sustained immune activation, certainly not all – some even have a dampening effect on immune responses. TB is another example of an infection associated with chronic immune activation. In none of these conditions is there such a profound loss of CD4 lymphocytes as in HIV disease. While individuals with active pulmonary TB have been reported to have lower CD4 counts than healthy individuals, the numbers were well above 500.
Is the difference between sustained immune activation associated with HIV and that associated with other chronic infections in HIV negative individuals a matter of degree – is it a quantitative difference?
Could the mechanisms that dampen and check immune activation be impaired in HIV disease? These mechanisms include the secretion of cytokines that have anti-inflammatory properties, such as IL-10, IL-13, and TGF-beta, among others. Specialized immune system cells can also dampen immune activation. Tregs, a subset of T lymphocytes, have such a dampening effect. Although there are conflicting reports on the relationship of Tregs to HIV disease, it is known that HIV targets some of these particular T lymphocytes.
This graphic comes from a previous post.
In the diagram, disease progression is represented by a circular clockwise movement propelled by a positive feedback interaction between HIV replication and immune activation. It can be accelerated by infections that contribute to immune activation, CMV in particular, but probably also some endemic infections in parts of Africa. CMV probably also has a positive feedback association with HIV in that it is more likely to be driven out of latency in the setting of HIV infection, and active CMV infections can enhance HIV replication by several mechanisms including their contribution to immune activation. Some endemic infections probably also have analogous reciprocal interactions with HIV. The influences that can slow the cycle are those mechanisms that dampen immune activation. They include the effects of Tregs, a subset of T cells with regulatory functions that dampen immune responses, and the effects of cytokines with anti-inflammatory properties.
In graphic terms, the speed of the clockwise circular movement will be the balance of forces that speed it up and those that slow it down.
HIV disease progression is represented as moving clockwise in a circle, reinforced by sources of immune activation other than HIV and retarded by Tregs and other mechanisms that dampen immune responses. Tregs act as brakes, but HIV can directly make the brakes less effective.
Could critical differences between HIV disease and other infectious causes of long standing immune activation where CD4 numbers are relatively preserved, be the preferential targeting of Tregs by HIV and a different pattern of cytokine secretion?
I wonder if this revised representation of HIV disease lends itself to a more formal modelling process.
In this particular model a disease process is represented by a circular motion in a clockwise direction, with forces that both propel and retard it. Some predictions can be made.
The degree of immune activation at the time of HIV seroconversion would favour more rapid HIV disease progression. The set point – the level from which CD4 lymphocytes decline following an acute HIV infection, would be lower, and the subsequent rate of CD4 decline higher when HIV infection occurs in a person where there already is a higher degree of immune activation, compared to an individual where this is not the case. There already is some evidence in support of this possibility.
It’s well established that HIV disease progresses more rapidly with increasing age. Could an explanation for this be that immune activation increases with age – indeed, it’s been suggested that immune activation contributes to the aging process.
HIV disease progresses more rapidly in individuals with active TB. CMV viremia was noted to carry an adverse prognostic significance in HIV disease very early in the epidemic. There are but two examples, but there are many more of of a more rapid course of HIV disease in the setting of other infections caused by bacteria, protozoa, viruses and helminthes. Some are referred to in a previous post.
Are Treg numbers at seroconversion and for a period immediately afterwards related to subsequent disease progression?
Could treatment with anti CMV agents during acute HIV infection retard subsequent disease progression?
There already is some evidence that treatment of HIV during acute infection might slow the subsequent course of HIV disease.
The utility of any model of a disease process lies in its ability to provide a common explanation for disparate observations as well as to make predictions that can be tested by an analysis of available data or by experimentation.
Viewing HIV disease as a process with a positive feedback interaction between HIV replication and immune activation with forces that both enhance and retard this interconnection, provides a useful descriptive framework as well as testable predictions.
Endemic Infections in Africa have everything to do with HIV/AIDS and are a long neglected therapeutic target.Posted on June 6th, 2009 1 comment
An article with the striking title “Africa’s 32 Cents Solution for HIV/AIDS” was just published in PLoS Neglected Tropical Diseases. It can be seen here:
This dramatic title refers to the cost of treatment of schistosomiasis with praziquantal.
Schistosomiasis is an infection caused by parasitic worms, or helminths., of the genus Schistosoma. Most of the 200 million cases of schistosomiasis in the world occur in Africa.
The species, Schistosoma haematobium is estimated to infect about 112 million people in sub Saharan Africa. So its high prevalence puts it in the same class as that of TB, malaria and HIV. It is responsible for a huge burden of morbidity particularly in children and young adults.
S. haematobium has a complicated life cycle, some of which takes place in snails. People are infected by organisms released by snails living in fresh water. These organisms can penetrate the skin of any body part that is immersed in snail infested water. S. haematobium affects the urinary tract. The disease it causes is commonly called bilharzia.
I was very conscious of its danger as a child growing up in Zimbabwe, with signs at several small lakes around Bulawayo warning one not to swim in them because of the danger of bilharzia.
Peter Hotez and colleagues article is a welcome addition to the already substantial literature that strongly suggests that many endemic infections, not only with helminths, but also with bacteria, protozoa and viruses can increase the transmission of HIV and most probably have a detrimental effect on the course of HIV infection.
This paper concentrates on the local effects of S.haematobium on the female genital tract , where lesions caused by schistosome egg deposition result in mucosal patches, that can bleed during sexual intercourse. The authors state “Presumably, the schistosome egg granulomas produce genital lesions and mucosal barrier breakdown to facilitate HIV viral entry” and go on to compare this to the process by which herpes simplex ulcers increase susceptibility to HIV.
This does seem obvious – there is a mucosal break, so HIV has a way in.
In fact in the case of herpes simplex, this seemingly obvious connection is probably not correct. The large Partners in Prevention study, recently completed, found that acyclovir, a drug effective in treating herpes does not reduce the risk of HIV transmission. The drug however was associated with a reduction in the number of recurrences of herpetic ulcerations, and significantly slowed HIV disease progression. I have written about this in another post.
As with herpes simplex, it is possible that systemic effects of schistosomiasis, may be much more significant, or at least as significant, as local effects in enhancing the transmission of HIV. Of course, both local and systemic effects may play a role in enhancing HIV transmission. The systemic effects include an impairment of virus specific immune responses; immune activation may also increase susceptibility to HIV and promote its replication.
The influence of associated infections on the infectivity of HIV extends far beyond that of schistosomiasis. Peter Hotez (the lead author of the above article) has done a great service by bringing attention to a number of devastating neglected tropical diseases. This important article can be seen in the Lancet of May 2nd, 2009, (Lancet 2009 373;1570-1575).
The title of the article is:
“Rescuing the bottom billion through control of neglected tropical diseases”
By Peter J Hotez, Alan Fenwick, Lorenzo Savioli and David Molyneux
I have copied this table from the above article:
These are incredibly huge numbers.
Many of these infections occur in children and young adults and not only have an impact on life expectancy, but significantly are the cause of chronic debility particularly in young people.
Some also have an activating effect on HIV replication by several mechanisms, some of which have been understood for well over ten years. The resulting acceleration of HIV infection, by increasing HIV viral loads, as well as by other mechanisms increases the transmission of this virus.
The health of hundreds of millions of individuals could be improved by efforts to prevent and treat these infections. These infections are also appropriate therapeutic targets in the fight against HIV/AIDS.
Despite a great deal of evidence for the interaction of multiple bacterial, viral, protozoal and helminthic infections and HIV, this association has been inexplicably neglected in providing additional approaches to controlling the epidemic..
I had what might be described as a misfortune to have been a member of President Mbeki’s panel on AIDS, an almost surreal experience I should write about. The following is an excerpt from something I wrote for this panel almost 10 years ago:
“The crucial difference in Africa, as opposed to the US, is the high prevalence of associated infections. These include STDs, TB, malaria and other protozoal infections, helminthic and bacterial infections. Such infections would supply sustained signals, such as IL-1 IL-6 and TNF, known to activate HIV. Some can also upregulate the expression of chemokine co receptors required for HIV entry. Some of these infections are somewhat immunosuppressive themselves, an effect contributed to by the secretion of IL-10.37 Sexual transmission of HIV is also known to be facilitated by a high viral burden.38 This would also be the consequence of the HIV activating effect of frequent associated infections in Africa.”
This was almost 10 years ago, and since then literature has continued to accumulate documenting the detrimental interactions between HIV and multiple infectious agents.
About two years ago I made a presentation at the Prevention Research Center at Berkeley, trying to understand why endemic diseases had been so neglected in our attempts to control AIDS, particularly in Africa. I thought that part of the problem was poor interdisciplinary communication and understanding. Specifically, there might be difficulties in communications between public health experts and microbiologists. Possible public health implications of the findings of microbiologists might not be perceived without additional explanation. I illustrated this with a specific article.
I used an excellent article to illustrate this problem.
The article is called “Contribution of Immune Activation to the Pathogenesis and transmission of HIV type 1 infection” and the authors are Stephen Lawn, Salvatore Butera and Thomas Folks. (Clinical Microbiology Reviews. Oct 2001 14; 753-777)
This is part of what I said in California in trying to illustrate the difficulty in communication:
“Of great interest – because of its implications for disease control was the discovery that other infections, viral, bacterial, protozoal and helminthic, could influence the course of HIV disease. Generally the effect was to enhance HIV replication, but a few seemed to ameliorate – at least temporarily, the course of infection. Scrub typhus, measles and perhaps a form of viral hepatitis, may have a transient beneficial effect on HIV disease, but these are exceptional cases. Most co-infections have the opposite effect.
We now come to an example of observations made by microbiologists and work done at a molecular level with enormous implications for the control of AIDS in Africa. This example is a review (cited above) explaining in great technical detail how the replication of HIV can be enormously enhanced by concurrent endemic infections, and how this not only accelerates the progression of HIV disease, but also facilitates its transmission. The authors show in molecular detail how many viral, bacterial, protozoan and helminthic infections can affect HIV replication. Included among these are common intestinal worms and water borne bacterial infections, causing severe diarrhea particularly in infants. The discussion is largely concerned with the possible beneficial effect of drugs that might counteract this enhancement of HIV replication. There is one short sentence on public health interventions that might eliminate this problem altogether. It is of particular interest because of its brevity in a rather long article. There is also a curious statement that where antiretroviral drugs are unavailable, measures to control endemic infections may be a useful approach. This comment is reproduced below, and somehow ignores the significance of the implication that control of these endemic infections requires no other justification than as a measure to control AIDS.
This paper, because of its immunological and molecular detail is not too likely to find its way to an epidemiologist or public health expert, but for one trained in these technicalities, I would suppose the public health implications would be immediately evident.
This particular paper also is a great illustration of the compartmentalization of information, and the difficulties of interdisciplinary communication.
Below is an illustration from the body of the article: there is much more just like this. A person with no training in molecular biology or virology would not be likely to spend any time with this illustration.
However if one turned a few pages the following diagram may just be of some interest. But again this is unlikely.
The part that would be of interest to a public health professional , if noted, is contained in the large arrow at the bottom right of the illustration. In this rather complex diagram it would be quite easy for the public health expert to be sufficiently distracted so that the bottom right hand corner would be easily missed.
There is a long discussion, quite technical in nature, but at least the authors find space for the following brief comment.
“Prevention and Treatment of Coinfections
The widespread use of HAART in the treatment of HIV-
infected persons in westernized countries has resulted in a
phenomenal decrease in the incidence of opportunistic infec-
tions and has greatly increased survival. For these individuals,
the antiretroviral drugs are the major determinant of prognosis
and the potential cofactor effect of opportunistic infections is
now a more minor consideration. However, the vast majority
(>95%) of the world’s HIV-infected people do not currently
have access to antiretroviral drugs. Most of these people live in
developing countries, where the quality and access to health
care is often limited and where there is a high incidence of
endemic infectious diseases such as malaria, TB, and infections
by helminths and waterborne pathogens which may adversely
affect HIV-1 disease progression. Prevention or early treat-
ment of these diseases may therefore represent an important
strategy in addressing the HIV-1 epidemic in developing coun-
In the above quotation, the authors are overoptimistic in their assertion that the cofactor effect of opportunistic infections is now a more minor consideration in developed countries. Valacyclovir, a drug that inhibits the replication of many members of the herpes virus group, but has no direct effect on HIV was reported to reduce HIV viral loads in the absence of antiretroviral therapy. In the developed world, active herpes virus infections are common in the setting of HIV infection, although most will be asymptomatic. For example, Cytomegalovirus, Epstein Barr Virus and Human herpes virus type 6 are not infrequently found to be active in HIV infected individuals. Valacyclovir will have an effect on these viruses, and may well find a place in the treatment of HIV infection in developed countries. Indeed it may not be uncommon for experienced physicians here (in the US) to prescribe related anti herpes medications to their HIV infected patients. I certainly do.
There is another aspect, a little more difficult to establish and perhaps altogether conjectural. This is that we are presented with the question of why we need AIDS to justify interventions that have long been established to themselves improve the health of populations. These include the provision of sanitation and clean water, the control of malaria and TB, and something as simple as getting rid of worms. In the public’s assessment of the health needs of developing countries the information that is used is largely to be found in popular media, newspapers, magazines and TV. Those who report in turn receive information from professional sources, and maybe it is here that the interdisciplinary barriers to communication I have been talking about have their effect. Thus the AIDS epidemic is perceived to be the greatest threat to the future of Africa, even though malaria kills more people, and common endemic infections contribute to an abysmal life expectancy. (This was written 2-3 years ago and was probably incorrect even at that time; estimates are that today there are 1.5-2 million deaths from AIDS in Africa, with close to 1 million deaths from malaria. Malaria though is responsible for a greater number of deaths in children under 5 years of age).
It continues to be remarkable that although evidence has existed for years that many of these infections can interact with HIV infection to increase its infectivity and accelerate disease progression, those who advocate for, and allocate funds to fight HIV/AIDS seem oblivious to the relevance and implications of these interactions.
This effort of course needs absolutely no justification, but its funding is small compared to the resources that have been made available to combat HIV/AIDS – but from all that has been described funding for these endemic infections is in fact also funding to fight HIV/AIDS “.
Those were comments made 2-3 years ago.
While malaria and tuberculosis are now receiving attention and are included with AIDS in some programs, many other endemic infections continue to be neglected.
Going back much further in time, interest in the activating effects of associated infections on HIV replication began within the first 10 years of the epidemic. This started with the demonstration that proinflammatory cytokines, TNF alpha or IL 6, for example could greatly accelerate HIV replication.
Of course these cytokines appear in the course of many different infections. When viral load tests became available this effect was well understood by patients and physicians in N America and Europe. It became common wisdom that an HIV infected person who had a febrile illness, or had even received a flu vaccine should delay viral load testing because the infection or vaccination was frequently associated with temporary rises in HIV viral loads.
The implications for geographic areas where the infections were far from temporary seemed to escape notice.
Thus endemic infections in Africa do have everything to do with HIV/AIDS. There are numerous preventative and therapeutic measures available to control many of these infections, and some are inexpensive. Even something as simple as deworming may be useful. Ascaris lumbricoides, the common intestinal round worm also is associated with immune activation and is easily got rid of. There is a report that doing this with a drug called albendazole actually raised CD4 counts. (Walson JL et al. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS 22:1601-1609, 2008).
The person who has been studying immune activation and the association of parasitic infestations and AIDS for the longest time is Zvi Bentwich. I can’t remember when his first publication on this issue appeared but by the mid 1990s he was publishing on this association in Ethiopian immigrants to Israel. Zvi Bentwich deserves the greatest credit for his early recognition of the importance of this association, its significance regarding immune activation and for his continuing contributions. He pointed out the relevance of schistosomiasis to AIDS (and TB) at least 10 years ago.
The connection of so many endemic infections with AIDS in Africa is also a connection of poverty with AIDS. I saw an absurd and instantly forgettable paper entitled something like “Poverty does not cause AIDS” a few years ago. Of course poverty is not the direct cause of ascariasis, schistosomiasis, tuberculosis, or any number of devastating infections. Poverty is a very significant factor in the acquisition of these infections, and as such can certainly be regarded as having a causative role.
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. For example the debility associated with schistosomiasis has an impact on an individual’s productivity, with economic consequences not only for the individual but for the larger community.
Controlling the AIDS epidemic in Africa must also include measures to prevent and treat the multiple endemic infections that affect hundreds of millions of individuals.
To conclude this post I want to recommend a book published about four years ago by Eileen Stillwaggon, a professor of economics. It is called “AIDS and the ecology of poverty” and is published by the Oxford University Press.