title: Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms.
abstract: Although CD8+ lymphocytes in human immunodeficiency virus type 1 (HIV-1)-infected individuals have been demonstrated to suppress viral replication, the mechanisms of inhibition have not been defined precisely. A large body of evidence indicates that these cells act via soluble inhibitory factors, but the potential role of HLA class I-restricted cytolysis has remained controversial. Here we demonstrate that HIV-1-specific cytotoxic T lymphocytes (CTL) mediate antiviral suppression by both cytolytic and noncytolytic mechanisms. The predominant mechanism requires direct contact of CTL with the infected cells, is HLA class I restricted, and can achieve complete elimination of detectable virus in infected cell cultures. Inhibition occurs even at high multiplicities of infection or at ratios of CTL to CD4 cells as low as 1:1,000. The other mechanism is mediated by soluble inhibitory factors which are triggered in an antigen-specific and HLA-restricted fashion but then act without HLA restriction. These include MIP-1alpha, MIP-1beta, and RANTES, as well as a distinct factor(s) capable of inhibiting HIV-1 strains insensitive to these chemokines. These data indicate that HIV-1-specific CTL are potent mediators of HIV-1 suppression at cell ratios existing in vivo and demonstrate an antigen-specific trigger for CD8+ cell-derived soluble inhibitory factors. These results suggest that CTL play an important role in the observed antiviral activity of CD8+ cells from infected individuals.
authors.affiliation: AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129, USA.
authors.forename: O O
authors.initials: OO
authors.lastname: Yang
authors.forename: S A
authors.initials: SA
authors.lastname: Kalams
authors.forename: A
authors.initials: A
authors.lastname: Trocha
authors.forename: H
authors.initials: H
authors.lastname: Cao
authors.forename: A
authors.initials: A
authors.lastname: Luster
authors.forename: R P
authors.initials: RP
authors.lastname: Johnson
authors.forename: B D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D015483:HIV Antibodies / Q000096:biosynthesis; D016655:HIV Core Protein p24 / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D015789:HLA-A2 Antigen / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology; D059909:HLA-B14 Antigen; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014779:Virus Replication
chemical_list: D015483:HIV Antibodies; D016655:HIV Core Protein p24; D015789:HLA-A2 Antigen; D015235:HLA-B Antigens; D059909:HLA-B14 Antigen; D015395:Histocompatibility Antigens Class I; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; C080633:macrophage inflammatory protein 1alpha receptor