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

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

Journal Article · Fri Oct 20 00:00:00 EDT 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]; ^[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.

View Accepted Manuscript (DOE)

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

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

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

References (65)

Mechanisms of CD8 ⁺ T cell-mediated suppression of HIV/SIV replication McBrien, Julia Bergild; Kumar, Nitasha A.; Silvestri, Guido European Journal of Immunology, Vol. 48, Issue 6 https://doi.org/10.1002/eji.201747172	journal	March 2018
Model Selection and Multimodel Inference: A Practical Information-Theoretic Approach Burnham, Kenneth P.; Anderson, David R. https://doi.org/10.1007/b97636	book	January 2002
Fas and Fas ligand: lpr and gld mutations Nagata, Shigekazu; Suda, Takashi Immunology Today, Vol. 16, Issue 1 https://doi.org/10.1016/0167-5699(95)80069-7	journal	January 1995
A Nonhuman Primate Model for the Selective Elimination of CD8+ Lymphocytes Using a Mouse-Human Chimeric Monoclonal Antibody Schmitz, Jörn E.; Simon, Meredith A.; Kuroda, Marcelo J. The American Journal of Pathology, Vol. 154, Issue 6 https://doi.org/10.1016/S0002-9440(10)65450-8	journal	June 1999
Perforin and the granule exocytosis cytotoxicity pathway Catalfamo, Marta; Henkart, Pierre A. Current Opinion in Immunology, Vol. 15, Issue 5 https://doi.org/10.1016/S0952-7915(03)00114-6	journal	October 2003
Parameter estimation and uncertainty quantification for systems biology models Mitra, Eshan D.; Hlavacek, William S. Current Opinion in Systems Biology, Vol. 18 https://doi.org/10.1016/j.coisb.2019.10.006	journal	December 2019
CD8 + Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy Cartwright, Emily K.; Spicer, Lori; Smith, S. Abigail Immunity, Vol. 45, Issue 3 https://doi.org/10.1016/j.immuni.2016.08.018	journal	September 2016
CD8+ T cells promote HIV latency by remodeling CD4+ T cell metabolism to enhance their survival, quiescence, and stemness Mutascio, Simona; Mota, Talia; Franchitti, Lavinia Immunity, Vol. 56, Issue 5 https://doi.org/10.1016/j.immuni.2023.03.010	journal	May 2023
The search for the CD8+ cell anti-HIV factor (CAF) Levy, Jay A. Trends in Immunology, Vol. 24, Issue 12 https://doi.org/10.1016/j.it.2003.10.005	journal	December 2003
Decreased perforin and granzyme B expression in senescent HIV-1-specific cytotoxic T lymphocytes Yang, Otto O.; Lin, Holly; Dagarag, Mirabelle Virology, Vol. 332, Issue 1 https://doi.org/10.1016/j.virol.2004.11.028	journal	February 2005
HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes Collins, Kathleen L.; Chen, Benjamin K.; Kalams, Spyros A. Nature, Vol. 391, Issue 6665 https://doi.org/10.1038/34929	journal	January 1998
Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition Phillips, Rodney E.; Rowland-Jones, Sarah; Nixon, Douglas F. Nature, Vol. 354, Issue 6353 https://doi.org/10.1038/354453a0	journal	December 1991
HIV preferentially infects HIV-specific CD4+ T cells Douek, Daniel C.; Brenchley, Jason M.; Betts, Michael R. Nature, Vol. 417, Issue 6884 https://doi.org/10.1038/417095a	journal	May 2002
Antiviral pressure exerted by HIV-l-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus Borrow, Persephone; Lewicki, Hanna; Wei, Xiping Nature Medicine, Vol. 3, Issue 2 https://doi.org/10.1038/nm0297-205	journal	February 1997
Characterization of CD56^–/CD16⁺natural killer (NK) cells: A highly dysfunctional NK subset expanded in HIV-infected viremic individuals Mavilio, Domenico; Lombardo, Gabriella; Benjamin, Janet Proceedings of the National Academy of Sciences, Vol. 102, Issue 8 https://doi.org/10.1073/pnas.0409872102	journal	February 2005
Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques Chen, H. Y.; Di Mascio, M.; Perelson, A. S. Proceedings of the National Academy of Sciences, Vol. 104, Issue 48 https://doi.org/10.1073/pnas.0707449104	journal	November 2007
Dramatic Rise in Plasma Viremia after CD8 ⁺ T Cell Depletion in Simian Immunodeficiency Virus–infected Macaques Jin, Xia; Bauer, Daniel E.; Tuttleton, Sarah E. The Journal of Experimental Medicine, Vol. 189, Issue 6 https://doi.org/10.1084/jem.189.6.991	journal	March 1999
Expression of Chemokine and Inhibitory Receptors on Natural Killer Cells: Effect of Immune Activation and HIV Viremia Kottilil, S.; Shin, K.; Planta, M. The Journal of Infectious Diseases, Vol. 189, Issue 7 https://doi.org/10.1086/382090	journal	April 2004
Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood Raue, A.; Kreutz, C.; Maiwald, T. Bioinformatics, Vol. 25, Issue 15 https://doi.org/10.1093/bioinformatics/btp358	journal	June 2009
The presence of protective cytotoxic T lymphocytes does not correlate with shorter lifespans of productively infected cells in HIV-1 infection Spits, Hilde B.; Mudrikova, Tania; Schellens, Ingrid M. M. AIDS, Vol. 30, Issue 1 https://doi.org/10.1097/QAD.0000000000000914	journal	January 2016
Modeling SIV kinetics supports that cytotoxic response drives natural control and unravels heterogeneous populations of infected cells Madelain, V.; Passaes, C.; Millet, A. https://doi.org/10.1101/2020.01.19.911594	posted_content	January 2020
The dynamics of simian immunodeficiency virus after depletion of CD8+ cells Cardozo, Erwing Fabian; Apetrei, Cristian; Pandrea, Ivona Immunological Reviews, Vol. 285, Issue 1 https://doi.org/10.1111/imr.12691	journal	August 2018
NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection Alter, G.; Altfeld, M. Journal of Internal Medicine, Vol. 265, Issue 1 https://doi.org/10.1111/j.1365-2796.2008.02045.x	journal	January 2009
CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication Walker, C.; Moody, D.; Stites, D. Science, Vol. 234, Issue 4783 https://doi.org/10.1126/science.2431484	journal	December 1986
Identification of RANTES, MIP-1alpha, and MIP-1beta as the Major HIV-Suppressive Factors Produced by CD8+ T Cells Cocchi, F.; DeVico, A. L.; Garzino-Demo, A. Science, Vol. 270, Issue 5243 https://doi.org/10.1126/science.270.5243.1811	journal	December 1995
Control of Viremia in Simian Immunodeficiency Virus Infection by CD8⁺ Lymphocytes Schmitz, Jorn E.; Kuroda, Marcelo J.; Santra, Sampa Science, Vol. 283, Issue 5403, p. 857-860 https://doi.org/10.1126/science.283.5403.857	journal	February 1999
Notwithstanding Circumstantial Alibis, Cytotoxic T Cells Can Be Major Killers of HIV-1-Infected Cells Gadhamsetty, Saikrishna; Coorens, Tim; de Boer, Rob J. Journal of Virology, Vol. 90, Issue 16 https://doi.org/10.1128/JVI.00306-16	journal	May 2016
Differential Impact of In Vivo CD8 ⁺ T Lymphocyte Depletion in Controller versus Progressor Simian Immunodeficiency Virus-Infected Macaques Chowdhury, Ankita; Hayes, Timothy L.; Bosinger, Steven E. Journal of Virology, Vol. 89, Issue 17 https://doi.org/10.1128/JVI.00869-15	journal	June 2015
Dynamics of Simian Immunodeficiency Virus Two-Long-Terminal-Repeat Circles in the Presence and Absence of CD8 ⁺ Cells Policicchio, Benjamin B.; Cardozo, Erwing Fabian; Sette, Paola Journal of Virology, Vol. 92, Issue 13 https://doi.org/10.1128/JVI.02100-17	journal	April 2018
Early Antigen Presentation of Protective HIV-1 KF11Gag and KK10Gag Epitopes from Incoming Viral Particles Facilitates Rapid Recognition of Infected Cells by Specific CD8⁺T Cells Kløverpris, Henrik N.; Payne, Rebecca P.; Sacha, Jonah B. Journal of Virology, Vol. 87, Issue 5 https://doi.org/10.1128/JVI.02131-12	journal	March 2013
Distinct HIV-1 Escape Patterns Selected by Cytotoxic T Cells with Identical Epitope Specificity Yagita, Yuichi; Kuse, Nozomi; Kuroki, Kimiko Journal of Virology, Vol. 87, Issue 4 https://doi.org/10.1128/JVI.02572-12	journal	February 2013
Selection and Accumulation of an HIV-1 Escape Mutant by Three Types of HIV-1-Specific Cytotoxic T Lymphocytes Recognizing Wild-Type and/or Escape Mutant Epitopes Akahoshi, Tomohiro; Chikata, Takayuki; Tamura, Yoshiko Journal of Virology, Vol. 86, Issue 4 https://doi.org/10.1128/JVI.06470-11	journal	February 2012
Administration of an Anti-CD8 Monoclonal Antibody Interferes with the Clearance of Chimeric Simian/Human Immunodeficiency Virus during Primary Infections of Rhesus Macaques Matano, Tetsuro; Shibata, Riri; Siemon, Christine Journal of Virology, Vol. 72, Issue 1 https://doi.org/10.1128/JVI.72.1.164-169.1998	journal	January 1998
Role of CD8+ Lymphocytes in Control of Simian Immunodeficiency Virus Infection and Resistance to Rechallenge after Transient Early Antiretroviral Treatment Lifson, J. D.; Rossio, J. L.; Piatak, M. Journal of Virology, Vol. 75, Issue 21 https://doi.org/10.1128/JVI.75.21.10187-10199.2001	journal	November 2001
CAF-Mediated Human Immunodeficiency Virus (HIV) Type 1 Transcriptional Inhibition Is Distinct from α-Defensin-1 HIV Inhibition Chang, Theresa Li-Yun; François, Fleur; Mosoian, Arevik Journal of Virology, Vol. 77, Issue 12 https://doi.org/10.1128/JVI.77.12.6777-6784.2003	journal	June 2003
Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. Koup, R. A.; Safrit, J. T.; Cao, Y. Journal of Virology, Vol. 68, Issue 7 https://doi.org/10.1128/jvi.68.7.4650-4655.1994	journal	January 1994
Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. Borrow, P.; Lewicki, H.; Hahn, B. H. Journal of Virology, Vol. 68, Issue 9 https://doi.org/10.1128/jvi.68.9.6103-6110.1994	journal	January 1994
Escape of Human Immunodeficiency Virus from Immune Control McMichael, Andrew J.; Phillips, Rodney E. Annual Review of Immunology, Vol. 15, Issue 1 https://doi.org/10.1146/annurev.immunol.15.1.271	journal	April 1997
Modeling the within-host dynamics of HIV infection Perelson, Alan S.; Ribeiro, Ruy M. BMC Biology, Vol. 11, Issue 1 https://doi.org/10.1186/1741-7007-11-96	journal	September 2013
Experimental depletion of CD8+ cells in acutely SIVagm-Infected African Green Monkeys results in increased viral replication Gaufin, Thaidra; Ribeiro, Ruy M.; Gautam, Rajeev Retrovirology, Vol. 7, Issue 1 https://doi.org/10.1186/1742-4690-7-42	journal	January 2010
Why Don't CD8+ T Cells Reduce the Lifespan of SIV-Infected Cells In Vivo? Elemans, Marjet; Seich al Basatena, Nafisa-Katrin; Klatt, Nichole R. PLoS Computational Biology, Vol. 7, Issue 9 https://doi.org/10.1371/journal.pcbi.1002200	journal	September 2011
Testing structural identifiability by a simple scaling method Castro, Mario; de Boer, Rob J. PLOS Computational Biology, Vol. 16, Issue 11 https://doi.org/10.1371/journal.pcbi.1008248	journal	November 2020
Implications of CTL-Mediated Killing of HIV-Infected Cells during the Non-Productive Stage of Infection Althaus, Christian L.; De Boer, Rob J. PLoS ONE, Vol. 6, Issue 2 https://doi.org/10.1371/journal.pone.0016468	journal	February 2011
Biologically-Directed Modeling Reflects Cytolytic Clearance of SIV-Infected Cells In Vivo in Macaques Wick, W. David; Yang, Otto O. PLoS ONE, Vol. 7, Issue 9 https://doi.org/10.1371/journal.pone.0044778	journal	September 2012
Driving the Model to Its Limit: Profile Likelihood Based Model Reduction Maiwald, Tim; Hass, Helge; Steiert, Bernhard PLOS ONE, Vol. 11, Issue 9 https://doi.org/10.1371/journal.pone.0162366	journal	September 2016
Inhibition of Adaptive Immune Responses Leads to a Fatal Clinical Outcome in SIV-Infected Pigtailed Macaques but Not Vervet African Green Monkeys Schmitz, Jörn E.; Zahn, Roland C.; Brown, Charles R. PLoS Pathogens, Vol. 5, Issue 12 https://doi.org/10.1371/journal.ppat.1000691	journal	December 2009
CD8+ Lymphocytes Control Viral Replication in SIVmac239-Infected Rhesus Macaques without Decreasing the Lifespan of Productively Infected Cells Klatt, Nichole R.; Shudo, Emi; Ortiz, Alex M. PLoS Pathogens, Vol. 6, Issue 1 https://doi.org/10.1371/journal.ppat.1000747	journal	January 2010
In Vivo CD8+ T-Cell Suppression of SIV Viremia Is Not Mediated by CTL Clearance of Productively Infected Cells Wong, Joseph K.; Strain, Matthew C.; Porrata, Rodin PLoS Pathogens, Vol. 6, Issue 1 https://doi.org/10.1371/journal.ppat.1000748	journal	January 2010
Functional Cure of SIVagm Infection in Rhesus Macaques Results in Complete Recovery of CD4+ T Cells and Is Reverted by CD8+ Cell Depletion Pandrea, Ivona; Gaufin, Thaidra; Gautam, Rajeev PLoS Pathogens, Vol. 7, Issue 8 https://doi.org/10.1371/journal.ppat.1002170	journal	August 2011
24 Hours in the Life of HIV-1 in a T Cell Line Mohammadi, Pejman; Desfarges, Sébastien; Bartha, István PLoS Pathogens, Vol. 9, Issue 1 https://doi.org/10.1371/journal.ppat.1003161	journal	January 2013
Can Non-lytic CD8+ T Cells Drive HIV-1 Escape? Seich al Basatena, Nafisa-Katrin; Chatzimichalis, Konstantinos; Graw, Frederik PLoS Pathogens, Vol. 9, Issue 11 https://doi.org/10.1371/journal.ppat.1003656	journal	November 2013
Multi-dose Romidepsin Reactivates Replication Competent SIV in Post-antiretroviral Rhesus Macaque Controllers Policicchio, Benjamin B.; Xu, Cuiling; Brocca-Cofano, Egidio PLOS Pathogens, Vol. 12, Issue 9 https://doi.org/10.1371/journal.ppat.1005879	journal	September 2016
Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration Cardozo, E. Fabian; Andrade, Adriana; Mellors, John W. PLOS Pathogens, Vol. 13, Issue 7 https://doi.org/10.1371/journal.ppat.1006478	journal	July 2017
CD8+ lymphocyte control of SIV infection during antiretroviral therapy Cao, Youfang; Cartwright, Emily K.; Silvestri, Guido PLOS Pathogens, Vol. 14, Issue 10 https://doi.org/10.1371/journal.ppat.1007350	journal	October 2018
Innate, non-cytolytic CD8+ T cell-mediated suppression of HIV replication by MHC-independent inhibition of virus transcription Zanoni, Michelle; Palesch, David; Pinacchio, Claudia PLOS Pathogens, Vol. 16, Issue 9 https://doi.org/10.1371/journal.ppat.1008821	journal	September 2020
Escape Mutations in HIV Infection and its Impact on CD8+ T Cell Responses No authors listed Current Molecular Medicine, Vol. 7, Issue 5 https://doi.org/10.2174/156652407781387091	journal	August 2007
Inhibition of adaptive immune responses leads to a fatal clinical outcome in SIV-infected pigtailed macaques but not vervet African green monkeys Schmitz, Jorn E.; Zahn, Roland C.; Brown, Charles R. PLoS Pathogens, Vol. 5, Issue 12 https://doi.org/10.3410/f.1326001.796109	journal	December 2009
CD8 ⁺ Cell Depletion of SHIV89.6P-Infected Macaques Induces CD4 ⁺ T Cell Proliferation that Contributes to Increased Viral Loads Mueller, Yvonne M.; Do, Duc H.; Boyer, Jean D. The Journal of Immunology, Vol. 183, Issue 8 https://doi.org/10.4049/jimmunol.0900141	journal	September 2009
Does Cytolysis by CD8 ⁺ T Cells Drive Immune Escape in HIV Infection? Balamurali, Mehala; Petravic, Janka; Loh, Liyen The Journal of Immunology, Vol. 185, Issue 9 https://doi.org/10.4049/jimmunol.1002204	journal	September 2010
CD8 ⁺ Memory T Cells Appear Exhausted within Hours of Acute Virus Infection Hosking, Martin P.; Flynn, Claudia T.; Botten, Jason The Journal of Immunology, Vol. 191, Issue 8 https://doi.org/10.4049/jimmunol.1300920	journal	September 2013
Suppression of simian immunodeficiency virus replication in vitro by CD8+ lymphocytes. Kannagi, M.; Chalifoux, L. V.; Lord, C. I. The Journal of Immunology, Vol. 140, Issue 7 https://doi.org/10.4049/jimmunol.140.7.2237	journal	April 1988
Simian Immunodeficiency Virus Evades a Dominant Epitope-Specific Cytotoxic T Lymphocyte Response Through a Mutation Resulting in the Accelerated Dissociation of Viral Peptide and MHC Class I Chen, Zheng W.; Craiu, Abie; Shen, Ling The Journal of Immunology, Vol. 164, Issue 12 https://doi.org/10.4049/jimmunol.164.12.6474	journal	June 2000
Increased Natural Killer Cell Activity in Viremic HIV-1 Infection Alter, Galit; Malenfant, Jessica M.; Delabre, Rosemary M. The Journal of Immunology, Vol. 173, Issue 8 https://doi.org/10.4049/jimmunol.173.8.5305	journal	October 2004
Gag-Specific CD8 ⁺ T Lymphocytes Recognize Infected Cells before AIDS-Virus Integration and Viral Protein Expression Sacha, Jonah B.; Chung, Chungwon; Rakasz, Eva G. The Journal of Immunology, Vol. 178, Issue 5 https://doi.org/10.4049/jimmunol.178.5.2746	journal	February 2007
Canonical Wnts Mediate CD8 ⁺ T Cell Noncytolytic Anti–HIV-1 Activity and Correlate with HIV-1 Clinical Status Wallace, Jennillee; Narasipura, Srinivas D.; Sha, Beverly E. The Journal of Immunology, Vol. 205, Issue 8 https://doi.org/10.4049/jimmunol.1801379	journal	September 2020

Similar Records

The dynamics of SIV 2-LTR Circles in the Presence and Absence of CD8⁺ Cells

Journal Article · Tue Apr 10 20:00:00 EDT 2018 · Journal of Virology · OSTI ID:1435533

CD8⁺ lymphocyte control of SIV infection during antiretroviral therapy

Journal Article · Wed Oct 10 20:00:00 EDT 2018 · PLoS Pathogens · OSTI ID:1484641

Effects of in Vivo Cd8⁺ T Cell Depletion on Virus Replication in Rhesus Macaques Immunized with a Live, Attenuated Simian Immunodeficiency Virus Vaccine

Journal Article · Sat Jun 05 20:00:00 EDT 1999 · Journal of Experimental Medicine · OSTI ID:1625182

Related Subjects

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

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

Citation Formats

References (65)

Similar Records

Related Subjects

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