Emerging concepts in the immunopathogenesis of AIDS

Abstract

There is an intense interplay between HIV and the immune system, and the literature is replete with studies describing various immunological phenomena associated with HIV infection. Many of these phenomena seem too broad in scope to be attributable either to HIV-infected cells or to the HIV-specific immune response. Recently, a more fundamental understanding of how HIV affects various T cells and T cell compartments has emerged. This review covers the role of immune activation in HIV immunopathogenesis, how that activation could be mediated directly by HIV replicating within and damaging the gut mucosal barrier, how HIV affects multiple T cell functions and phenotypes, and how chronic HIV replication induces immune modulatory pathways to negatively regulate certain functions in HIV-specific T cells.

Figure 1. Central role of HIV in immunopathogenesis

In acute infection CD4 T cell depletion and enteropathy results in microbial translocation which contributes to immune activation. The virus itself may also contribute to immune activation. Activation leads to the generation of more target cells for the virus thus perpetuating viral replication and mucosal damage. Infection and depletion of the critical central memory CD4 T cell pool results in reduced tissue delivery of effector memory CD4 T cells and further loss of immune control at mucosal and other tissue sites.

Figure 2. Functionally-defined T cell differentiation and HIV disease progression

T cell stages can be defined either by phenotype (expression of cell surface markers such as CD45RA, CCR7, and CD28), or by function (expression of cytokines, chemokines, or other activities immediately following antigenic stimulation). Clinically-defined correlates of progression in HIV disease have been associated with T cell functions: better clinical outcome is associated with a prevalence of polyfunctional T cells. These cells are highly optimized for effector function by expressing multiple functions simultaneously as well as expressing high levels of cytokines on a per-cell basis. In contrast, there is little correlation between clinical outcome and the phenotype of antigen-specific cells, likely because of the broad overlaps between phenotypically-defined subsets and function.

Figure 3. Model of PD-1 activity and therapeutic intervention

Chronic stimulation of antigen presenting cells (APC) by HIV induces high expression of PD-L1 on the APC, and strong expression of PD-1 on responding CTL. Negative signaling through PD-1 in association with the peptide/MHC–TCR interaction leads to decreased proliferation and increased apoptosis of HIV-specific CTL. Anti-PD-1 therapy could block the negative regulatory signal through PD-1 thereby restoring proliferative potential in HIV-specific CTL despite the high expression of PD-1.