IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV.

Progressive T cell depletion during chronic human immunodeficiency virus type 1 (HIV) infection is a key mechanism that leads to the development of AIDS. Recent studies have suggested that most T cells in the tissue die through pyroptosis triggered by abortive infection, i.e., infection of resting T cells in which HIV failed to complete reverse transcription. However, the contribution of abortive infection to T cell loss and how quickly abortively infected cells die in vivo, key parameters for a quantitative understanding of T cell population dynamics, are not clear. Here, we infected rhesus macaques with simian-human immunodeficiency viruses (SHIV) and followed the dynamics of both plasma SHIV RNA and total cell-associated SHIV DNA. Fitting mathematical models to the data, we estimate that upon infection a majority of CD4+ T cells (approximately 65%, on average) become abortively infected and die at a relatively high rate of 0.27 day-1 (half-life, 2.6 days). This confirms the importance of abortive infection in driving T cell depletion. Further, we find evidence suggesting that an immune response may be restricting viral infection 1 to 3 weeks after infection. Our study serves as a step forward toward a quantitative understanding of the mechanisms driving T cell depletion during HIV infection.IMPORTANCE In HIV-infected patients, progressive CD4+ T cell loss ultimately leads to the development of AIDS. The mechanisms underlying this T cell loss are not clear. Recent experimental data suggest that the majority of CD4+ T cells in tissue die through abortive infection, where the accumulation of incomplete HIV transcripts triggers cell death. To investigate the role of abortive infection in driving CD4+ T cell loss in vivo, we infected macaques with simian-human immunodeficiency viruses (SHIV) and followed the viral kinetics of both plasma RNA and cell-associated DNA during infection. Fitting mathematical models, we estimated that a large fraction of infected cells dies through abortive infection and has a half-life of approximately 2.6 days. Our results provide the first in vivo quantitative estimates of parameters characterizing abortive infection and support the notion that abortive infection represents an important mechanism underlying progressive CD4+ T cell depletion in vivo.

TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice.

SummaryHIV-1 replicates in CD4+ T cells, leading to AIDS. Determining how HIV-1 shapes its niche to create a permissive environment is central to informing efforts to limit pathogenesis, disturb reservoirs, and achieve a cure. A key roadblock in understanding HIV-T cell interactions is the requirement to activate T cells in vitro to make them permissive to infection. This dramatically alters T cell biology and virus-host interactions. Here we show that HIV-1 cell-to-cell spread permits efficient, productive infection of resting memory T cells without prior activation. Strikingly, we find that HIV-1 infection primes resting T cells to gain characteristics of tissue-resident memory T cells (TRM), including upregulating key surface markers and the transcription factor Blimp-1 and inducing a transcriptional program overlapping the core TRM transcriptional signature. This reprogramming is driven by Vpr and requires Vpr packaging into virions and manipulation of STAT5. Thus, HIV-1 reprograms resting T cells, with implications for viral replication and persistence.

Pyroptosis, a proinflammatory form of programmed cell death, has emerged as a central driver of chronic inflammation, CD4⁺ T cell depletion, and non-AIDS comorbidities in HIV infection. This review synthesizes current evidence on the molecular mechanisms and pathological consequences of pyroptosis in HIV. We conducted a comprehensive analysis of the literature, examining the molecular pathways of pyroptosis triggered by abortive HIV infection, the roles of specific inflammasomes (e.g., AIM2, NLRP3, CARD8) and viral proteins, and the subsequent amplification of inflammation through cytokine release and gut barrier dysfunction. Abortive infection in resting CD4⁺ T cells generates cytosolic viral DNA, activating inflammasomes (primarily AIM2/IFI16) and executing pyroptosis via GSDMD. This process initiates a vicious cycle of immune activation, mucosal damage, microbial translocation, and systemic inflammation, leading to CD4⁺ T cell loss, reservoir persistence, and end-organ damage. Therapeutic targeting of key nodes (e.g., caspase-1, NLRP3, GSDMD) shows promise in preclinical models. Pyroptosis is a critical pathological engine in HIV, linking viral infection to chronic immunodeficiency and comorbidities. Adjunctive therapies targeting this pathway may reduce inflammation, preserve immune function, and support strategies toward a functional cure.

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

The Gastrointestinal Tract and AIDS Pathogenesis

The role of thiamine in HIV infection

Human immunodeficiency virus type 2 (HIV-2) infection results in a milder course of disease and slower progression to AIDS than does HIV-1. We hypothesized that this difference may be due to degradation of the sterile alpha motif and HD domain 1 (SAMHD1) host restriction factor by the HIV-2 Vpx gene product, thereby diminishing abortive infection and pyroptotic cell death within bystander CD4 T cells. We have compared CD4 T cell death in tonsil-derived human lymphoid aggregate cultures (HLACs) infected with wild-type HIV-2, HIV-2 ΔVpx, or HIV-1. In contrast to our hypothesis, HIV-2, HIV-2 ΔVpx, and HIV-1 induced similar levels of bystander CD4 T cell death. In all cases, cell death was blocked by AMD3100, a CXCR4 entry inhibitor, but not by raltegravir, an integrase, indicating that only early life cycle events were required. Cell death was also blocked by a caspase-1 inhibitor, a key enzyme promoting pyroptosis, but not by a caspase-3 inhibitor, an important enzyme in apoptosis. HIV-1-induced abortive infection and pyroptotic cell death were also not reduced by forced encapsidation of HIV-2 Vpx into HIV-1 virions. Together, these findings indicate that HIV-2 and HIV-1 support similar levels of CD4 T cell depletion in vitro despite HIV-2 Vpx-mediated degradation of the SAMHD1 transcription factor. The milder disease course observed with HIV-2 infection likely stems from factors other than abortive infection and caspase-1-dependent pyroptosis in bystander CD4 T cells.IMPORTANCE CD4 T cell depletion during HIV-1 infection involves the demise of bystander CD4 T cells due to abortive infection, viral DNA sensing, inflammasome assembly, and death by caspase-1-dependent pyroptosis. HIV-2 infection is associated with milder disease and lower rates of CD4 T cell loss. We hypothesized that HIV-2 infection produces lower levels of pyroptosis due to the action of its Vpx gene product. Vpx degrades the SAMHD1 restriction factor, potentially reducing abortive forms of infection. However, in tonsil cell cultures, HIV-2, HIV-2 ΔVpx, and HIV-1 induced indistinguishable levels of pyroptosis. Forced encapsidation of Vpx into HIV-1 virions also did not reduce pyroptosis. Thus, SAMHD1 does not appear to play a key role in the induction of bystander cell pyroptosis. Additionally, the milder clinical course of HIV-2-induced disease is apparently not explained by a decrease in this inflammatory form of programmed cell death.

HIV-1 infection leads to the progressive depletion of the CD4 T cell compartment by various known and unknown mechanisms. In vivo, HIV-1 infects both activated and resting CD4 T cells, but in vitro, in the absence of any stimuli, resting CD4 T cells from peripheral blood are resistant to infection. This resistance is generally attributed to an intracellular environment that does not efficiently support processes such as reverse transcription (RT), resulting in abortive infection. Here, we show that in vitro HIV-1 infection of resting CD4 T cells induces substantial cell death, leading to abortive infection. In vivo, however, various microenvironmental stimuli in lymphoid and mucosal tissues provide support for HIV-1 replication. For example, common gamma-chain cytokines (CGCC), such as interleukin-7 (IL-7), render resting CD4 T cells permissible to HIV-1 infection without inducing T cell activation. Here, we find that CGCC primarily allow productive infection by preventing HIV-1 triggering of apoptosis, as evidenced by early release of cytochrome c and caspase 3/7 activation. Cell death is triggered both by products of reverse transcription and by virion-borne Vpr protein, and CGCC block both mechanisms. When HIV-1 RT efficiency was enhanced by SIVmac239 Vpx protein, cell death was still observed, indicating that the speed of reverse transcription and the efficiency of its completion contributed little to HIV-1-induced cell death in this system. These results show that a major restriction on HIV-1 infection in resting CD4 T cells resides in the capacity of these cells to survive the early steps of HIV-1 infection. A major consequence of HIV-1 infection is the destruction of CD4 T cells. Here, we show that delivery of virion-associated Vpr protein and the process of reverse transcription are each sufficient to trigger apoptosis of resting CD4 T cells isolated from peripheral blood. While these 2 mechanisms have been previously described in various cell types, we show for the first time their concerted effect in inducing resting CD4 T cell depletion. Importantly, we found that cytokines such as IL-7 and IL-4, which are particularly active in sites of HIV-1 replication, protect resting CD4 T cells from these cytopathic effects and, primarily through this protection, rather than through enhancement of specific replicative steps, they promote productive infection. This study provides important new insights for the understanding of the early steps of HIV-1 infection and T cell depletion.

Viral-Induced Enzymes and the Problem of Viral Oncogenesis

N6-methyladenosine (m6A) is the most prevalent cellular mRNA modification and plays a critical role in regulating RNA stability, localization, and gene expression. m6A modification plays a vital role in modulating the expression of viral and cellular genes during HIV-1 infection. HIV-1 infection increases cellular RNA m6A levels in many cell types, which facilitates HIV-1 replication and infectivity in target cells. However, the function of m6A modification in regulating HIV-1 infection of primary CD4+ T cells remains unclear. Here, we demonstrate that HIV-1 infection of Jurkat CD4+ T cells and primary CD4+ T cells promotes the interaction between the m6A writer complex subunits methyltransferase-like 3 and 14 (METTL3/METTL14). Using single-base m6A-specific RNA sequencing, we identified several differentially m6A-modified cellular mRNAs, including perilipin 3 (PLIN3), during HIV-1 infection in primary CD4+ T cells. Interestingly, HIV-1 infection increased PLIN3 mRNA level by enhancing its stability, but PLIN3 protein level was decreased. Knocking down PLIN3 in primary CD4+ T cells reduced HIV-1 production but enhanced virion infectivity. In contrast, in Jurkat cells, PLIN3 mRNA and protein expression levels were unaffected by HIV-1 infection, and knocking out PLIN3 did not impact HIV-1 production or infectivity. These results indicate that the interplay between HIV-1 and PLIN3 is cell-type specific and only observed in primary CD4+ T cells. Overall, our results highlight the importance of m6A RNA modification in HIV-1-infected primary CD4+ T cells and suggest its significance as a regulatory mechanism in HIV-1 infection.

Diagnosis and Natural History of HIV-Associated Nephropathy

Limited efficiency of endogenous interleukin-7 levels in T cell reconstitution during HIV-1 infection: will exogenous interleukin-7 therapy work?

Replication of viral DNA in SPO1-infected Bacillus subtilis: II. DNA maturation during abortive infection

The role of CD4 and CD8 T cells in primary Chlamydia trachomatis pneumonia was investigated by using in vivo depletion techniques to eliminate T-cell populations. Reduction of either CD4 T cells or CD8 T cells caused a significant increase in organism burden in the lungs, as measured by both quantitative culture and detection of chlamydial antigen on day 14 postinfection. Chlamydia-specific antibody levels in plasma or antigen-induced gamma interferon (IFN-gamma) production by spleen cells was dramatically reduced by depletion of CD4 cells. The reduction in IFN-gamma achieved by depletion of CD8 cells did not reach statistical significance. In the survival studies, depletion of CD4 cells led to a significant increase in mortality. Although there was a trend toward higher mortality, depletion of CD8 cells did not significantly increase mortality. The role of CD8 T cells in host defense was clarified in studies using beta 2-microglobulin-deficient (major histocompatibility class I antigen-deficient, C1D) mice which are defective in CD8 T-cell function. In this model, a significant increase in organism burden was seen during infection in C1D mice compared with that C57BL/6 controls and a significant increase in mortality was observed as well. However, surviving C1D mice were able to clear the infection by day 34. C1D mice had increased numbers of CD4 T cells in both the spleen and the lungs during infection compared with those of C57BL/6 controls. IFN-gamma in C57BL/6 mice was produced by both CD4 and CD8 cells. Thus, there is a protective role for both CD4 and CD8 cells in host defense against Chlamydia infection, but the former appear to be dominant.