CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production

Policicchio, Benjamin B.; Cardozo-Ojeda, Erwing Fabian; Xu, Cuiling; Ma, Dongzhu; He, Tianyu; Raehtz, Kevin D.; Sivanandham, Ranjit; Kleinman, Adam J.; Perelson, Alan S.; Apetrei, Cristian; Pandrea, Ivona; Ribeiro, Ruy M.

doi:10.1038/s41467-023-42435-8

Title: CD8⁺ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production

Journal Article · 19 October 2023 · Nature Communications

DOI: https://doi.org/10.1038/s41467-023-42435-8 · OSTI ID:2222620

Policicchio, Benjamin B. ^[1];

^[2]; Xu, Cuiling ^[1]; Ma, Dongzhu ^[1]; He, Tianyu ^[1]; Raehtz, Kevin D. ^[1];

^[1]; Kleinman, Adam J. ^[1];

^[3];

^[1];

^[4]

Univ. of Pittsburgh, PA (United States)
Fred Hutchinson Cancer Research Center, Seattle, WA (United States)
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); Univ. of Lisbon (Portugal). Biomathematics Laboratory

Whether CD8⁺ T lymphocytes control human immunodeficiency virus infection by cytopathic or non-cytopathic mechanisms is not fully understood. Multiple studies highlighted non-cytopathic effects, but one hypothesis is that cytopathic effects of CD8⁺ T cells occur before viral production. Here, to examine the role of CD8⁺ T cells prior to virus production, we treated SIVmac251-infected macaques with an integrase inhibitor combined with a CD8-depleting antibody, or with either reagent alone. We analyzed the ensuing viral dynamics using a mathematical model that included infected cells pre- and post- viral DNA integration to compare different immune effector mechanisms. Macaques receiving the integrase inhibitor alone experienced greater viral load decays, reaching lower nadirs on treatment, than those treated also with the CD8^-depleting antibody. Models including CD8⁺ cell-mediated reduction of viral production (non-cytolytic) were found to best explain the viral profiles across all macaques, in addition an effect in killing infected cells pre-integration (cytolytic) was supported in some of the best models. Our results suggest that CD8⁺ T cells have both a cytolytic effect on infected cells before viral integration, and a direct, non-cytolytic effect by suppressing viral production.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH); Fundação para a Ciência e Tecnologia

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 2222620

Report Number(s):: LA-UR--21-32239

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
biological science
simian immunodeficiency virus
rhesus macaques
integrase inhibitor
raltegravir
CD8+ cell depletion
viral dynamics
CTLs
cytotoxic

Title: CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production

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Title: CD8⁺ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production