title: Multilayered defense in HLA-B51-associated HIV viral control.
abstract: Polymorphism in the HLA region of a chromosome is the major source of host genetic variability in HIV-1 outcome, but there is limited understanding of the mechanisms underlying the beneficial effect of protective class I alleles such as HLA-B57, -B27, and -B51. Taking advantage of a unique cohort infected with clade B' HIV-1 through contaminated blood, in which many variables such as the length of infection, the infecting viral strain, and host genetic background are controlled, we performed a comprehensive study to understand HLA-B51-associated HIV-1 control. We focused on the T cell responses against three dominant HLA-B51-restricted epitopes: Gag327-345(NI9) NANPDCKTI, Pol743-751(LI9) LPPVVAKEI, and Pol283-289(TI8) TAFTIPSI. Mutations in all three dominant epitopes were significantly associated with HLA-B51 in the cohort. A clear hierarchy in selection of epitope mutations was observed through epitope sequencing. L743I in position 1 of epitope LI9 was seen in most B51(+) individuals, followed by V289X in position 8 of the TI8, and then, A328S, in position 2 of the NI9 epitope, was also seen in some B51(+) individuals. Good control of viral load and higher CD4(+) counts were significantly associated with at least one detectable T cell response to unmutated epitopes, whereas lower CD4(+) counts and higher viral loads were observed in patients who had developed escape mutations in all three epitopes or who lacked T cell responses specific to these epitope(s). We propose that patients with HLA-B51 benefit from having multiple layers of effective defense against the development of immune escape mutations.
authors.affiliation: Beijing You An Hospital, Capital Medical University, Beijing 100069, People's Republic of China.
authors.forename: YongHong
authors.initials: Y
authors.lastname: Zhang
authors.forename: YanChun
authors.initials: Y
authors.lastname: Peng
authors.forename: HuiPing
authors.initials: H
authors.lastname: Yan
authors.forename: Keyi
authors.initials: K
authors.lastname: Xu
authors.forename: Masumichi
authors.initials: M
authors.lastname: Saito
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: XinYue
authors.initials: X
authors.lastname: Chen
authors.forename: Srinika
authors.initials: S
authors.lastname: Ranasinghe
authors.forename: Nozomi
authors.initials: N
authors.lastname: Kuse
authors.forename: Tim
authors.initials: T
authors.lastname: Powell
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: WeiHua
authors.initials: W
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Xia
authors.initials: X
authors.lastname: Feng
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Leligdowicz
authors.forename: XiaoNing
authors.initials: X
authors.lastname: Xu
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Andrew
authors.initials: A
authors.lastname: McMichael
authors.forename: Sarah
authors.initials: S
authors.lastname: Rowland-Jones
authors.forename: Tao
authors.initials: T
authors.lastname: Dong
mesh_terms: D002999:Clone Cells; D015331:Cohort Studies; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics / Q000502:physiology*; D059949:HLA-B51 Antigen; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D059949:HLA-B51 Antigen; D016056:Immunodominant Epitopes; D054301:gag Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus