title: Superior control of HIV-1 replication by CD8+ T cells targeting conserved epitopes: implications for HIV vaccine design.
abstract: A successful HIV vaccine will likely induce both humoral and cell-mediated immunity, however, the enormous diversity of HIV has hampered the development of a vaccine that effectively elicits both arms of the adaptive immune response. To tackle the problem of viral diversity, T cell-based vaccine approaches have focused on two main strategies (i) increasing the breadth of vaccine-induced responses or (ii) increasing vaccine-induced responses targeting only conserved regions of the virus. The relative extent to which set-point viremia is impacted by epitope-conservation of CD8(+) T cell responses elicited during early HIV-infection is unknown but has important implications for vaccine design. To address this question, we comprehensively mapped HIV-1 CD8(+) T cell epitope-specificities in 23 ART-naïve individuals during early infection and computed their conservation score (CS) by three different methods (prevalence, entropy and conseq) on clade-B and group-M sequence alignments. The majority of CD8(+) T cell responses were directed against variable epitopes (p<0.01). Interestingly, increasing breadth of CD8(+) T cell responses specifically recognizing conserved epitopes was associated with lower set-point viremia (r = - 0.65, p = 0.009). Moreover, subjects possessing CD8(+) T cells recognizing at least one conserved epitope had 1.4 log10 lower set-point viremia compared to those recognizing only variable epitopes (p = 0.021). The association between viral control and the breadth of conserved CD8(+) T cell responses may be influenced by the method of CS definition and sequences used to determine conservation levels. Strikingly, targeting variable versus conserved epitopes was independent of HLA type (p = 0.215). The associations with viral control were independent of functional avidity of CD8(+) T cell responses elicited during early infection. Taken together, these data suggest that the next-generation of T-cell based HIV-1 vaccines should focus on strategies that can elicit CD8(+) T cell responses to multiple conserved epitopes of HIV-1.
authors.affiliation: Viral Vaccine Program, Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Pratima
authors.initials: P
authors.lastname: Kunwar
authors.forename: Natalie
authors.initials: N
authors.lastname: Hawkins
authors.forename: Warren L
authors.initials: WL
authors.lastname: Dinges
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Erin E
authors.initials: EE
authors.lastname: Gabriel
authors.forename: David A
authors.initials: DA
authors.lastname: Swan
authors.forename: Claire E
authors.initials: CE
authors.lastname: Stevens
authors.forename: Janine
authors.initials: J
authors.lastname: Maenza
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Tomer
authors.initials: T
authors.lastname: Hertz
authors.forename: Xuesong
authors.initials: X
authors.lastname: Yu
authors.forename: Helen
authors.initials: H
authors.lastname: Horton
mesh_terms: D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D017124:Conserved Sequence; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D018740:Genetic Heterogeneity; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000254:growth & development / Q000276:immunology*; D018451:Homosexuality, Male; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D008969:Molecular Sequence Data; D019562:Viral Load / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte