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. 2021 Feb 12;11:626431. doi: 10.3389/fimmu.2020.626431

Figure 7.

Figure 7

Blockade of ATM promotes HIV-infected cell survival via inhibiting T cell activation, HIV infection, and DNA damage. (A) p24 expression in HIV-infected CD4 T cells treated with DMSO or ATM inhibitor (ATMi). (B–F) Summary data of the % of CD25 and γH2AX expressions in uninfected and HIV-infected (p24+ and p24-) CD4 T cells treated with DMSO or ATMi for 3, 5, and 7 days. (G) A schematic model of the fate of productively infected CD4 T cells and bystander cells during early HIV infection. HIV promotes CD4 T cell death through enhancing various programmed cell death pathways, including apoptosis and pyroptosis (especially in p24+ cells) or ferroptosis (especially in p24- cells) during early viral infection. Mechanistically, HIV infection promotes secretion of inflammatory cytokines as well as viral particles and proteins (such as Gag) that can differentially regulate the pro- and anti-apoptotic proteins, such as Bad, pBad, Bcl-2, OX40, Nur77, Mcl-1, and Birc5, in p24+ and p24- cells. HIV infection also dysregulates T cell receptor (TCR) signaling pathways, in particular PI3K (such as AKT/ATM) and telomerase hTERT activities, and thus affects telomere length and cell survival or death machineries in p24+ and p24- cells. While productively infected (p24+) cells experience more death than p24- bystander cells, p24+ cells appear to exhibit survival activity, thus favoring HIV reservoir formation and latency establishment. Specifically, productively infected CD4 T cells show prolonged telomeres, increased levels of telomerase, and more activated TCR signaling pathways compared to bystander CD4 T cells, indicating the involvement of cell survival and pro-reservoir machineries during HIV infection. Importantly, blocking the ATM pathway promotes uninfected cell death but enhances virus-infected cell survival, and blocking HIV infection enhances overall cell survival, both through regulating the signaling pathways involved in the maintenance of genomic telomere integrity. These results indicate that HIV-infected and uninfected cells employ different mechanisms for survival and death during HIV infection.