title: Genetic and stochastic influences on the interaction of human immunodeficiency virus type 1 and cytotoxic T lymphocytes in identical twins.
abstract: Human immunodeficiency virus type 1 (HIV-1) evolves in vivo under selective pressure from CD8+ T-lymphocyte (CTL) responses, which are in turn determined by host and viral genetic factors, such as restricting major histocompatibility complex molecules and the available viral epitope sequences. However, CTL are derived stochastically through the random gene rearrangements to produce T-cell receptors (TCR), and the relative impact of genetic versus stochastic processes on CTL targeting of HIV and immune-driven viral evolution is unclear. Here we evaluate identical twins infected with HIV-1 as neonates from a common blood transfusion, with subsequently similar environmental exposures, thereby allowing controlled comparisons of CTL targeting and viral evolution. Seventeen years after infection, their CTL targeting of HIV-1 was remarkably similar. In contrast, their overall TCR profiles were highly dissimilar, and a dominant epitope was recognized by distinctly different TCR in each twin. Furthermore, their viral epitopes had diverged, and there was ongoing viral phylogenetic divergence between the twins between 12 and 17 years after infection. These results indicate that while CTL targeting is predominately genetically determined, stochastic influences render the interaction of HIV-1 and host immunity, and therefore viral escape and CTL efficacy, unpredictable.
authors.affiliation: UCLA AIDS Institute and Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. oyang@mednet.ucla.edu
authors.forename: Otto O
authors.initials: OO
authors.lastname: Yang
authors.forename: Joseph
authors.initials: J
authors.lastname: Church
authors.forename: Christina M R
authors.initials: CM
authors.lastname: Kitchen
authors.forename: Ryan
authors.initials: R
authors.lastname: Kilpatrick
authors.forename: Ayub
authors.initials: A
authors.lastname: Ali
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Geng
authors.forename: M Scott
authors.initials: MS
authors.lastname: Killian
authors.forename: Rachel Lubong
authors.initials: RL
authors.lastname: Sabado
authors.forename: Hwee
authors.initials: H
authors.lastname: Ng
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Suen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Bryson
authors.forename: Beth D
authors.initials: BD
authors.lastname: Jamieson
authors.forename: Paul
authors.initials: P
authors.lastname: Krogstad
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D006679:HIV Seropositivity / Q000276:immunology / Q000382:microbiology; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*; D014427:Twins
chemical_list: D016056:Immunodominant Epitopes