This blog more or less duplicates that at the aidsperspective.net site, explained in the “about” page above.
HIV Disease and Positive Feedback. An additional comment.
AUGUST 31ST 2010
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 my earlier post on positive feedback characteristics of HIV disease.
In this diagram HIV pathogenesis is represented by a circular process moving in a clockwise direction. It is started by HIV infection and can be propelled by a positive feedback association between HIV replication with immune activation. Immune activation is reinforced by CMV, and in certain settings, by some endemic infections. This is represented by the + sign in the diagram. Immune activation is retarded by those influences that dampen the immune response, including anti-inflammatory cytokines and Tregs, represented by the – sign in the diagram.
Here is a revised version of this diagram:
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.
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.