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https://www.arca.fiocruz.br/handle/icict/14437
VACCINE-INDUCED SIMIAN IMMUNODEFICIENCY VIRUS-SPECIFIC CD8 TCELL RESPONSES FOCUSED ON A SINGLE NEF EPITOPE SELECT FOR ESCAPE VARIANTS SHORTLY AFTER INFECTION
Author
Martins, Maurício A.
Tully, Damien C.
Cruz, Michael A.
Power, Karen A.
Santana, Marlon G. Veloso de
Bean, David J.
Ogilvie, Colin B.
Gadgil, Rujuta
Lima, Noemia S.
Magnani, Diogo M.
Ejima, Keisuke
Allison, David B.
Platak Jr., Michael
Altman, John D.
Parks, Christopher L.
Rakasz, Eva G.
Capuano III, Saverio
Galler, Ricardo
Bonaldo, Myrna C.
Lifson, Jeffrey D.
Allen, Todd M.
Watkins, David I.
Tully, Damien C.
Cruz, Michael A.
Power, Karen A.
Santana, Marlon G. Veloso de
Bean, David J.
Ogilvie, Colin B.
Gadgil, Rujuta
Lima, Noemia S.
Magnani, Diogo M.
Ejima, Keisuke
Allison, David B.
Platak Jr., Michael
Altman, John D.
Parks, Christopher L.
Rakasz, Eva G.
Capuano III, Saverio
Galler, Ricardo
Bonaldo, Myrna C.
Lifson, Jeffrey D.
Allen, Todd M.
Watkins, David I.
Affilliation
University of Miami. Department of Pathology. Miami, FL, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
University of Miami. Department of Pathology. Miami, FL, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
University of Miami. Department of Pathology. Miami, FL, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular de Flavivírus. Rio de Janeiro, RJ, Brasil.
University of Miami. Department of Pathology. Miami, FL, USA.
University of Alabama. Department of Biostatistics. Section on Statistical Genetics. Birmingham, AL, USA.
University of Alabama. Department of Biostatistics. Section on Statistical Genetics. Birmingham, AL, USA.
Frederick National Laboratory. Leidos Biomedical Research, Inc. AIDS and Cancer Virus Program. Frederick, MD, USA.
Emory University. Department of Microbiology and Immunology. Atlanta, GA, USA.
Brooklyn Army Terminal. AIDS Vaccine Design and Development Laboratory. International AIDS Vaccine Initiative. Brooklyn, NY, USA.
University of Wisconsin-Madison. Wisconsin National Primate Research Center. Madison, WI, USA.
University of Wisconsin-Madison. Wisconsin National Primate Research Center. Madison, WI, USA.
Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular de Flavivírus. Rio de Janeiro, RJ, Brasil.
Frederick National Laboratory. Leidos Biomedical Research, Inc. AIDS and Cancer Virus Program. Frederick, MD, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
University of Miami. Department of Pathology. Miami, FL, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
University of Miami. Department of Pathology. Miami, FL, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
University of Miami. Department of Pathology. Miami, FL, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular de Flavivírus. Rio de Janeiro, RJ, Brasil.
University of Miami. Department of Pathology. Miami, FL, USA.
University of Alabama. Department of Biostatistics. Section on Statistical Genetics. Birmingham, AL, USA.
University of Alabama. Department of Biostatistics. Section on Statistical Genetics. Birmingham, AL, USA.
Frederick National Laboratory. Leidos Biomedical Research, Inc. AIDS and Cancer Virus Program. Frederick, MD, USA.
Emory University. Department of Microbiology and Immunology. Atlanta, GA, USA.
Brooklyn Army Terminal. AIDS Vaccine Design and Development Laboratory. International AIDS Vaccine Initiative. Brooklyn, NY, USA.
University of Wisconsin-Madison. Wisconsin National Primate Research Center. Madison, WI, USA.
University of Wisconsin-Madison. Wisconsin National Primate Research Center. Madison, WI, USA.
Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular de Flavivírus. Rio de Janeiro, RJ, Brasil.
Frederick National Laboratory. Leidos Biomedical Research, Inc. AIDS and Cancer Virus Program. Frederick, MD, USA.
Ragon Institute of MGH, MIT and Harvard. Cambridge, MA, USA.
University of Miami. Department of Pathology. Miami, FL, USA.
Abstract
Certain major histocompatibility complex class I (MHC-I) alleles (e.g., HLA-B*27) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed "elite controllers" [ECs]). Likewise, Mamu-B*08 expression also predisposes rhesus macaques to control simian immunodeficiency virus (SIV) replication. Given the similarities between Mamu-B*08 and HLA-B*27, SIV-infected Mamu-B*08(+) animals provide a model to investigate HLA-B*27-mediated elite control. We have recently shown that vaccination with three immunodominant Mamu-B*08-restricted epitopes (Vif RL8, Vif RL9, and Nef RL10) increased the incidence of elite control in Mamu-B*08(+) macaques after challenge with the pathogenic SIVmac239 clone. Furthermore, a correlate analysis revealed that CD8(+) T cells targeting Nef RL10 was correlated with improved outcome. Interestingly, this epitope is conserved between SIV and HIV-1 and exhibits a delayed and atypical escape pattern. These features led us to postulate that a monotypic vaccine-induced Nef RL10-specific CD8(+) T-cell response would facilitate the development of elite control in Mamu-B*08(+) animals following repeated intrarectal challenges with SIVmac239. To test this, we vaccinated Mamu-B*08(+) animals with nef inserts in which Nef RL10 was either left intact (group 1) or disrupted by mutations (group 2). Although monkeys in both groups mounted Nef-specific cellular responses, only those in group 1 developed Nef RL10-specific CD8(+) T cells. These vaccine-induced effector memory CD8(+) T cells did not prevent infection. Escape variants emerged rapidly in the group 1 vaccinees, and ultimately, the numbers of ECs were similar in groups 1 and 2. High-frequency vaccine-induced CD8(+) T cells focused on a single conserved epitope and therefore did not prevent infection or increase the incidence of elite control in Mamu-B*08(+) macaques.
IMPORTANCE:
Since elite control of chronic-phase viremia is a classic example of an effective immune response against HIV/SIV, elucidating the basis of this phenomenon may provide useful insights into how to elicit such responses by vaccination. We have previously established that vaccine-induced CD8(+) T-cell responses against three immunodominant epitopes can increase the incidence of elite control in SIV-infected Mamu-B*08(+) rhesus macaques—a model of HLA-B*27-mediated elite control. Here, we investigated whether a monotypic vaccine-induced CD8(+) T-cell response targeting the conserved "late-escaping" Nef RL10 epitope can increase the incidence of elite control in Mamu-B*08(+) monkeys. Surprisingly, vaccine-induced Nef RL10-specific CD8(+) T cells selected for variants within days after infection and, ultimately, did not facilitate the development of elite control. Elite control is, therefore, likely to involve CD8(+) T-cell responses against more than one epitope. Together, these results underscore the complexity and multidimensional nature of virologic control of lentivirus infection.
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