title: Identification of a potential pharmacological sanctuary for HIV type 1 in a fraction of CD4(+) primary cells.
abstract: We have identified a subset of HIV-susceptible CD4(+)CCR5(+) cells in human PBMCs that can efficiently exclude protease inhibitors (PI) due to high P-glycoprotein (P-gp) efflux activity. Phenotypically these cells are heterogeneous, include both T and non-T cells, and some display markers of memory cells. Cells with high P-gp represent 16-56% (median = 37.3) of all CD4(+)CCR5(+) cells in healthy donors, and are selectively depleted in HIV-1-infected individuals (4.1-33%, median = 10.1). A fraction of primary cells productively infected by HIV-1, in vitro, have high P-gp pump activity, demonstrating that infection does not inhibit P-gp function. In agreement with these data, HIV-susceptible cells expressing high levels of P-gp require higher levels of PI for complete inhibition of virus spread. We conclude that the PI concentrations achieved in plasma could be suboptimal for full inhibition of virus spread in high P-gp cells, indicating that they may represent a pharmacological sanctuary for HIV-1.
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute-Frederick, Maryland 21702-1201, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Valentin
authors.forename: Matthew
authors.initials: M
authors.lastname: Morrow
authors.forename: Richard H
authors.initials: RH
authors.lastname: Poirier
authors.forename: Karen
authors.initials: K
authors.lastname: Aleman
authors.forename: Richard
authors.initials: R
authors.lastname: Little
authors.forename: Robert
authors.initials: R
authors.lastname: Yarchoan
authors.forename: George N
authors.initials: GN
authors.lastname: Pavlakis
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001693:Biological Transport, Active; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors