The frequency of vaccine-induced T-cell responses does not predict the rate of acquisition after repeated intrarectal SIVmac239 challenges in MAMU-B*08 rhesus macaques

Mauricio Martins, Lucas Gonzalez-Nieto, Young C. Shin, Aline Domingues, Martin J. Gutman, Helen S. Maxwell, Diogo M. Magnani, Michael J. Ricciardi, Núria Pedreño-Lopez, Varian K. Bailey, John D. Altman, Christopher L. Parks, David B. Allison, Keisuke Ejima, Eva G. Rakasz, Saverio Capuano, Ronald Charles Desrosiers, Jeffrey D. Lifson, David Watkins

Research output: Contribution to journalArticle

Abstract

Approximately 50% of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) allele Mamu-B*08 spontaneously control chronic-phase viremia after infection with the pathogenic simian immunodeficiency virus mac239 (SIVmac239) clone. CD8 T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infected Mamu-B*08-positive (Mamu-B*08) RMs. Here we evaluated if robust vaccine-elicited CD8 T-cell responses against Vif and Nef can prevent systemic infection in Mamu-B*08 RMs following mucosal SIV challenges. Ten Mamu-B*08 RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8 T cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsy specimens. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges, and three of them remained aviremic after 3 or 4 additional challenges. The rate of SIV acquisition in the vaccinees was numerically lower (albeit not statistically significantly) than that in the controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection from those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection. IMPORTANCE It is generally accepted that the antiviral effects of vaccine-induced classical CD8 T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a lower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8 T cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection.

Original languageEnglish (US)
Article numbere01626-18
JournalJournal of Virology
Volume93
Issue number5
DOIs
StatePublished - Mar 1 2019

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Simian immunodeficiency virus
Simian Immunodeficiency Virus
Macaca mulatta
Vaccines
T-lymphocytes
vaccines
T-Lymphocytes
major histocompatibility complex
Virus Diseases
Major Histocompatibility Complex
Viremia
viremia
infection
epitopes
Epitopes
Cellular Immunity
cell-mediated immunity
Clone Cells
Infection
Alleles

Keywords

  • Human immunodeficiency virus
  • Simian immunodeficiency virus
  • Vaccines

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

The frequency of vaccine-induced T-cell responses does not predict the rate of acquisition after repeated intrarectal SIVmac239 challenges in MAMU-B*08 rhesus macaques. / Martins, Mauricio; Gonzalez-Nieto, Lucas; Shin, Young C.; Domingues, Aline; Gutman, Martin J.; Maxwell, Helen S.; Magnani, Diogo M.; Ricciardi, Michael J.; Pedreño-Lopez, Núria; Bailey, Varian K.; Altman, John D.; Parks, Christopher L.; Allison, David B.; Ejima, Keisuke; Rakasz, Eva G.; Capuano, Saverio; Desrosiers, Ronald Charles; Lifson, Jeffrey D.; Watkins, David.

In: Journal of Virology, Vol. 93, No. 5, e01626-18, 01.03.2019.

Research output: Contribution to journalArticle

Martins, M, Gonzalez-Nieto, L, Shin, YC, Domingues, A, Gutman, MJ, Maxwell, HS, Magnani, DM, Ricciardi, MJ, Pedreño-Lopez, N, Bailey, VK, Altman, JD, Parks, CL, Allison, DB, Ejima, K, Rakasz, EG, Capuano, S, Desrosiers, RC, Lifson, JD & Watkins, D 2019, 'The frequency of vaccine-induced T-cell responses does not predict the rate of acquisition after repeated intrarectal SIVmac239 challenges in MAMU-B*08 rhesus macaques', Journal of Virology, vol. 93, no. 5, e01626-18. https://doi.org/10.1128/JVI.01626-18
Martins, Mauricio ; Gonzalez-Nieto, Lucas ; Shin, Young C. ; Domingues, Aline ; Gutman, Martin J. ; Maxwell, Helen S. ; Magnani, Diogo M. ; Ricciardi, Michael J. ; Pedreño-Lopez, Núria ; Bailey, Varian K. ; Altman, John D. ; Parks, Christopher L. ; Allison, David B. ; Ejima, Keisuke ; Rakasz, Eva G. ; Capuano, Saverio ; Desrosiers, Ronald Charles ; Lifson, Jeffrey D. ; Watkins, David. / The frequency of vaccine-induced T-cell responses does not predict the rate of acquisition after repeated intrarectal SIVmac239 challenges in MAMU-B*08 rhesus macaques. In: Journal of Virology. 2019 ; Vol. 93, No. 5.
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abstract = "Approximately 50{\%} of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) allele Mamu-B*08 spontaneously control chronic-phase viremia after infection with the pathogenic simian immunodeficiency virus mac239 (SIVmac239) clone. CD8 T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infected Mamu-B*08-positive (Mamu-B*08) RMs. Here we evaluated if robust vaccine-elicited CD8 T-cell responses against Vif and Nef can prevent systemic infection in Mamu-B*08 RMs following mucosal SIV challenges. Ten Mamu-B*08 RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8 T cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsy specimens. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges, and three of them remained aviremic after 3 or 4 additional challenges. The rate of SIV acquisition in the vaccinees was numerically lower (albeit not statistically significantly) than that in the controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection from those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection. IMPORTANCE It is generally accepted that the antiviral effects of vaccine-induced classical CD8 T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a lower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8 T cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection.",
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author = "Mauricio Martins and Lucas Gonzalez-Nieto and Shin, {Young C.} and Aline Domingues and Gutman, {Martin J.} and Maxwell, {Helen S.} and Magnani, {Diogo M.} and Ricciardi, {Michael J.} and N{\'u}ria Pedre{\~n}o-Lopez and Bailey, {Varian K.} and Altman, {John D.} and Parks, {Christopher L.} and Allison, {David B.} and Keisuke Ejima and Rakasz, {Eva G.} and Saverio Capuano and Desrosiers, {Ronald Charles} and Lifson, {Jeffrey D.} and David Watkins",
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T1 - The frequency of vaccine-induced T-cell responses does not predict the rate of acquisition after repeated intrarectal SIVmac239 challenges in MAMU-B*08 rhesus macaques

AU - Martins, Mauricio

AU - Gonzalez-Nieto, Lucas

AU - Shin, Young C.

AU - Domingues, Aline

AU - Gutman, Martin J.

AU - Maxwell, Helen S.

AU - Magnani, Diogo M.

AU - Ricciardi, Michael J.

AU - Pedreño-Lopez, Núria

AU - Bailey, Varian K.

AU - Altman, John D.

AU - Parks, Christopher L.

AU - Allison, David B.

AU - Ejima, Keisuke

AU - Rakasz, Eva G.

AU - Capuano, Saverio

AU - Desrosiers, Ronald Charles

AU - Lifson, Jeffrey D.

AU - Watkins, David

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Approximately 50% of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) allele Mamu-B*08 spontaneously control chronic-phase viremia after infection with the pathogenic simian immunodeficiency virus mac239 (SIVmac239) clone. CD8 T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infected Mamu-B*08-positive (Mamu-B*08) RMs. Here we evaluated if robust vaccine-elicited CD8 T-cell responses against Vif and Nef can prevent systemic infection in Mamu-B*08 RMs following mucosal SIV challenges. Ten Mamu-B*08 RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8 T cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsy specimens. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges, and three of them remained aviremic after 3 or 4 additional challenges. The rate of SIV acquisition in the vaccinees was numerically lower (albeit not statistically significantly) than that in the controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection from those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection. IMPORTANCE It is generally accepted that the antiviral effects of vaccine-induced classical CD8 T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a lower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8 T cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection.

AB - Approximately 50% of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) allele Mamu-B*08 spontaneously control chronic-phase viremia after infection with the pathogenic simian immunodeficiency virus mac239 (SIVmac239) clone. CD8 T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infected Mamu-B*08-positive (Mamu-B*08) RMs. Here we evaluated if robust vaccine-elicited CD8 T-cell responses against Vif and Nef can prevent systemic infection in Mamu-B*08 RMs following mucosal SIV challenges. Ten Mamu-B*08 RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8 T cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsy specimens. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges, and three of them remained aviremic after 3 or 4 additional challenges. The rate of SIV acquisition in the vaccinees was numerically lower (albeit not statistically significantly) than that in the controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection from those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection. IMPORTANCE It is generally accepted that the antiviral effects of vaccine-induced classical CD8 T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a lower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8 T cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection.

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