Using death to one's advantage: HIV modulation of apoptosis

Abstract

Infection by human immunodeficiency virus (HIV) is associated with an early immune dysfunction and progressive destruction of CD4+ T lymphocytes. This progressive disappearance of T cells leads to a lack of immune control of HIV replication and to the development of immune deficiency resulting in the increased occurrence of opportunistic infections associated with acquired immune deficiency syndrome (AIDS). The HIV-induced, premature destruction of lymphocytes is associated with the continuous production of HIV viral proteins that modulate apoptotic pathways. The viral proteins, such as Tat, Env, and Nef, are associated with chronic immune activation and the continuous induction of apoptotic factors. Viral protein expression predisposes lymphocytes, particularly CD4+ T cells, CD8+ T cells, and antigen-presenting cells, to evolve into effectors of apoptosis and as a result, to lead to the destruction of healthy, non-infected T cells. Tat and Nef, along with Vpu, can also protect HIV-infected cells from apoptosis by increasing anti-apoptotic proteins and down-regulating cell surface receptors recognized by immune system cells. This review will discuss the validity of the apoptosis hypothesis in HIV disease and the potential mechanism(s) that HIV proteins perform in the progressive T cell depletion observed in AIDS pathogenesis.

Figure 1

Model describing mechanisms of HIV modulation of apoptosis. HIV virions bind to cell surface CD4 and a coreceptor (primarily CCR5 or CXCR4) via Env initiating fusion with the cell membrane and releasing the virus-containing capsid into the cell cytoplasm. After reverse transcription process, the provirus is translocated to the nucleus and integrates into the host genome. Transcription of viral mRNA leads to the production of viral gene products. (1) Nef is expressed early in the life cycle and associates with the cell membrane where it interacts with a variety of proteins including p56lck. Nef interaction with the ζ chain of the TCR results in the up-regulation of Fas-L expression. (2) Fas-L expression can protect infected cells from cytotoxic T cell lymphocyte (CTL) killing by destroying immune cells expressing Fas. (3) Nef can down-regulate the expression of cell surface receptors CD4 and MHC class I and (4) protect the infected cells from recognition by CTLs. (5) Vpu can also prevent the cell surface expression of CD4 and therefore also protect infected cells from killing by CTLs. (6) In contrast to Nef and Vpu, Vpr expression can induce apoptosis by the induction of cell arrest at the G₂ phase of the cell cycle in HIV-infected cells. (7) Tat is among the first viral gene products to be expressed after proviral integration. Tat increases the expression of IL-2 (a T cell growth factor) and Bcl-2 (an anti-apoptotic protein), both of which protect infected cells from the induction of apoptosis. (8) However, expression of an exogenous, soluble form of Tat (sTat) induces apoptosis in many bystander cells. Interacting with cell surface receptors on T cells and macrophages, sTat can induce bystander cells to undergo apoptosis by initiating the expression of Fas, Fas-L, and TNF-α. In addition, sTat can down-regulate the expression of Bcl-2. Both TNF-α/TNFRII and Fas/Fas-L interactions can induce apoptosis in T cells by activation of caspases and the upregulation of Fas and Fas-L expression. (9) Progeny virion release can also induce apoptosis in bystander cells. The interaction of Env with cell receptors initiates CD4 and CXCR4 cell signaling pathways and subsequently activates various caspases leading to cell death.