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AIDS pathogenesis: HIV disease and Positive feedback: An additional comment.

August 31, 2010 Leave a comment

 

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.

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