title: Targeting of a CD8 T cell env epitope presented by HLA-B*5802 is associated with markers of HIV disease progression and lack of selection pressure.
abstract: In HIV-infected persons, certain HLA class I alleles are associated with effective control of viremia, while others are associated with rapid disease progression. Among the most divergent clinical outcomes are the relatively good prognosis in HLA-B*5801 expressing persons and poor prognosis with HLA-B*5802. These two alleles differ by only three amino acids in regions involved in HLA-peptide recognition. This study evaluated a cohort of over 1000 persons with chronic HIV clade C virus infection to determine whether clinical outcome differences associated with B*5801 (n = 93) and B*5802 ( n = 259) expression are associated with differences in HIV-1-specific CD8 (+) T cell responses. The overall breadth and magnitude of HIV-1-specific CD8(+) T cell responses were lower in persons expressing B*5802, and epitope presentation by B*5802 contributed significantly less to the overall response as compared to B*5801-restricted CD8 (+) T cells. Moreover, viral load in B*5802-positive persons was higher and CD4 cell counts lower when this allele contributed to the overall CD8 (+) T cell response, which was detected exclusively through a single epitope in Env. In addition, persons heterozygous for B*5802 compared to persons homozygous for other HLA-B alleles had significantly higher viral loads. Viral sequencing revealed strong selection pressure mediated through B*5801-restricted responses but not through B*5802. These data indicate that minor differences in HLA sequence can have a major impact on epitope recognition, and that selective targeting of Env through HLA-B*5802 is at least ineffectual if not actively adverse in the containment of viremia. These results provide experimental evidence that not all epitope-specific responses contribute to immune containment, a better understanding of which is essential to shed light on mechanisms involved in HIV disease progression.
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Durban 4013, South Africa.
authors.forename: K C
authors.initials: KC
authors.lastname: Ngumbela
authors.forename: C L
authors.initials: CL
authors.lastname: Day
authors.forename: Z
authors.initials: Z
authors.lastname: Mncube
authors.forename: K
authors.initials: K
authors.lastname: Nair
authors.forename: D
authors.initials: D
authors.lastname: Ramduth
authors.forename: C
authors.initials: C
authors.lastname: Thobakgale
authors.forename: E
authors.initials: E
authors.lastname: Moodley
authors.forename: S
authors.initials: S
authors.lastname: Reddy
authors.forename: C
authors.initials: C
authors.lastname: de Pierres
authors.forename: N
authors.initials: N
authors.lastname: Mkhwanazi
authors.forename: K
authors.initials: K
authors.lastname: Bishop
authors.forename: M
authors.initials: M
authors.lastname: van der Stok
authors.forename: N
authors.initials: N
authors.lastname: Ismail
authors.forename: I
authors.initials: I
authors.lastname: Honeyborne
authors.forename: H
authors.initials: H
authors.lastname: Crawford
authors.forename: D G
authors.initials: DG
authors.lastname: Kavanagh
authors.forename: C
authors.initials: C
authors.lastname: Rousseau
authors.forename: D
authors.initials: D
authors.lastname: Nickle
authors.forename: J
authors.initials: J
authors.lastname: Mullins
authors.forename: D
authors.initials: D
authors.lastname: Heckerman
authors.forename: B
authors.initials: B
authors.lastname: Korber
authors.forename: H
authors.initials: H
authors.lastname: Coovadia
authors.forename: P
authors.initials: P
authors.lastname: Kiepiela
authors.forename: P J R
authors.initials: PJ
authors.lastname: Goulder
authors.forename: B D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D018450:Disease Progression; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015686:Gene Products, env / Q000737:chemistry / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D015235:HLA-B Antigens / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D019562:Viral Load
chemical_list: D018984:Epitopes, T-Lymphocyte; D015686:Gene Products, env; D015235:HLA-B Antigens; C500126:HLA-B*58:01 antigen