"... no longer solely of interest to academic immunologists ..."
At the recent International AIDS Society conference in Sydney, Mike Lederman reminded attendees that abnormally high levels of immune activation were described in the first case reports of gay men with AIDS in 1981. The authors of those reports, led by Michael Gottlieb, specifically noted the "increased percentage of cells bearing the thymocyte-associated antigen T10." This antigen is now known as CD38, and an extensive literature -- particularly the work of the late Janis Giorgi, an immunologist at UCLA -- demonstrates that CD38 expression on CD8 T cells correlates strongly with the rate of disease progression in people with HIV infection (in many instances, more strongly than viral load and peripheral blood CD4 T cell counts). It has also become clear that immune activation is a broader phenomenon than just CD38 expression on CD8 T cells. CD4 T cells are also over-activated and additional T cell activation markers -- such as HLA-DR -- are elevated along with levels of pro-inflammatory cytokines including TNF-alpha, IL-6 and IL-1beta.
The role of immune activation in HIV infection has generally received less attention than HIV-associated immune deficiency. But recently, immune activation has received renewed attention for a number of important reasons:
Taken together, these findings argue strongly for a renewed focus on unraveling the causes and consequences of immune activation and inflammation in HIV infection. The intimate correlation between viral load levels and immune activation markers and the precipitous decline in activation that occurs on ART are compelling evidence that HIV is driving the phenomenon. But exactly how this is occurring -- particularly the extent to which HIV antigens are involved versus other potential sources of activation such as bacteria leaking across the gut mucosa -- remains unresolved. Even the exact types of CD4 and CD8 T cell that are expressing high levels of CD38 in HIV is still uncertain; are they naïve T cells that have been activated, memory T cells that have been activated, or some mix of both? What antigens are these T cells specific for?
These questions are no longer solely of interest to academic immunologists, they are now increasingly recognized to have a vital relation to the transmission and pathogenesis of HIV infection and AIDS. Obtaining answers will require a multipronged approach involving studies addressing clinical questions -- such as the best time to start ART -- and translational research to evaluate therapies that might both ameliorate immune activation and shed light on its causes, such as toll-like receptor antagonists, CCR5 inhibitors and anti-inflammatory approaches. HIV research has come a long way in addressing immune deficiency; it's now time to take on immune activation.
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