title: Sexual transmission of single human immunodeficiency virus type 1 virions encoding highly polymorphic multisite cytotoxic T-lymphocyte escape variants.
abstract: Antigenic variation inherent in human immunodeficiency virus type 1 (HIV-1) virions that successfully instigate new infections transferred by sex has not been well defined. Yet this is the viral "challenge" which any vaccine-induced immunity must deal with. Closely timed comparisons of the virus circulating in the "donor" and that which initiates new infection are difficult to carry out rigorously, as suitable samples are very hard to get in the face of ethical hurdles. Here we investigate HIV-1 variation in four homosexual couples where we sampled blood from both parties within several weeks of the estimated transmission event. We analyzed variation within highly immunogenic HIV-1 internal proteins encoding epitopes recognized by cytotoxic T lymphocytes (CTLs). These responses are believed to be crucial as a means of containing viral replication. In the donors we detected virions capable of evading host CTL recognition at several linked epitopes of distinct HLA class I restriction. When a donor transmitted escape variants to a recipient with whom he had HLA class I molecules in common, the recipient's CTL response to those epitopes was prevented, thus impeding adequate viral control. In addition, we show that even when HLA class I alleles are disparate in the transmitting couple, a single polymorphism can abolish CTL recognition of an overlapping epitope of distinct restriction and so confer immune escape properties to the recipient's seroconversion virus. In donors who are themselves controlling an early, acute infection, the precise timing of onward transmission is a crucial determinant of the viral variants available to compose the inoculum.
authors.affiliation: The Peter Medawar Building for Pathogen Research and The James Martin 21st Century School, Nuffield Department of Clinical Medicine, University of Oxford, South Parks Road, Oxford OX1 3SY, United Kingdom
authors.forename: Anita
authors.initials: A
authors.lastname: Milicic
authors.forename: Charles T T
authors.initials: CT
authors.lastname: Edwards
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hué
authors.forename: Julie
authors.initials: J
authors.lastname: Fox
authors.forename: Helen
authors.initials: H
authors.lastname: Brown
authors.forename: Tilly
authors.initials: T
authors.lastname: Pillay
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Weber
authors.forename: Edward C
authors.initials: EC
authors.lastname: Holmes
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Fidler
authors.forename: Hua-Tang
authors.initials: HT
authors.lastname: Zhang
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Phillips
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000635:transmission*; D000595:Amino Acid Sequence; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000635:transmission*; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity*; D006680:HLA Antigens / Q000276:immunology; D018451:Homosexuality, Male; D006801:Humans; D008297:Male; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012749:Sexually Transmitted Diseases / Q000276:immunology / Q000635:transmission / Q000821:virology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014771:Virion / Q000276:immunology / Q000472:pathogenicity
chemical_list: D000939:Epitopes; D006680:HLA Antigens