Induction of Apoptosis by HIV1

Viruses have evolved numerous mechanisms to evade the host immune system and one of the strategies developed by HIV1 is to activate apoptotis of immune effectors. The HIV genome encodes pro-apoptotic proteins that kill both infected and uninfected lymphocytes through either members of TNF family or the mitochondrial pathway.The adaptive immune response against HIV1 requires MHC-I to present viral antigens on the surface of infected cells. HIV1 attenuates MHC-I cell surface expression by inducing endocytosis of MHC-I molecules. HIV1 infection activates the two main pathways of cell death in lymphocytes: 1) Activation-induced cell death (AICD) through the TNF family of death receptors, and 2)Activated T-Cell Autonomous Death (ACAD) through BCL2-related proteins. Among the HIV1 proteins that have been implicated in regulating apoptosis are GP120, Vpr, Nef, and Tat. These HIV1 proteins trigger death receptors such as Fas and TNFR, as well as act through the mitochondrial pathway via phosphorylation of p53, upregulation of BAX, dissipation of mitochondrial transmembrane potential, CytoC release, and activation of caspases. Nef downregulates cell surface expression of CD4 by increasing endocytosis and lysosomal degradation of CD4. Nef assembles with and inhibits the enzymatic activity of ASK1.HIV1 typically enters host cells through the interaction of GP120 with CD4 and chemokine receptors CCR5 and CXCR4 on the surface of host cells. The relative expression of these coreceptors determines the relative susceptibility of cells to HIV1 infection. Signaling through the death receptor Fas results in recruitment of the adaptor protein FADD. The binding of FADD to Fas recruits Caspase 8, which results in autoproteolytic activation of Caspase 8. The expression of Caspase 8 is upregulated by Tat and GP120.The extrinsic pathway is initiated by the binding of TNF family ligands to their receptors. Through their death domain, multimerized receptors interact with the death domains of adaptor proteins, RIP and TRAF1/2, which facilitate binding to pro-caspase 8 and pro-caspase 10 to form the Death-Inducing Signal Complex (DISC). The pro-caspases are cleaved into their active forms, followed by cleavage of BID to produce tBID. Death-receptor-induced apoptosis can be blocked by FLIP, which inhibits the proteolytic processing of caspase 8. HIV-encoded proteins GP120, Nef and Tat upregulate the expression of Fas and FasL. In addition, Tat upregulates the expression of TRAIL. GP120 and Nef increase the activity of Caspase 3. The intrinsic apoptotic pathway is initiated by internal sensors, such as p53, which activate BH3-containing proteins such as PUMA1 and mediate the assembly of BAX and BAK into hetero-oligomeric pores in the mitochondrial membrane. This results in the release of pro-apoptotic factors such as CytoC, SMAC and HTRA2 into the cytoplasm. This is associated with the loss of mitochondrial membrane potential, which can be blocked by anti-apoptotic proteins BCL2/BCL-XL. Release of CytoC promotes the formation of the apoptosome, which includes APAF1 and pro-caspase9. Autolytic activation of Caspase9 activates ICAD leading to DNA fragmentation. Caspase activation is negatively regulated by IAPs, which are counterbalanced by SMAC and HTRA2. GP120 induces the phosphorylation of p53; Tat and GP120 promote BAX insertion into the mitochondrial membrane and subsequent release of CytoC; Vpr has a direct effect on the mitochondrial permeability transition pore; GP120, Tat and Nef inhibit expression of BCL2, and Nef inhibits the expression of Bcl-XL. Chronic activation of the TNF-α-signaling pathway plays a pivotal role in HIV1 pathogenesis, leading to increased HIV1 transcription, induction of apoptosis, and suppression of hematopoiesis.