Abstract
Apoptosis of uninfected bystander cells is a key element of HIV pathogenesis and believed to be the driving force behind the selective depletion of CD4+ T cells leading to immunodeficiency. While several viral proteins have been implicated in this process the complex interaction between Env glycoprotein expressed on the surface of infected cells and the receptor and co-receptor expressing bystander cells has been proposed as a major mechanism. HIV-1 utilizes CD4 as the primary receptor for entry into cells; however, it is the viral co-receptor usage that greatly influences CD4 decline and progression to AIDS. This phenomenon is relatively simple for X4 viruses, which arise later during the course of the disease, are considered to be highly fusogenic, and cause a rapid CD4+ T cell decline. However, in contrast, R5 viruses in general have a greater transmissibility, are encountered early during the disease and have a lesser pathogenic potential than the former. The above generalization gets complicated in numerous situations where R5 viruses persist throughout the disease and are capable of causing a rigorous CD4+ T cell decline. This review will discuss the multiple factors that are reported to influence HIV induced bystander apoptosis and pathogenesis including Env glycoprotein phenotype, virus tropism, disease stage, co-receptor expression on CD4+ T cells, immune activation and therapies targeting the viral envelope.
Highlights
HIV infections cause a progressive depletion of a select group of immune cells namely the CD4+ T helper cells leading to immunodeficiency
While the process of fusion mediated by Env glycoprotein is complex, it is clear that it involves several sequential steps starting with gp120 binding to CD4 and a co-receptor and culminating in gp41 mediated membrane fusion
In the same study we found that bystander apoptosis was limited in V38E infected mice compared to Wild type which correlated with CD4 decline [59]
Summary
HIV infections cause a progressive depletion of a select group of immune cells namely the CD4+ T helper cells leading to immunodeficiency. In the 1990s, Gougeon et al proposed that apoptosis was involved in the selective loss of CD4+ T cells via unknown mechanisms [3] This led to a plethora of studies trying to determine the mechanism of apoptosis induction during HIV infection [4,5,6,7,8]. While it is clear from both in vitro and in vivo studies as well as ex vivo culture of Peripheral Blood Mononuclear Cells (PBMCs) from HIV infected individuals that apoptosis is one of the major cause of CD4+ T cell loss in HIV infections, the mechanism behind this phenomenon still remains highly debated [9]. Bystander apoptosis appears to encompass an explanation for most of the phenomenon observed during HIV infection that lead to progression to AIDS and remains one of the leading hypothesis for CD4+ T cell loss [3,12,13]
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