title: Balance between transmitted HLA preadapted and nonassociated polymorphisms is a major determinant of HIV-1 disease progression.
abstract: HIV-1 adapts to a new host through mutations that facilitate immune escape. Here, we evaluate the impact on viral control and disease progression of transmitted polymorphisms that were either preadapted to or nonassociated with the new host's HLA. In a cohort of 169 Zambian heterosexual transmission pairs, we found that almost one-third of possible HLA-linked target sites in the transmitted virus Gag protein are already adapted, and that this transmitted preadaptation significantly reduced early immune recognition of epitopes. Transmitted preadapted and nonassociated polymorphisms showed opposing effects on set-point VL and the balance between the two was significantly associated with higher set-point VLs in a multivariable model including other risk factors. Transmitted preadaptation was also significantly associated with faster CD4 decline (<350 cells/µl) and this association was stronger after accounting for nonassociated polymorphisms, which were linked with slower CD4 decline. Overall, the relative ratio of the two classes of polymorphisms was found to be the major determinant of CD4 decline in a multivariable model including other risk factors. This study reveals that, even before an immune response is mounted in the new host, the balance of these opposing factors can significantly influence the outcome of HIV-1 infection.
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30322.
authors.forename: Daniela C
authors.identifier: 0000-0002-3807-3534
authors.initials: DC
authors.lastname: Mónaco
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30322.
authors.forename: Dario A
authors.identifier: 0000-0001-8222-8655
authors.initials: DA
authors.lastname: Dilernia
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors.forename: Andrew
authors.initials: A
authors.lastname: Fiore-Gartland
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322.
authors.forename: Tianwei
authors.identifier: 0000-0003-2502-1628
authors.initials: T
authors.lastname: Yu
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30322.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Prince
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30322.
authors.forename: Kristine K
authors.identifier: 0000-0003-2753-7329
authors.initials: KK
authors.lastname: Dennis
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233.
authors.forename: Kai
authors.identifier: 0000-0003-1721-6054
authors.initials: K
authors.lastname: Qin
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30322.
authors.forename: Malinda
authors.identifier: 0000-0002-3348-3462
authors.initials: M
authors.lastname: Schaefer
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30322.
authors.forename: Daniel T
authors.identifier: 0000-0002-2091-1456
authors.initials: DT
authors.lastname: Claiborne
authors.affiliation: Zambia-Emory HIV Research Project, Lusaka, Zambia.
authors.forename: William
authors.initials: W
authors.lastname: Kilembe
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233.
authors.forename: Jianming
authors.identifier: 0000-0003-0137-7486
authors.initials: J
authors.lastname: Tang
authors.affiliation: International AIDS Vaccine Initiative (IAVI), San Francisco, CA 94105 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94105.
authors.forename: Matt A
authors.initials: MA
authors.lastname: Price
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30322.
authors.forename: Paul
authors.identifier: 0000-0002-4441-2264
authors.initials: P
authors.lastname: Farmer
authors.affiliation: IAVI, London SW10 9NH, England, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilmour
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233.
authors.forename: Anju
authors.identifier: 0000-0003-1880-4093
authors.initials: A
authors.lastname: Bansal
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233.
authors.forename: Paul
authors.initials: P
authors.lastname: Goepfert
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30322 Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 ehunte4@emory.edu.
authors.forename: Eric
authors.identifier: 0000-0002-4273-8631
authors.initials: E
authors.lastname: Hunter
mesh_terms: D000222:Adaptation, Physiological / Q000276:immunology*; D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018450:Disease Progression; D000939:Epitopes / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007109:Immunity; D008297:Male; D008954:Models, Biological; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019562:Viral Load / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D054301:gag Gene Products, Human Immunodeficiency Virus