Rhesus Cytomegalovirus-Specific CD8+ Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 Infection
CD8+ cytotoxic T lymphocytes (CTLs) exert potent antiviral activity after HIV/SIV infection. However, efforts to harness the antiviral efficacy of CTLs for HIV/SIV prophylaxis and therapy have been severely hindered by two major problems: viral escape and exhaustion. By contrast, CTLs directed again...
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01960/full |
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| author | Brandon C. Rosen Brandon C. Rosen Nuria Pedreño-Lopez Michael J. Ricciardi Jason S. Reed Jason S. Reed Jonah B. Sacha Jonah B. Sacha Eva G. Rakasz David I. Watkins |
| author_facet | Brandon C. Rosen Brandon C. Rosen Nuria Pedreño-Lopez Michael J. Ricciardi Jason S. Reed Jason S. Reed Jonah B. Sacha Jonah B. Sacha Eva G. Rakasz David I. Watkins |
| author_sort | Brandon C. Rosen |
| collection | DOAJ |
| description | CD8+ cytotoxic T lymphocytes (CTLs) exert potent antiviral activity after HIV/SIV infection. However, efforts to harness the antiviral efficacy of CTLs for HIV/SIV prophylaxis and therapy have been severely hindered by two major problems: viral escape and exhaustion. By contrast, CTLs directed against human cytomegalovirus (HCMV), a ubiquitous chronic herpesvirus, seldom select for escape mutations and remain functional and refractory to exhaustion during chronic HCMV and HIV infection. Recently, attempts have been made to retarget HCMV-specific CTLs for cancer immunotherapy. We speculate that such a strategy may also be beneficial in the context of HIV/SIV infection, facilitating CTL-mediated control of HIV/SIV replication. As a preliminary assessment of the validity of this approach, we investigated the phenotypes and functionality of rhesus CMV (RhCMV)-specific CTLs in SIVmac239-infected Indian rhesus macaques (RMs), a crucial HIV animal model system. We recently identified two immunodominant, Mamu-A∗02-restricted CTL epitopes derived from RhCMV proteins and sought to evaluate the phenotypic and functional characteristics of these CTL populations in chronic SIVmac239 infection. We analyzed and directly compared RhCMV- and SIVmac239-specific CTLs during SIVmac239 infection in a cohort of Mamu-A∗01+ and Mamu-A∗02+ RMs. CTL populations specific for at least one of the RhCMV-derived CTL epitopes were detected in ten of eleven Mamu-A∗02+ animals tested, and both populations were detected in five of these animals. Neither RhCMV-specific CTL population exhibited significant changes in frequency, memory phenotype, granzyme B expression, exhaustion marker (PD-1 and CTLA-4) expression, or polyfunctionality between pre- and chronic SIVmac239 infection timepoints. In chronic SIVmac239 infection, RhCMV-specific CTLs exhibited higher levels of granzyme B expression and polyfunctionality, and lower levels of exhaustion marker expression, than SIVmac239-specific CTLs. Additionally, compared to SIVmac239-specific CTLs, greater proportions of RhCMV-specific CTLs were of the terminally differentiated effector memory phenotype (CD28– CCR7–) during chronic SIVmac239 infection. These results suggest that, in contrast to SIVmac239-specific CTLs, RhCMV-specific CTLs maintain their phenotypes and cytolytic effector functions during chronic SIVmac239 infection, and that retargeting RhCMV-specific CTLs might be a promising SIV immunotherapeutic strategy. |
| first_indexed | 2024-12-13T00:31:40Z |
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| last_indexed | 2024-12-13T00:31:40Z |
| publishDate | 2020-08-01 |
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| spelling | doaj.art-134aa1a3a121485ab813ba24be22cd4c2022-12-22T00:05:18ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-08-011110.3389/fimmu.2020.01960570737Rhesus Cytomegalovirus-Specific CD8+ Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 InfectionBrandon C. Rosen0Brandon C. Rosen1Nuria Pedreño-Lopez2Michael J. Ricciardi3Jason S. Reed4Jason S. Reed5Jonah B. Sacha6Jonah B. Sacha7Eva G. Rakasz8David I. Watkins9Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL, United StatesDepartment of Pathology, University of Miami Miller School of Medicine, Miami, FL, United StatesDepartment of Pathology, George Washington University School of Medicine, Washington, DC, United StatesDepartment of Pathology, George Washington University School of Medicine, Washington, DC, United StatesVaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, United StatesOregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, United StatesVaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, United StatesOregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, United StatesWisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, United StatesDepartment of Pathology, George Washington University School of Medicine, Washington, DC, United StatesCD8+ cytotoxic T lymphocytes (CTLs) exert potent antiviral activity after HIV/SIV infection. However, efforts to harness the antiviral efficacy of CTLs for HIV/SIV prophylaxis and therapy have been severely hindered by two major problems: viral escape and exhaustion. By contrast, CTLs directed against human cytomegalovirus (HCMV), a ubiquitous chronic herpesvirus, seldom select for escape mutations and remain functional and refractory to exhaustion during chronic HCMV and HIV infection. Recently, attempts have been made to retarget HCMV-specific CTLs for cancer immunotherapy. We speculate that such a strategy may also be beneficial in the context of HIV/SIV infection, facilitating CTL-mediated control of HIV/SIV replication. As a preliminary assessment of the validity of this approach, we investigated the phenotypes and functionality of rhesus CMV (RhCMV)-specific CTLs in SIVmac239-infected Indian rhesus macaques (RMs), a crucial HIV animal model system. We recently identified two immunodominant, Mamu-A∗02-restricted CTL epitopes derived from RhCMV proteins and sought to evaluate the phenotypic and functional characteristics of these CTL populations in chronic SIVmac239 infection. We analyzed and directly compared RhCMV- and SIVmac239-specific CTLs during SIVmac239 infection in a cohort of Mamu-A∗01+ and Mamu-A∗02+ RMs. CTL populations specific for at least one of the RhCMV-derived CTL epitopes were detected in ten of eleven Mamu-A∗02+ animals tested, and both populations were detected in five of these animals. Neither RhCMV-specific CTL population exhibited significant changes in frequency, memory phenotype, granzyme B expression, exhaustion marker (PD-1 and CTLA-4) expression, or polyfunctionality between pre- and chronic SIVmac239 infection timepoints. In chronic SIVmac239 infection, RhCMV-specific CTLs exhibited higher levels of granzyme B expression and polyfunctionality, and lower levels of exhaustion marker expression, than SIVmac239-specific CTLs. Additionally, compared to SIVmac239-specific CTLs, greater proportions of RhCMV-specific CTLs were of the terminally differentiated effector memory phenotype (CD28– CCR7–) during chronic SIVmac239 infection. These results suggest that, in contrast to SIVmac239-specific CTLs, RhCMV-specific CTLs maintain their phenotypes and cytolytic effector functions during chronic SIVmac239 infection, and that retargeting RhCMV-specific CTLs might be a promising SIV immunotherapeutic strategy.https://www.frontiersin.org/article/10.3389/fimmu.2020.01960/fullsimian immunodeficiency viruscytotoxic T lymphocytescytomegalovirusrhesus macaqueshuman immunodeficiency virus |
| spellingShingle | Brandon C. Rosen Brandon C. Rosen Nuria Pedreño-Lopez Michael J. Ricciardi Jason S. Reed Jason S. Reed Jonah B. Sacha Jonah B. Sacha Eva G. Rakasz David I. Watkins Rhesus Cytomegalovirus-Specific CD8+ Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 Infection Frontiers in Immunology simian immunodeficiency virus cytotoxic T lymphocytes cytomegalovirus rhesus macaques human immunodeficiency virus |
| title | Rhesus Cytomegalovirus-Specific CD8+ Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 Infection |
| title_full | Rhesus Cytomegalovirus-Specific CD8+ Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 Infection |
| title_fullStr | Rhesus Cytomegalovirus-Specific CD8+ Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 Infection |
| title_full_unstemmed | Rhesus Cytomegalovirus-Specific CD8+ Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 Infection |
| title_short | Rhesus Cytomegalovirus-Specific CD8+ Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 Infection |
| title_sort | rhesus cytomegalovirus specific cd8 cytotoxic t lymphocytes do not become functionally exhausted in chronic sivmac239 infection |
| topic | simian immunodeficiency virus cytotoxic T lymphocytes cytomegalovirus rhesus macaques human immunodeficiency virus |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01960/full |
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