CD4+ T cell depletion in human immunodeficiency virus (HIV) infection: role of apoptosis

Abstract

Human immunodeficiency virus (HIV) infection is principally a mucosal disease and the gastrointestinal (GI) tract is the major site of HIV replication. Loss of CD4+ T cells and systemic immune hyperactivation are the hallmarks of HIV infection. The end of acute infection is associated with the emergence of specific CD4+ and CD8+ T cell responses and the establishment of a chronic phase of infection. Abnormal levels of immune activation and inflammation persist despite a low steady state level of viremia. Although the causes of persistent immune hyperactivation remain incompletely characterized, physiological alterations of gastrointestinal tract probably play a major role. Failure to restore Th17 cells in gut-associated lymphoid tissues (GALT) might impair the recovery of the gut mucosal barrier. This review discusses recent advances on understanding the contribution of CD4+ T cell depletion to HIV pathogenesis.

Keywords: HIV; apoptosis; viral proteins.

Figure 1

The extrinsic (death receptor-mediated) and intrinsic (mitochondria-mediated) pathways that lead to apoptosis of HIV infected helper T cells. The main HIV proteins (in red) implicated in CD4⁺ T cell death are the envelope glycoprotein gp120, the negative effector Nef, the transactivator of transcription (TAT) and the viral protein R (vpr). HIV gp120 uses CD4 on helper T cells and the chemokine receptors CCR5 or CXCR4 as coreceptors for virus cell entry and upregulates Fas-ligand (FASL) on these cells. Soluble Nef protein interacts directly with CXCR4 to induce cell apoptosis. Exogenous Nef protein directly stimulates TCR-CD3 complex and upregulates Fas/FasL expression on the cell surface while inhibiting the anti-apoptotic proteins Bcl-2 family. As endogenous Nef protein, Tat upregulates the Fas/FasL pathway and directly activates caspase 8. Tat and Vpr inhibit bcl-2 family while increasing mitochondria dysfunctions and cytochrome c release that promotes the formation of the apoptosome. HIV-1 Vpr also arrests cells in the G2 phase of the cell cycle. TCR: T cell receptor; CTL: cytotoxic T lymphocyte; FasL: Fas ligand; FADD: Fas-associated death domain; Caspase: cysteinyl aspartic acid-protease; BCL-2: B-cell lymphoma protein 2; BCL-X: BCL-2 like 1; Bax: BCL2 associated X protein; APAF: Apoptotic protease activating factor; PTPC : permeability transition pore complex.

Figure 2

Differentiation of effector CD4⁺ T cells. Following activation by a given antigen, cytokines secreted in the microenvironment dictate the type of effector cells subsequently induced from naive T cells. Th1, Th2, Th9, Th17, TH22, T_FH and Treg lineages are defined depending on the expression of transcription factors, effector cytokines, and chemokine receptors. Fully functional Th cells contribute to the immune response.