Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses.
Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control.
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
Gemma
G
Hancock
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
Hongbing
H
Yang
Faculty of Medicine, University of Toronto, Toronto, Canada.
Elisabeth
E
Yorke
Department of Sexual Health, Royal Berkshire NHS Foundation Trust, Reading, United Kingdom.
Emma
E
Wainwright
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Victoria
V
Bourne
Departments of Molecular Genetics and Microbiology, Surgery, Immunology, and Duke Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America.
Alyse
A
Frisbee
Departments of Molecular Genetics and Microbiology, Surgery, Immunology, and Duke Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America.
Tamika L
TL
Payne
Departments of Molecular Genetics and Microbiology, Surgery, Immunology, and Duke Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America.
Mark
M
Berrong
Departments of Molecular Genetics and Microbiology, Surgery, Immunology, and Duke Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America.
Guido
G
Ferrari
Institute of Infectious Diseases and Molecular Medicine & Division of Medical Virology, University of Cape Town, Cape Town, South Africa.
Denis
D
Chopera
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Tomas
T
Hanke
Irsicaixa AIDS Research Institute-HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain.
Beatriz
B
Mothe
Irsicaixa AIDS Research Institute-HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Christian
C
Brander
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
M Juliana
MJ
McElrath
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Andrew
A
McMichael
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
Nilu
N
Goonetilleke
Departments of Molecular Genetics and Microbiology, Surgery, Immunology, and Duke Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America.
Georgia D
GD
Tomaras
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Nicole
N
Frahm
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
Lucy
L
Dorrell
D016915:AIDS Vaccines / Q000276:immunology / Q000627:therapeutic use*; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000473:pathology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D016056:Immunodominant Epitopes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D014611:Vaccination; D019562:Viral Load / Q000276:immunology; D055815:Young Adult
D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes