title: Innate immune dysfunction in HIV infection: effect of HIV envelope-NK cell interactions.
abstract: We have previously described a number of NK cell dysfunctions in HIV-viremic individuals. In the present study, we performed DNA microarray analysis followed by phenotypic and functional characterization in an effort to investigate which HIV envelope glycoproteins (gp120) affect the physiologic functions of NK cells. Upon treatment of NK cells with HIV gp120, DNA microarray analyses indicated up-regulation of several categories of genes that are associated with apoptosis, suppression of both cellular proliferation and survival, as well as down-regulation of genes that play a vital role in cell proliferation, innate immune defense mechanism, and cell survival. Both subtypes of gp120 suppressed NK cell cytotoxicity, proliferation, and the ability to secrete IFN-gamma. NK cells exposed to X4-subtype HIV gp120 showed a significant decrease in the levels of CC chemokines, while exposure to R5-subtype HIV gp120 had minimal effect. Extended exposure to HIV gp120 resulted in apoptosis of NK cells, further validating the microarray data. Our data demonstrate that exposure of NK cells to HIV envelope proteins results in profound cellular abnormalities at the level of gene expression as well as generic cell functions. These findings are likely to be a consequence of a direct HIV gp120-mediated effect on NK cells. Identification of specific surface receptors on NK cells that interact with HIV envelope proteins might explain how HIV is capable of circumventing innate immune defense mechanisms and establishing infection in susceptible individuals.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Skottilil@niaid.nih.gov
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Shin
authors.forename: Julia O
authors.initials: JO
authors.lastname: Jackson
authors.forename: Kristin N
authors.initials: KN
authors.lastname: Reitano
authors.forename: Marie Angeline
authors.initials: MA
authors.lastname: O'Shea
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Claire W
authors.initials: CW
authors.lastname: Hallahan
authors.forename: Richard
authors.initials: R
authors.lastname: Lempicki
authors.forename: James
authors.initials: J
authors.lastname: Arthos
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
mesh_terms: D017209:Apoptosis; D019742:Chemokines, CC / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D020869:Gene Expression Profiling; D015699:HIV Envelope Protein gp120 / Q000145:classification / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000145:classification / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D019742:Chemokines, CC; D016207:Cytokines; D015699:HIV Envelope Protein gp120