title: Multifactorial nature of noncytolytic CD8+ T cell-mediated suppression of HIV replication: beta-chemokine-dependent and -independent effects.
abstract: Chemokines were originally characterized by their ability to direct migration and induce activation of selected leukocyte populations. The beta-chemokines MIP-1 alpha, MIP-beta, and RANTES have been implicated in the suppression of viral replication by CD8+ T cells from HIV-infected individuals. The present study was undertaken to evaluate the effect of beta-chemokines on HIV replication in cocultures of dendritic cells (DCs) and CD4+ T cells, and an in vitro model of the lymphoid microenvironment. In the acute infection system, where DCs from uninfected individuals are pulsed with HIV and cocultured with autologous CD4+ T cells, no inhibition of replication of monocytotropic or T cell tropic viral isolates by MIP-1 alpha, MIP-1 beta, and RANTES, alone or in combination, was observed. In contrast, in an endogenous infection system, where the DCs and CD4+ T cells were obtained from HIV-infected subjects, addition of recombinant beta-chemokines suppressed HIV replication. However, neutralizing antibodies to beta-chemokines did not affect the suppressive activity of CD8+ T cells from HIV-infected donors in either system, suggesting that CD8+ T cell-mediated suppression is not due exclusively to beta-chemokines. Furthermore, no significant differences in secretion of MIP-1 alpha, MIP-1 beta, and RANTES by purified CD8+ T cells were noted in uninfected versus HIV-infected donors, regardless of the stage of disease. These results indicate that HIV suppression by CD8+ T cells derived from HIV-infected donors is a multifactorial phenomenon and not limited to the action of MIP-1 alpha, MIP-1 beta, and RANTES.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rubbert
authors.forename: D
authors.initials: D
authors.lastname: Weissman
authors.forename: C
authors.initials: C
authors.lastname: Combadiere
authors.forename: K A
authors.initials: KA
authors.lastname: Pettrone
authors.forename: J A
authors.initials: JA
authors.lastname: Daucher
authors.forename: P M
authors.initials: PM
authors.lastname: Murphy
authors.forename: A S
authors.initials: AS
authors.lastname: Fauci
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000821:virology; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D006801:Humans; D014779:Virus Replication / Q000276:immunology*
chemical_list: D018925:Chemokines