title: Impaired viral entry cannot explain reduced CD4+ T cell susceptibility to HIV type 1 in certain highly exposed individuals.
abstract: Rare individuals report repeated unprotected HIV-1 sexual exposures, yet remain seronegative for years. We investigated the possibility that reduced in vitro CD4(+) T cell susceptibility to HIV-1 infection protects such highly exposed seronegative (ES) individuals. Susceptibility to three R5-tropic HIV-1 isolates, regardless of inoculating dose, was remarkably similar between 81 ES and 33 low-risk controls. In 94% (99/105) of donors, we observed a 1.36 log-unit range in HIV-1(JR-CSF) production, with similar results for HIV-1(1192). The median frequency of intracellular Gag(+) T cells after single-round infection was similar in ES (5.2%) and controls (7.2%), p = 0.456. However, in repeated testing, CD4(+) T cells from two controls (6.1%) and four ES (4.9%) exhibited a 10- to 2500-fold reduction in HIV-1 production and required 5- to 12-fold greater HIV-1(1192) and HIV-1(JR-CSF) inocula to establish infection (TCID(50)). Reduced viral entry cannot explain the low producer phenotype; no differences in CCR5 receptor density or beta-chemokine production were observed. In conclusion, we have identified a remarkably narrow range of HIV-1 susceptibility in seronegative donors regardless of risk activity, which can be applied as a benchmark to assess vaccine-induced antiviral effector activities. However, CD4(+) T cells from a subset of individuals demonstrated reduced HIV-1 susceptibility unexplained by impaired entry, lending support to the possibility that cellular restriction of HIV-1 may account for continued seronegativity in some of those having repeated sexual exposure. Identifying the host-virus interactions responsible for diminished in vitro susceptibility may contribute to the development of novel therapeutic strategies.
authors.affiliation: Medical Scientist Training Program, University of Washington, Seattle, Washington 98105, USA.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Speelmon
authors.forename: Devon
authors.initials: D
authors.lastname: Livingston-Rosanoff
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Desbien
authors.forename: Jean
authors.initials: J
authors.lastname: Lee
authors.forename: W David
authors.initials: WD
authors.lastname: Wick
authors.forename: Florian
authors.initials: F
authors.lastname: Hladik
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000821:virology*; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000096:biosynthesis; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008875:Middle Aged; D019713:Receptors, CCR5 / Q000032:analysis; D053586:Virus Internalization
chemical_list: D019742:Chemokines, CC; D019713:Receptors, CCR5