CAUSES AND MECHANISMS OF IMMUNE ACTIVATION IN HIV INFECTION

Although considerable strides have been made in this field, the mechanism of aberrant immune activation in HIV infection remains incompletely understood. Immune activation, per se, is an essential component of an immune response when it involves activation of antigen-specific T cells in response to an antigen, usually in the context of an infectious organism.

Many factors can contribute to the heightened immune activation in HIV infection. Many of the virally encoded proteins, particularly, Nef, Env, Tat, and Vpr, can induce chronic immune activation,^9-16 thereby creating an environment that favors the ability of the virus to persist in the host. For example, Nef has the capacity to modify the plasma membrane signaling by regulation of receptor/ligand endocytosis and to promote lymphocyte activation and apoptosis.^9,13,15 HIV Env was shown in numerous studies to induce CD4 T cell activation via CD4 cross-linking and binding to chemokine receptors, which, in turn, can prime the cells to undergo AICD.^10,14 HIV-envelope interaction with CD4 T cells results in activation of NF-κB transcription factors, which amplifies the host inflammatory response and activates the HIV-1 long terminal repeat (LTR) sequences. HIV Tat, when presented to T cells exogenously, can promote their activation and apoptosis.¹¹ HIV infection in humans and SIV infection in rhesus macaques interfere with cell-cycle control in T lymphocytes in association with chronic immune activation and excess apoptosis.²⁹ HIV Vpr can cause cell-cycle arrest in G₂ and lymphocyte apoptosis, which can occur independently of the cell-cycle dysfunction.¹²

Independently of the effect of HIV viral gene products, another important cause of immune activation stems from co-infections with non-HIV pathogens.

In the healthy state, upon completion of an immune effector function, the immune response comes to an end through an incompletely understood process. Recently, regulatory T cells (T regs) were identified, both natural and induced, that play important roles in maintaining immunologic balance.^31-34 The forkhead/winged helix transcription factor FoxP3 is a marker for T regs, and the best-studied regulatory T cells are CD4⁺ CD25⁺ T cells that express FoxP3. The original role of T reg was in mediating tolerance, because deficiencies of T regs are associated with autoimmunity; however, several subsets of T reg with distinct phenotypes and functions were identified.

The generation of T regs in the adaptive immune response is dependent on dendritic cells (DC).^32-34 The differential roles of myeloid vs. plasmacytoid dendritic cell (DC) in the induction of T regs are under investigation. Moreover, the roles of immature vs. mature DC, and their ability to generate as well as overcome the suppressive properties of T regs, are being identified. In one model, DC blocked normal CD4⁺ CD25⁺ T-reg-mediated suppression, partially via IL-6 secretion. DC can thus control the suppressive ability, expansion, and differentiation of T reg cells in vivo. Thus, in addition to the definitive role of DC in the pathogenesis of immune activation secondary to infection with a co-pathogen, these cells likely play important and even essential independent roles in immune activation. The absence of immune activation in the nonpathogenic natural infection of sooty mangabeys with SIV seems to be linked to the function of plasmacytoid DCs.³⁶ The mechanism of action of regulatory T cells is mediated by TGF-β or IL-10 in some models, whereas others have failed to show a need for these cytokines.

It is possible that other “regulatory” cells are also important in the immune activation of HIV infection. It was demonstrated that the function of natural killer (NK) cells is compromised in HIV infection³⁷ and that γδ T cells are rapidly and permanently depleted in HIV infection.³⁸ Whether or not these cells also play a role in the regulation of immune activation merits exploration.