TY - JOUR
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 A.
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 C.
AU - Lifson, Jeffrey D.
AU - Watkins, David I.
N1 - Funding Information:
This work was funded by Public Health Service grants R01 AI108421 (to D.I.W.) and R37 AI052056 (to D.I.W.) from the National Institute of Allergy and Infectious Diseases. Partial support came from federal funds from the Office of Research Infrastructure Programs (P51 OD011106) and the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E (to J.D.L.). We also acknowledge the Miami Center for AIDS Research (P30 AI073961) for its support. The International AIDS Vaccine Initiative’s work is made possible by generous support from many donors, including The Bill & Melinda Gates Foundation, the Ministry of Foreign Affairs of Denmark, Irish Aid, the Ministry of Finance of Japan, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation (NORAD), the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at www.iavi.org.
Publisher Copyright:
© 2019 American Society for Microbiology. All Rights Reserved.
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.
KW - Human immunodeficiency virus
KW - Simian immunodeficiency virus
KW - Vaccines
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U2 - 10.1128/JVI.01626-18
DO - 10.1128/JVI.01626-18
M3 - Article
C2 - 30541854
AN - SCOPUS:85061846681
VL - 93
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 5
M1 - e01626-18
ER -