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- W4313360100 abstract "Abstract Although CD4+ T cells represent the main target cell for HIV/SIV infection, macrophages also contribute to viral reservoirs. Given CD8+ cytotoxic T lymphocytes (CTL) are essential for controlling viral replication, characterizing how they interact with HIV-infected targets will provide insights into mechanisms of reservoir persistence and cure strategies. CTL killing of SIV-infected macrophages is less efficient than CD4+ T cells, but the mechanism of this differential killing and whether this applies to HIV is not known. Here, we demonstrate that in contrast to infected CD4+ T cells, HIV-infected macrophages are intrinsically resistant to ex vivo CTL-mediated killing, resulting in inefficient suppression of viral infection. However, when macrophages are killed, apoptosis is delayed and caspase-3-dependent versus CD4+ T cell apoptosis, which is rapid and caspase-independent. Induction of these separate apoptosis pathways is a result of differential sensitivity to granzymes, specifically granzyme B, which is poorly expressed by ex vivo HIV-specific CTLs. Differential killing is not a consequence of poor recognition. On the contrary, CTL interaction with antigen-loaded macrophages is associated with longer effector-target contact time and increased CTL production of IFN-γ. This excess IFN-γ induces production of macrophage pro-inflammatory chemokines, CXCL9 and CXCL10, which recruit activated CD4+ T cell targets. These results suggest that inefficient CTL killing of HIV-infected macrophages may contribute to reservoir persistence, chronic inflammation, and recruitment of CD4+ T cells to sites of infection." @default.
- W4313360100 created "2023-01-06" @default.
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- W4313360100 date "2017-05-01" @default.
- W4313360100 modified "2023-09-27" @default.
- W4313360100 title "Differential susceptibility to granzymes drives delayed apoptosis of HIV-infected macrophages and promotes CTL pro-inflammatory cytokine release" @default.
- W4313360100 doi "https://doi.org/10.4049/jimmunol.198.supp.78.4" @default.
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