CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production
Abstract
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.
- Authors:
-
[2];
[1];
[3];
[1];
[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
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH); Fundação para a Ciência e Tecnologia
- OSTI Identifier:
- 2222620
- Report Number(s):
- LA-UR-21-32239
Journal ID: ISSN 2041-1723
- Grant/Contract Number:
- 89233218CNA000001; P01 AI169615; R01 AI152703; R01 AI104373; UM1 AI164561; R01 AI028433; R01 OD011095; R01 AI150500; R01 HL117715; R01 AI119346; R01 DK119936; DK131476; T32 AI065380; T32 AI060525; PTDC/MAT-APL/31602/2017
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 14; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; biological science; simian immunodeficiency virus; rhesus macaques; integrase inhibitor; raltegravir; CD8+ cell depletion; viral dynamics; CTLs; cytotoxic
Citation Formats
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, and Ribeiro, Ruy M. CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production. United States: N. p., 2023.
Web. doi:10.1038/s41467-023-42435-8.
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. CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production. United States. https://doi.org/10.1038/s41467-023-42435-8
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, and Ribeiro, Ruy M. Fri .
"CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production". United States. https://doi.org/10.1038/s41467-023-42435-8. https://www.osti.gov/servlets/purl/2222620.
@article{osti_2222620,
title = {CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production},
author = {Policicchio, Benjamin B. and Cardozo-Ojeda, Erwing Fabian and Xu, Cuiling and Ma, Dongzhu and He, Tianyu and Raehtz, Kevin D. and Sivanandham, Ranjit and Kleinman, Adam J. and Perelson, Alan S. and Apetrei, Cristian and Pandrea, Ivona and Ribeiro, Ruy M.},
abstractNote = {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.},
doi = {10.1038/s41467-023-42435-8},
journal = {Nature Communications},
number = 1,
volume = 14,
place = {United States},
year = {Fri Oct 20 00:00:00 EDT 2023},
month = {Fri Oct 20 00:00:00 EDT 2023}
}
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