How Does Programmed Cell Death Contribute to AIDS Pathogenesis?

Abstract

The pathogenesis of human immunodeficiency virus (HIV) infection is complex and multifactorial (Fig. 1). Primary infection with HIV is rapidly followed by dissemination of the virus to the lymphoid organs, in which high virus replication occurs throughout the entire course of infection, even when the patient is clinically asymptomatic (Pantaleo et al. 1993). An intense cellular and humoral immune response is generated, which inhibits viral replication within weeks, but the virus almost invariably escapes from immune control, producing a chronic and persistent infection, and leading to the development of AIDS in the absence of an efficient anti-retroviral therapy (Fauci 1996). The targets of HIV infection are CD4 expressing cells, such as lymphocytes and mono- cytes, the first identified receptor for HIV being the CD4 molecule. All strains of HIV infect primary CD4+ T lymphocytes, and many primary isolates (referred to as M-tropic) also replicate well in monocytes, but not in transformed T cell lines. Other isolates that have been passaged in lymphoid cells in vitro infect primary CD4+ T lymphocytes, but not monocytes, and are referred to as T-tropic viruses. The viral determinant of cellular tropism maps to the gpl20 subunit of the HIV-1 Env protein and studies to delineate the molecular basis of cellular tropism led to the identification of co-receptors for HIV. The receptor CXCR4 was identified as the co-receptor responsible for the efficient entry of T-tropic strains of HIV-1 into target cells, and the β-chemokine receptor CCR5 was identified as the co-receptor for M-tropic HIV-1. As a corollary, the CXC chemokine SDF-1, the ligand for CXCR4, and the β-chemokines RANTES, MlP-lα and MIP-1β ligands for CCR5, block infection by T-tropic or M-tropic HIV-1. Other co-receptors have been recently identified which seem to be used at later stages of the disease (Fcauci 1996).