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Review
. 2017 Aug 22;9(8):237.
doi: 10.3390/v9080237.

Host and Viral Factors in HIV-Mediated Bystander Apoptosis

Himanshu Garg  1 , Anjali Joshi  2
Affiliations
Review

Host and Viral Factors in HIV-Mediated Bystander Apoptosis

Himanshu Garg et al. Viruses. .

Abstract

Human immunodeficiency virus (HIV) infections lead to a progressive loss of CD4 T cells primarily via the process of apoptosis. With a limited number of infected cells and vastly disproportionate apoptosis in HIV infected patients, it is believed that apoptosis of uninfected bystander cells plays a significant role in this process. Disease progression in HIV infected individuals is highly variable suggesting that both host and viral factors may influence HIV mediated apoptosis. Amongst the viral factors, the role of Envelope (Env) glycoprotein in bystander apoptosis is well documented. Recent evidence on the variability in apoptosis induction by primary patient derived Envs underscores the role of Env glycoprotein in HIV disease. Amongst the host factors, the role of C-C Chemokine Receptor type 5 (CCR5), a coreceptor for HIV Env, is also becoming increasingly evident. Polymorphisms in the CCR5 gene and promoter affect CCR5 cell surface expression and correlate with both apoptosis and CD4 loss. Finally, chronic immune activation in HIV infections induces multiple defects in the immune system and has recently been shown to accelerate HIV Env mediated CD4 apoptosis. Consequently, those factors that affect CCR5 expression and/or immune activation in turn indirectly regulate HIV mediated apoptosis making this phenomenon both complex and multifactorial. This review explores the complex role of various host and viral factors in determining HIV mediated bystander apoptosis.

Keywords: AIDS; CCR5; Env; HIV; apoptosis; bystander; fusion; gp41; hemifusion; immune activation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Model of host and viral factors in human immunodeficiency virus (HIV)-mediated bystander apoptosis. HIV mediated bystander apoptosis and CD4 decline can be attributed to both host and viral factors. Fundamental to this process is active virus replication (viremia) as suppressing virus replication via highly active anti-retroviral therapy (HAART) suppresses the major immunopathological variables of the disease including CD4 apoptosis and immune activation. The phenotype of the Envelope (Env) glycoprotein is another major determinant of HIV pathogenesis as the Env apoptosis inducing potential (AIP) correlates with CD4 loss. Other genotypic and phenotypic variations in Env like coreceptor usage, virus subtype, fusogenic activity of Env, etc. have been associated with disease. The binding of Env to CCR5 is also fundamental to HIV induced bystander apoptosis and variations in CCR5 levels can influence this phenomenon. Immune activation is a key immunopathological feature of HIV infections that correlates with CD4 decline and can be affected via multiple pathways as shown by arrows. TLR: toll-like receptor).
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