Getting to the guts of HIV pathogenesis

Abstract

Two groups have shown that, as in macaques infected with simian immunodeficiency virus (SIV), intestinal CD4(+) T cells are selectively and rapidly depleted in the intestine of HIV-infected patients. Depletion of intestinal CD4(+) T cells occurred at all stages of infection regardless of highly active antiretroviral therapy (HAART). Here we discuss the important implications of these papers for our understanding of HIV pathogenesis, treatment, and vaccine design.

Figure 1.

Target cell distribution and viral replication in the intestinal tract. (A) In normal intestinal lymphoid tissue, naïve (CCR5⁻) CD4⁺ T cells mostly reside in inductive sites (Peyer's patches or organized lymphoid tissues; left), but these cells become activated and coexpress CCR5 as they are exposed to the variety of antigens routinely encountered in the intestinal tract. After activation, CD4⁺CCR5⁺ T cells rapidly recirculate and home to effector sites (lamina propria) where they reside in large numbers (right). (B) During acute HIV infection, activated CCR5⁺CD4⁺ T cells are rapidly eliminated from the lamina propria by HIV replication. This correlates with high levels of plasma viremia in primary infection, and loss of this subset may be a major contributor to the post-peak decline in viremia. (C) In subacute/chronic HIV infection, substantial loss of CCR5⁺CD4⁺ T cells in the lamina propria results in lower levels of virus in effector sites, but continual lymphocyte activation (from dietary antigens or intestinal microflora) in inductive sites maintains viral replication within intestinal organized lymphoid tissues. In chronic infection, the majority of infected cells may be destroyed before reaching effector sites, resulting in higher numbers of infected cells observed in organized lymphoid tissues. Intestinal lymphoid tissues with its inherent mechanisms for lymphocyte activation and homing, thus serves as a reservoir for both viral persistence and ongoing replication. As a result, intestinal effector CD4⁺CCR5⁺ T cells are never restored in HIV-infected patients, even in patients receiving highly active antiretroviral therapy.