CD8+ lymphocyte control of SIV infection during antiretroviral therapy

Cao, Youfang; Cartwright, Emily; Silvestri, Guido; Perelson, Alan S.

doi:10.1371/journal.ppat.1007350

CD8⁺ lymphocyte control of SIV infection during antiretroviral therapy

Journal Article · Thu Oct 11 00:00:00 EDT 2018 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1007350· OSTI ID:1484641

^[1]; Cartwright, Emily ^[2]; Silvestri, Guido ^[2]; ^[1]

Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Emory Univ., Atlanta, GA (United States)

CD8⁺ lymphocytes play an important role in suppressing in vivo viral replication in HIV infection. However, both the extent to which and the mechanisms by which CD8⁺ lymphocytes contribute to viral control are not completely understood. A recent experiment depleted CD8⁺ lymphocytes in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) on antiretroviral treatment (ART) to study the role of CD8⁺ lymphocytes. CD8⁺ lymphocytes depletion resulted in temporary plasma viremia in all studied RMs. Viral control was restored when CD8⁺ lymphocytes repopulated. We developed a viral dynamic model to fit the viral load (VL) data from the CD8 depletion experiment. We explicitly modeled the dynamics of the latent reservoir and the SIV-specific effector cell population including their exhaustion and their potential cytolytic and noncytolytic functions. We found that the latent reservoir significantly contributes to the size of the peak VL after CD8 depletion, while drug efficacy plays a lesser role. Our model suggests that the overall CD8⁺ lymphocyte cytolytic killing rate is dynamically changing depending on the levels of antigen-induced effector cell activation and exhaustion. Based on estimated parameters, our model suggests that before ART or without ART the overall CD8 cytolytic killing rate is small due to exhaustion. However, after the start of ART, the overall CD8 cytolytic killing rate increases due to an expansion of SIV-specific CD8 effector cells. Further, we estimate that the cytolytic killing rate can be significantly larger than the cytopathic death rate in some animals during the second phase of ART-induced viral decay. Lastly, our model provides a new explanation for the puzzling findings by Klatt et al. and Wong et al. that CD8 depletion done immediately before ART has no noticeable effect on the first phase viral decay slope seen after ART initiation Overall, by incorporating effector cells and their exhaustion, our model can explain the effects of CD8 depletion on VL during ART, reveals a detailed dynamic role of CD8⁺ lymphocytes in controlling viral infection, and provides a unified explanation for CD8 depletion experimental data.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE

Grant/Contract Number:: 89233218CNA000001; AC52-06NA25396

OSTI ID:: 1484641

Report Number(s):: LA-UR-18-22077

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 10 Vol. 14; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

References (54)

Controlling HIV pathogenesis: the role of the noncytotoxic anti-HIV response of CD8+ T cells Levy, Jay A.; Mackewicz, Carl E.; Barker, Edward Immunology Today, Vol. 17, Issue 5 https://doi.org/10.1016/0167-5699(96)10011-6	journal	May 1996
An Evolutionary Role for HIV Latency in Enhancing Viral Transmission Rouzine, Igor M.; Weinberger, Ariel D.; Weinberger, Leor S. Cell, Vol. 160, Issue 5 https://doi.org/10.1016/j.cell.2015.02.017	journal	February 2015
What do mathematical models tell us about killing rates during HIV-1 infection? Gadhamsetty, Saikrishna; Beltman, Joost B.; de Boer, Rob J. Immunology Letters, Vol. 168, Issue 1 https://doi.org/10.1016/j.imlet.2015.07.009	journal	November 2015
Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis Ramratnam, Bharat; Bonhoeffer, Sebastian; Binley, James The Lancet, Vol. 354, Issue 9192 https://doi.org/10.1016/s0140-6736(99)02035-8	journal	November 1999
Decay characteristics of HIV-1-infected compartments during combination therapy Perelson, Alan S.; Essunger, Paulina; Cao, Yunzhen Nature, Vol. 387, Issue 6629 https://doi.org/10.1038/387188a0	journal	May 1997
Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy Fleury, S.; Rizzardi, G. P.; Chapuis, A. Proceedings of the National Academy of Sciences, Vol. 97, Issue 10 https://doi.org/10.1073/pnas.97.10.5393	journal	May 2000
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
Analysis of left-censored longitudinal data with application to viral load in HIV infection Jacqmin-Gadda, H. Biostatistics, Vol. 1, Issue 4 https://doi.org/10.1093/biostatistics/1.4.355	journal	December 2000
HIV–1 dynamics revisited: biphasic decay by cytotoxic T lymphocyte killing? Arnaout, Ramy A.; Martin A., Nowak; Wodarz, Dominik Proceedings of the Royal Society of London. Series B: Biological Sciences, Vol. 267, Issue 1450 https://doi.org/10.1098/rspb.2000.1149	journal	July 2000
CD8+ cell noncytotoxic anti-human immunodeficiency virus response inhibits expression of viral RNA but not reverse transcription or provirus integration Levy, Jay A.; Mackewicz, Carl E.; Patterson, Bruce K. Journal of General Virology, Vol. 81, Issue 5 https://doi.org/10.1099/0022-1317-81-5-1261	journal	May 2000
Rapid Turnover of T Lymphocytes in SIV-Infected Rhesus Macaques Mohri, H. Science, Vol. 279, Issue 5354 https://doi.org/10.1126/science.279.5354.1223	journal	February 1998
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
Rapid Viral Decay in Simian Immunodeficiency Virus-Infected Macaques Receiving Quadruple Antiretroviral Therapy Brandin, E.; Thorstensson, R.; Bonhoeffer, S. Journal of Virology, Vol. 80, Issue 19 https://doi.org/10.1128/jvi.00394-06	journal	September 2006
A Simian Immunodeficiency Virus-Infected Macaque Model To Study Viral Reservoirs That Persist during Highly Active Antiretroviral Therapy Dinoso, J. B.; Rabi, S. A.; Blankson, J. N. Journal of Virology, Vol. 83, Issue 18 https://doi.org/10.1128/jvi.00840-09	journal	July 2009
Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8+ T-Lymphocyte Reactivity during Combination Antiretroviral Therapy in HIV-1-Infected Patients with Advanced Immunodeficiency Rinaldo, C. R.; Huang, X. -L.; Fan, Z. Journal of Virology, Vol. 74, Issue 9 https://doi.org/10.1128/jvi.74.9.4127-4138.2000	journal	May 2000
Decay Kinetics of Human Immunodeficiency Virus-Specific CD8+ T Cells in Peripheral Blood after Initiation of Highly Active Antiretroviral Therapy Casazza, J. P.; Betts, M. R.; Picker, L. J. Journal of Virology, Vol. 75, Issue 14 https://doi.org/10.1128/jvi.75.14.6508-6516.2001	journal	July 2001
In a Subset of Subjects on Highly Active Antiretroviral Therapy, Human Immunodeficiency Virus Type 1 RNA in Plasma Decays from 50 to <5 Copies per Milliliter, with a Half-Life of 6 Months Di Mascio, M.; Dornadula, G.; Zhang, H. Journal of Virology, Vol. 77, Issue 3 https://doi.org/10.1128/jvi.77.3.2271-2275.2003	journal	February 2003
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
Residual Viremia in Treated HIV+ Individuals Conway, Jessica M.; Perelson, Alan S. PLOS Computational Biology, Vol. 12, Issue 1 https://doi.org/10.1371/journal.pcbi.1004677	journal	January 2016
The Cell Cycle Time of CD8+ T Cells Responding In Vivo Is Controlled by the Type of Antigenic Stimulus Yoon, Heesik; Kim, Taeg S.; Braciale, Thomas J. PLoS ONE, Vol. 5, Issue 11 https://doi.org/10.1371/journal.pone.0015423	journal	November 2010
Noncytolytic CD8+ Cell Mediated Antiviral Response Represents a Strong Element in the Immune Response of Simian Immunodeficiency Virus-Infected Long-Term Non-Progressing Rhesus Macaques Javed, Aneela; Leuchte, Nicole; Neumann, Berit PLOS ONE, Vol. 10, Issue 11 https://doi.org/10.1371/journal.pone.0142086	journal	November 2015
CD8+ T Cell Control of HIV—A Known Unknown Davenport, Miles P.; Petravic, Janka PLoS Pathogens, Vol. 6, Issue 1 https://doi.org/10.1371/journal.ppat.1000728	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
Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study Sáez-Cirión, Asier; Bacchus, Charline; Hocqueloux, Laurent PLoS Pathogens, Vol. 9, Issue 3 https://doi.org/10.1371/journal.ppat.1003211	journal	March 2013
Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies Rosalie, Bateson,; M., Margolis, David; J., Eron, Joseph The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/mre9-5k02	text	January 2015
HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy Goujard, Cécile; Girault, Isabelle; Rouzioux, Christine Antiviral Therapy, Vol. 17, Issue 6 https://doi.org/10.3851/imp2273	journal	January 2012
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
Numerical Optimization Nocedal, Jorge; Wright, Stephen J. Springer Series in Operations Research and Financial Engineering https://doi.org/10.1007/978-0-387-40065-5	book	January 2006
Numerical Optimization Nocedal, Jorge; Wright, Stephen J. Springer Series in Operations Research and Financial Engineering https://doi.org/10.1007/b98874	book	January 1999
Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis Ramratnam, Bharat; Bonhoeffer, Sebastian; Binley, James The Lancet, Vol. 354, Issue 9192 https://doi.org/10.1016/S0140-6736(99)02035-8	journal	November 1999
HIV dynamics: Modeling, data analysis, and optimal treatment protocols Adams, B. M.; Banks, H. T.; Davidian, M. Journal of Computational and Applied Mathematics, Vol. 184, Issue 1 https://doi.org/10.1016/j.cam.2005.02.004	journal	December 2005
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
Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells Siliciano, Janet D.; Kajdas, Joleen; Finzi, Diana Nature Medicine, Vol. 9, Issue 6 https://doi.org/10.1038/nm880	journal	May 2003
Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy Palmer, S.; Maldarelli, F.; Wiegand, A. Proceedings of the National Academy of Sciences, Vol. 105, Issue 10 https://doi.org/10.1073/pnas.0800050105	journal	March 2008
Post-treatment control of HIV infection Conway, Jessica M.; Perelson, Alan S. Proceedings of the National Academy of Sciences, Vol. 112, Issue 17 https://doi.org/10.1073/pnas.1419162112	journal	April 2015
Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies Crooks, Amanda M.; Bateson, Rosalie; Cope, Anna B. Journal of Infectious Diseases, Vol. 212, Issue 9 https://doi.org/10.1093/infdis/jiv218	journal	April 2015
Risks and benefits of structured antiretroviral drug therapy interruptions in HIV-1 infection Bonhoeffer, Sebastian; Rembiszewski, Michal; Ortiz, Gabriel M. AIDS, Vol. 14, Issue 15 https://doi.org/10.1097/00002030-200010200-00012	journal	January 2000
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
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
Rapid Viral Decay in Simian Immunodeficiency Virus-Infected Macaques Receiving Quadruple Antiretroviral Therapy Brandin, E.; Thorstensson, R.; Bonhoeffer, S. Journal of Virology, Vol. 80, Issue 19 https://doi.org/10.1128/JVI.00394-06	journal	September 2006
A Simian Immunodeficiency Virus-Infected Macaque Model To Study Viral Reservoirs That Persist during Highly Active Antiretroviral Therapy Dinoso, J. B.; Rabi, S. A.; Blankson, J. N. Journal of Virology, Vol. 83, Issue 18 https://doi.org/10.1128/JVI.00840-09	journal	July 2009
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
Decay Kinetics of Human Immunodeficiency Virus-Specific Effector Cytotoxic T Lymphocytes after Combination Antiretroviral Therapy Ogg, G. S.; Jin, X.; Bonhoeffer, S. Journal of Virology, Vol. 73, Issue 1 https://doi.org/10.1128/JVI.73.1.797-800.1999	journal	January 1999
Levels of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Effector and Memory Responses Decline after Suppression of Viremia with Highly Active Antiretroviral Therapy Kalams, Spyros A.; Goulder, Philip J.; Shea, Amy K. Journal of Virology, Vol. 73, Issue 8 https://doi.org/10.1128/JVI.73.8.6721-6728.1999	journal	August 1999
Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8+ T-Lymphocyte Reactivity during Combination Antiretroviral Therapy in HIV-1-Infected Patients with Advanced Immunodeficiency Rinaldo, C. R.; Huang, X. -L.; Fan, Z. Journal of Virology, Vol. 74, Issue 9 https://doi.org/10.1128/JVI.74.9.4127-4138.2000	journal	May 2000
Decay Kinetics of Human Immunodeficiency Virus-Specific CD8+ T Cells in Peripheral Blood after Initiation of Highly Active Antiretroviral Therapy Casazza, J. P.; Betts, M. R.; Picker, L. J. Journal of Virology, Vol. 75, Issue 14 https://doi.org/10.1128/JVI.75.14.6508-6516.2001	journal	July 2001
In a Subset of Subjects on Highly Active Antiretroviral Therapy, Human Immunodeficiency Virus Type 1 RNA in Plasma Decays from 50 to <5 Copies per Milliliter, with a Half-Life of 6 Months Di Mascio, M.; Dornadula, G.; Zhang, H. Journal of Virology, Vol. 77, Issue 3 https://doi.org/10.1128/JVI.77.3.2271-2275.2003	journal	February 2003
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
Estimation of dynamical model parameters taking into account undetectable marker values Thiébaut, Rodolphe; Guedj, Jérémie; Jacqmin-Gadda, Hélène BMC Medical Research Methodology, Vol. 6, Issue 1 https://doi.org/10.1186/1471-2288-6-38	journal	August 2006
ART Suppresses Plasma HIV-1 RNA to a Stable Set Point Predicted by Pretherapy Viremia Maldarelli, Frank; Palmer, Sarah; King, Martin S. PLoS Pathogens, Vol. 3, Issue 4 https://doi.org/10.1371/journal.ppat.0030046	journal	January 2007
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
HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy Goujard, Cécile; Girault, Isabelle; Rouzioux, Christine Antiviral Therapy, Vol. 17, Issue 6 https://doi.org/10.3851/IMP2273	journal	January 2012
Dynamics of HIV-Specific CD8 ⁺ T Lymphocytes with Changes in Viral Load Mollet, Lucile; Li, Tai-Sheng; Samri, Assia The Journal of Immunology, Vol. 165, Issue 3 https://doi.org/10.4049/jimmunol.165.3.1692	journal	August 2000

Cited By (5)

Towards multiscale modeling of the CD8 ⁺ T cell response to viral infections Baral, Subhasish; Raja, Rubesh; Sen, Pramita WIREs Systems Biology and Medicine, Vol. 11, Issue 4 https://doi.org/10.1002/wsbm.1446	journal	February 2019
Development of a quantitative relationship between CAR-affinity, antigen abundance, tumor cell depletion and CAR-T cell expansion using a multiscale systems PK-PD model Singh, Aman P.; Zheng, Xirong; Lin-Schmidt, Xiefan mAbs, Vol. 12, Issue 1 https://doi.org/10.1080/19420862.2019.1688616	journal	December 2019
Role of Dendritic Cells in Exposing Latent HIV-1 for the Kill Kristoff, Jan; Rinaldo, Charles R.; Mailliard, Robbie B. Viruses, Vol. 12, Issue 1 https://doi.org/10.3390/v12010037	journal	December 2019
Probabilistic control of HIV latency and transactivation by the Tat gene circuit Cao, Youfang; Lei, Xue; Ribeiro, Ruy M. Proceedings of the National Academy of Sciences, Vol. 115, Issue 49 https://doi.org/10.1073/pnas.1811195115	journal	November 2018
Cat and Mouse: HIV Transcription in Latency, Immune Evasion and Cure/Remission Strategies Delannoy, Aurélie; Poirier, Mikaël; Bell, Brendan Viruses, Vol. 11, Issue 3 https://doi.org/10.3390/v11030269	journal	March 2019

Similar Records

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

Journal Article · Thu Oct 19 20:00:00 EDT 2023 · Nature Communications · OSTI ID:2222620

Multi-dose Romidepsin Reactivates Replication Competent SIV in Post-antiretroviral Rhesus Macaque Controllers

Journal Article · Wed Sep 14 20:00:00 EDT 2016 · PLoS Pathogens · OSTI ID:1627913

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

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
Biological Science