Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human CD14+ peripheral blood monocytes from HIV patients vs uninfected controls suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons

ABSTRACT: The effect of human immunodeficiency virus (HIV) infection and high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated levels of spontaneous production of some or all of the monocyte proinflammatory cytokines measured (interleukin-1beta [IL-1beta], IL-6, and tumor necrosis factor alpha [TNF-alpha]) compared to uninfected controls. In patients on therapy with high frequencies of monocytes producing proinflammatory cytokines, this frequency was diminished in the context of viremia during an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culture with autologous CD4(+) T cells or monocytes from an on-therapy time point or lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated type I interferon-stimulated gene transcripts. The addition of exogenous alpha 2A interferon diminished the spontaneous production of IL-1beta, IL-6, and TNF-alpha but did not affect responses to LPS, recapitulating the changes observed for HIV-viremic patients. These results suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons. This effect on monocytes during viremia may play a role in diminished innate or adaptive immune system functions in HIV-infected patients. In addition, the restoration of these functions may also play a role in some immune reconstitution syndromes observed during initiation of therapy.

ORGANISM(S): Homo sapiens

DISEASE(S): aviremic HIV

SUBMITTER: Richard Lempicki

PROVIDER: E-GEOD-5220 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Diminished production of monocyte proinflammatory cytokines during human immunodeficiency virus viremia is mediated by type I interferons.

Tilton John C JC Johnson Alison J AJ Luskin Marlise R MR Manion Maura M MM Yang Jun J Adelsberger Joseph W JW Lempicki Richard A RA Hallahan Claire W CW McLaughlin Mary M Mican Joann M JM Metcalf Julia A JA Iyasere Christiana C Connors Mark M

Journal of virology 20060927 23

The effect of human immunodeficiency virus (HIV) infection and high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated levels of spontaneous production of some or all of the monocyte proinflammatory cytokines measured (interleukin-1beta [IL-1beta], IL-6, and tumor necrosis factor alpha [TNF-alpha]) compared to uninfected controls. In patients on therapy with high frequencies of monocytes producing proinflammatory cytokines, this frequency was ...[more]

PMID: 17005663

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Project description:NYVAC, a highly attenuated, replication-restricted poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the poxvirus genome is an attractive strategy for improving the immunogenic properties of poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade C env, gag, pol, and nef genes (NYVAC-C) with single or double deletions of genes encoding type I (B19R) or type II (B8R) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with the B19R deletion (NYVAC-C- B19R), or NYVAC-C with B8R and B19R deletions (NYVAC-C- B8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C- B19R and NYVAC-C- B8RB19R than with NYVAC-C. Deletion of B8R and B19R resulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C- B8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF-], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C- B19R as well as a strong inflammasome response (caspase-1 and IL-1 ) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion of B8R and B19R was organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C- B8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4 T cell response than monocytes infected with NYVAC-C or NYVAC-C- B19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1 and make it an attractive candidate HIV vaccine vector. Primary Human monocytes from 5 donors were incubated with each following vectors nyvacdb, nyvadb19r, nyvaccdb8rb19r_6h, untreated control and collected at 6h.

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Dataset Information

Transcription profiling of human CD14+ peripheral blood monocytes from HIV patients vs uninfected controls suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons

Publications

Diminished production of monocyte proinflammatory cytokines during human immunodeficiency virus viremia is mediated by type I interferons.

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