Abortive HIV Infection Mediates CD4 T Cell Depletion and Inflammation in Human Lymphoid Tissue

Abstract

Summary The mechanism by which CD4 T-cells are depleted in HIV-infected hosts remains poorly understood. In ex vivo cultures of human tonsil tissue, CD4 T cells undergo a pronounced cytopathic response following HIV infection. Strikingly, >95% of these dying cells are not productively infected but instead correspond to bystander cells. We now show that the death of these “bystander” cells involves abortive HIV infection. Inhibitors blocking HIV entry or early steps of reverse transcription prevent CD4 T-cell death while inhibition of later events in viral life cycle does not. We propose that the nonpermissive state exhibited by the majority of resting CD4 tonsil T-cells leads to accumulation of incomplete reverse transcripts. These cytoplasmic nucleic acids activate a host defense program that elicits a coordinated proapoptotic and proinflammatory response involving caspase-3 and caspase-1 activation. While this response likely evolved to protect the host, it centrally contributes to the immunopathogenic effects of HIV.

The Majority of CD4 + T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

“…Recent cross-sectional evaluations suggest that 95% of the dying cells in lymphoid tissue are uninfected and that their death results from abortive HIV infection, where the virus enters the cell but is not able to replicate (17). Our results are in alignment with an increasing body of literature suggesting that the role of bystander cell death during HIV infection is much larger than the loss of CD4 ϩ T cells due to direct infection (12,51,52,53,54,55,56,57,58,59).…”

“…HIV envelope glycoprotein 120 induces expression of preapoptotic membrane-bound and -soluble factors, such as Fas, Fas ligand, and tumor necrosis factor alpha (14,15,16). HIV proteases cleave host proteins into cellular mediators of apoptosis, and HIV induces an accumulation of incomplete reverse transcripts, leading to a proapoptotic response (17). While less than 1% of CD4 ϩ T cells are infected during chronic infection (18,19), CD4…”

Activation and Regulation of DNA-Driven Immune Responses

“…By using a similar system, the type I IFN response to wild-type and mutant HIV-1 was found to be dependent on both IFI16 and cGAS (31,112). In the case of HIV, reverse transcription DNA intermediates were also found to induce bystander cell death in abortively infected CD4 ϩ T cells, through a mechanism involving caspases 1 and 3 (84). This work was subsequently extended by the demonstration of IFI16 as the DNA sensor in CD4 ϩ T cells mediating pyroptotic cell death (68).…”

“…One possibility is that they have different requirements regarding adaption to environmental changes. For instance, for keratinocytes, it may be advantageous to be able to respond to DNA when the challenge is sustained (13), and for activated T cells, DNA sensing may preferentially stimulate death pathways as opposed to IFN responses (82,84).…”

HIV-1 Gag, Envelope, and Extracellular Determinants Cooperate To Regulate the Stability and Turnover of Virological Synapses

“…Contactmediated spread can increase the frequency of multiploid (i.e., multigenome) inheritance (20,(24)(25)(26) and protect transmission from some antiviral drugs, neutralizing antibodies, or host restriction factors (20,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Furthermore, Env-dependent intercellular signaling is implicated in potentiating cell responses relevant to the efficiency of viral replication (41) and/or immune dysregulation linked to HIV/AIDS pathogenesis (42,43).…”