Plumbing HIV pathogenesis.

More than 25 years have passed since the first cases of AIDS were reported, and from the very beginning the pathogenesis of the disease has presented scientists with a paradox: HIV infection is associated with the persistent activation (revving up) of the immune system, and yet also with eventual immune deficiency. Immune activation was described in the earliest cases based on swollen lymph nodes, or "lymphadenopathy," something typically associated with activation of the immune system that occurs just transiently during acute infections (with the flu or the measles, for example). But in HIV infection, research has shown that such immune activation does not resolve, but rather persists after the acute stage of infection. This prolonged, low-level activation of the immune system is associated with a gradual decline in the numbers of CD4 T cells measurable in the blood and a spreading dysfunction among remaining CD4 T cells. This ultimately renders these vital immune system components unable to coordinate the suppression of pathogens (such as Cytomegalovirus, Mycobacterium avium complex, toxoplasmosis, etc) that are easily kept in check in healthy people.

Unraveling the mechanisms by which these phenomena occur is vital to gaining a full understanding of AIDS pathogenesis and, by extension, designing therapies that might ameliorate HIV's harmful effects on the immune system (immune-based therapies). But the human immune system is vast and dauntingly complex, and this complexity presents an enormous challenge to those scientists who are working in the field. It also presents a challenge to anyone seeking to explain where pathogenesis research stands at the end of 2006! Nevertheless, it is well worth surveying the current terrain, highlighting the areas of consensus and controversy among researchers and the key questions that must be answered to gain a fuller understanding of the disease.

Taps and Drains

The first widely publicized theory that attempted to resolve the immune activation/immunodeficiency conundrum was David Ho's "tap and drain" model of pathogenesis, published in the journal Nature in 1995. In this relatively simple formulation, immune activation simply reflected the body's attempt to generate new CD4 T cells ("tap") to replace those that HIV was assumed to be killing ("drain"). The fact that this idea was relatively easy to grasp made it very seductive and even in 2006, it is possible to find information on HIV/AIDS that treats the tap and drain model as the leading theory of pathogenesis.

However, few immunologists were convinced by the simple plumbing scheme that Ho invoked. Several leading immunology researchers wrote to Nature to point out obvious flaws in this theory as soon as it was published, but their correspondence received little media attention. Over time, the dissenters in the immunology community produced data conclusively rejecting Ho's theory. The increase in CD4 T-cell counts that occurs immediately after initiation of antiretroviral therapy (ART) was shown to primarily reflect the redistribution into the blood of CD4 T ceils that had been trapped in the lymph nodes and other tissues; the initial rise in CD4 T cells did not signify the production of new cells as Ho's model predicted. Also, it had already been reported (by the late Janis Giorgi at UCLA) that immune activation markers on CD8 T cells were elevated and correlated with disease progression. And yet, CD8 T cells are not depleted by HIV. Subsequent sophisticated analyses of T-cell activation and proliferation in people with HIV showed that CD4 and CD8 T-cell activations are tightly correlated, confirming that immune activation does not reflect an attempt by the immune system to replace CD4 T cells killed by HIV. A number of studies have also reported that markers of immune activation correlate better with disease progression than viral load. Taken together, these data have led to a near total consensus in the scientific community that immune activation plays a critical causative role in HIV pathogenesis.

Leaks and Patches

The widespread agreement about the importance of immune activation reflects progress in the study of HIV pathogenesis, but it still leaves many questions to be addressed. Examples include:

* What is causing immune activation in HIV infection?

* Why and how does immune activation persist?

* Why are peripheral blood CD4 T-cell counts more affected than peripheral blood CD8 T-cell counts?

* How does immune activation lead to the eventual development of immunodeficiency?

A number of theories are emerging that go some way towards suggesting answers to these questions, but controversies remain. A recently popularized theory posits that HIV does most of its damage very early, by decimating the memory CD4 T-cell population in the gut within weeks of infection. However, skeptics point out that gut CD4 T cells have distinct properties that may make them unrepresentative of the CD4 T-cell population as a whole, and that the proportion of CD4 T cells that reside in the gut--often incorrectly said to be more than half of the total--has been overestimated.

An additional provocative suggestion associated with the gut CD4 T-cell depletion theory is that HIV's early impact on the gut compromises the integrity of the gut surface, allowing the "friendly" bacteria that aid digestion to leak into the system, thereby provoking an immune response and causing systemic immune activation. Some preliminary evidence has recently been published in support of this notion, but it remains unproven and controversial.

Another line of reasoning posits that HIV has the ability to alter the behavior of CD4 T cells by binding to CD4 and CCR5, potentially inducing activation, affecting immune trafficking patterns, and/or triggering cell death. Other researchers are looking at HIV's early impact on the development of the CD4 T-cell response to the virus itself (the HIV-specific CD4 T-cell response) as potentially setting the stage for the failure of the immune system to control HIV replication over the long term.

One research collaboration that is attempting to address a broad array of pathogenesis questions is the Cleveland Immunopathogenesis Consortium, headed by Mike Lederman from Case Western Reserve University. Lederman and a diverse group of colleagues have drawn up a plan to conduct small trials of a variety of potential immune-based therapies, with the goal of both assessing their potential and examining whether the effects of the therapies can shed light on the veracity of current pathogenesis theories.

The Pipeline

A full understanding of HIV pathogenesis would represent a colossal milestone on the road towards a cure for AIDS, but the opacity of the human immune system remains a stern challenge to researchers pursuing this goal. It's also important to recognize that this pursuit is occurring in an increasingly challenging funding environment; the number of government grants to new investigators is dwindling and the era of large increases to the National Institutes of Health's budget appears to be over. For community activists, the issues involved in HIV pathogenesis research can seem overwhelmingly complex. However, it is crucial for us to support scientists working in this area and to advocate for appropriate funding for not just HIV research, but for basic immunology research that will enable us to understand the complex milieu in which the virus is operating.

Suggested resources:

* The AIDS Treatment Activists Coalition (ATAC) Vaccine & Immune-Based Therapy Working Group website at atac-usa.org/ibt.htm.

* The Forum for Collaborative HIV Research-Immune-Based Therapies website at hivforum.org/projects/immune.htm.

* The Project Inform's hnmune Restoration Think Tank website at projectinform.org/fs/pir.html.

* TAG's Basic Science & Vaccine Project at aidsinfonyc.org/tag/science/science.html.

Recent pathogenesls reviews:

* Brenchley JM, Price DA, Douek DC. Nat Immunol. 2006;7:235-239.

* Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ. Nat Med. 2006; 12:289-295.

* Kelleher AD, Zaunders JJ. Curr HIV/AIDS Rep. 2006;3:5-12

Richard Jefferys is Coordinator at the Michael Palm Basic Science, Vaccines & Prevention Project at Treatment Action Group in New York City.