Mechanisms of Human Immunodeficiency Virus-Associated Lymphocyte Regulated Cell Death

Abstract

Human immunodeficiency virus-1 (HIV-1) causes CD4 T cell depletion through a number of mechanisms, including programmed cell death pathways (both apoptotic and nonapoptotic). In the setting of HIV-1 infection, the enhanced lymphocyte cell death occurs as a consequence of complex interactions between the host immune system and viral factors, which are reviewed herein. On the other hand, the main challenge to HIV-1 eradication is the development of latent infection in a subset of long lived cells, including CD4⁺ T cells and macrophages, which resist HIV-induced cell death. Understanding the potential mechanisms of how HIV-1 induces lymphocyte cell death is critical to the "kick and kill" cure strategy, which relies on the effective killing of reactivated, HIV-1-infected cells.

Keywords: apoptosis; autophagy; human immunodeficiency virus; necroptosis.

FIG. 1.

Extrinsic pathway of apoptosis. (A) FasL/Fas interaction leads to the activation of Fas-associated protein with death domain (FADD). FADD binds to the receptor death domain, c-FLIP, and sequentially activates caspase-8. The multiprotein complex formed by the receptor death domain, FADD, and caspase-8 is called the DISC. Conformational changes of activated caspase-8 result in activation of the effector downstream caspase-3 and caspase-7, which in turn leads to cleavage of vital cellular proteins, activation of DNase, and consequent cell death. (B) TNF/TNFR1 interaction leads to FADD recruitment as well as activation of a protein called TNFR1-associated death domain (TRADD). TRADD recruits RIPK1. When RIPK1 is deubiquitylated, the TNF pathway outcome is apoptosis. RIPK1 assembles in the cytosol with TRADD, FADD, procaspase-8, and a long isoform of c-FLIP generating autocatalytic cleavage and activation, releasing active caspase-8, and culminating in cell death. (C) TRADD by itself can also activate the mitochondrial (intrinsic pathway). In addition, the generated caspase-8 downstream to TRADD promotes proteolysis of BID, generating tBID, which can also engage the mitochondrial (intrinsic) pathway to amplify the apoptotic response. Effects of individual HIV proteins are annotated. TNF, tumor necrosis factor; HIV, human immunodeficiency virus; BID, BH3 interacting domain death agonist; tBID, truncated BID; c-FLIP, cellular FLICE (FADD-like interleukin-1 beta-converting enzyme)-inhibitory protein; DISC, death-inducing signaling complex; RIPK, receptor-interacting serine/threonine protein kinase.

FIG. 2.

Intrinsic pathway of apoptosis. The permeabilization of the OMM induces the efflux of intermembrane proteins, which act as apoptogenic factors through pores formed by BAX and BAK. The first to be released is cytochrome c, although endonuclease G, AIF, SMAC/DIABLO, and HtrA2/OMI are also released. Cytochrome c binds to Apaf-1 and dATP, leading to activation of caspase-9, which also binds to the other factors and forms the apoptosome. The apoptosome activates caspase-3 and caspase-7 leading to DNA fragmentation and apoptosis. BCL2 antiapoptotic proteins execute antiapoptotic function by directly binding BAX and BAK or by sequestering their activators (BH3-only proteins). BH3-only proteins execute their proapoptotic function neutralizing the antiapoptotic BCL-2 proteins and also by direct activation of BAX and BAK. Effects of individual HIV proteins are annotated. OMM, outer mitochondrial membrane; BCL2, B cell lymphoma 2; BAK, BCL2 antagonist/killer 1; BAX, BCL2-associated X, apoptosis regulator; BOK, BCL2 family apoptosis regulator BOK; AIF, apoptosis-inducing factor; DIABLO, diablo IAP-binding mitochondrial protein; HTRA2, HtrA serine peptidase 2.

FIG. 3.

Perforin/granzyme pathway of apoptosis. Granzyme A and B are released from cytoplasmic granules within CTLs and NK cells. Granzyme B, once released, enters the target cell and leads to activation of caspase-8 as well as caspase-3, caspase-6, caspase-7, and caspase-9. It also can induce apoptosis by cleaving BID, inducing OMM permeabilization and cytochrome c release. Granzyme A targets the endoplasmic reticulum-associated SET complex, which translocates to the nucleus of target cells and interferes with DNA damage repair. CTL, cytotoxic T lymphocyte; NK, natural killer; SET, Suppressor of Variegation, Enhancer of Zeste, and Trithorax.

FIG. 4.

HIV-1 and necroptosis. Necroptosis pathway is started by interaction between TNF/TNFR1, leading to RIPK3 activation by RIPK1. Active RIPK-3 catalyzes the phosphorylation of MLKL, resulting in MLKL oligomers, which insert themselves in the plasma membrane, forming an ion channel and triggering plasma membrane permeabilization. The ionic dysregulation promotes the formation of the inflammasome, which leads to activation of caspase-1 and consequent secretion of mature IL-β1, IL-18, and DAMPs. The final products are inflammatory response and necrotic cell morphology with cell swelling, diffuse fragmentation, and membrane integrity loss. The HIV-1 Tat protein leads to increased TNFα production and necroptosis stimulation. MLKL, mixed-lineage kinase domain-like pseudokinase; IL, interleukin; DAMP, damage-associated molecular pattern; Tat, transactivator of transcription.

FIG. 5.

HIV-1 and pyroptosis. In quiescent lymphoid cells, pyroptosis is induced by the accumulation of viral DNA intermediates transferred from actively infected (permissive) CD4+ T cells through cell-to-cell spread (virological synapse). The initial step of the pyroptotic pathway is the recognition of the PAMPs by TLRs. They expose the external antigen to the intracellular environment and to a second line of receptors, NLRs. Next step is activation of caspase-1, which further activates caspase-3, caspase-4, and caspase-5 and increases secretion of proinflammatory cytokines IL-1β and IL-18, which travel to the extracellular environment once the intracellular protein, Gasdermin D, is cleaved in two subunits, which will be inserted in the cellular membrane and form pores. Final products are inflammation and cell death. PAMP, pathogen-associated molecular pattern; TLR, Toll-like receptor; NLR, Nod-like receptor.

FIG. 6.

HIV-1 and autophagy. Autophagic pathway starts with the formation of double membrane-bound compartments, termed autophagosomes, which engulf and sequester cytoplasmic constituents (e.g., dysfunctional organelles, protein aggregates, and microbial pathogens). Degradation happens by fusion of autophagosomes with lysosomes. The HIV-1-encoded Nef protein inhibits autophagy by binding and sequestering beclin-1. It also inhibits lysosomal activity through phosphorylation of TFEB protein. Envelope glycoproteins (gp120 and gp41) activate beclin-1 (and autophagy) in bystander cells, but inhibits beclin-1 in HIV-1 infected CD4 T cells. Vpr protein is also able to induce autophagy and beclin-1 expression. HIV-1 Tat protein is degraded by autophagy, generating decreased viral transcription and replication. TFEB, transcriptor factor EB; Nef, Negative regulatory factor; Vpr, viral protein R; gp120, glycoprotein 120.