title: High-avidity, high-IFNγ-producing CD8 T-cell responses following immune selection during HIV-1 infection.
abstract: HIV-1 mutations, which reduce or abolish CTL responses against virus-infected cells, are frequently selected in acute and chronic HIV infection. Among population HIV-1 sequences, immune selection is evident as human leukocyte antigen (HLA) allele-associated substitutions of amino acids within or near CD8 T-cell epitopes. In these cases, the non-adapted epitope is susceptible to immune recognition until an escape mutation renders the epitope less immunogenic. However, several population-based studies have independently identified HLA-associated viral changes, which lead to the formation of a new T-cell epitope, suggesting that the immune responses that these variants or 'neo-epitopes' elicit provide an evolutionary advantage to the virus rather than the host. Here, we examined the functional characteristics of eight CD8 T-cell responses that result from viral adaptation in 125 HLA-genotyped individuals with chronic HIV-1 infection. Neo-epitopes included well-characterized immunodominant epitopes restricted by common HLA alleles, and in most cases the T-cell responses against the neo-epitope showed significantly greater functional avidity and higher IFNγ production than T cells for non-adapted epitopes, but were not more cytotoxic. Neo-epitope formation and emergence of cognate T-cell response coincident with a rise in viral load was then observed in vivo in an acutely infected individual. These findings show that HIV-1 adaptation not only abrogates the immune recognition of early targeted epitopes, but may also increase immune recognition to other epitopes, which elicit immunodominant but non-protective T-cell responses. These data have implications for immunodominance associated with polyvalent vaccines based on the diversity of chronic HIV-1 sequences.
authors.affiliation: Centre for Clinical Immunology and Biomedical Statistics, Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia.
authors.forename: Niamh M
authors.initials: NM
authors.lastname: Keane
authors.forename: Steven G
authors.initials: SG
authors.lastname: Roberts
authors.forename: Coral-Ann M
authors.initials: CA
authors.lastname: Almeida
authors.forename: Tanya
authors.initials: T
authors.lastname: Krishnan
authors.forename: Abha
authors.initials: A
authors.lastname: Chopra
authors.forename: Emma
authors.initials: E
authors.lastname: Demaine
authors.forename: Rebecca
authors.initials: R
authors.lastname: Laird
authors.forename: Monika
authors.initials: M
authors.lastname: Tschochner
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Mina
authors.initials: M
authors.lastname: John
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008213:Lymphocyte Activation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019562:Viral Load
chemical_list: D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D007371:Interferon-gamma