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Vpx is critical for reverse transcription of the human immunodeficiency virus type 2 genome in macrophages.

ABSTRACT: The abilities of wild-type and vpx-defective human immunodeficiency virus type 2 (HIV-2) clones to synthesize viral DNA in human monocyte-derived macrophages (MDMs) and lymphocytic cells were comparatively and quantitatively evaluated. While the vpx-defective mutant directed the synthesis of viral DNA comparably to the wild-type virus and normally in lymphocytic cells, no appreciable viral DNA was detected in MDMs infected with the mutant. To substantiate this finding and to determine whether there is some specific region(s) in Vpx crucial for viral DNA synthesis in MDMs, we generated a series of site-specific point mutants of vpx and examined their phenotypes. The resultant five mutants, with no infectivity for MDMs, showed, without exception, the same defect as the vpx-defective mutant. Our results here clearly demonstrated that the entire Vpx protein is critical for reverse transcription of the HIV-2 genome in human MDMs.

SUBMITTER: Fujita M

PROVIDER: S-EPMC2493314 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Vpx is critical for reverse transcription of the human immunodeficiency virus type 2 genome in macrophages.

Fujita Mikako M Otsuka Masami M Miyoshi Masami M Khamsri Boonruang B Nomaguchi Masako M Adachi Akio A

Journal of virology 20080521 15

The abilities of wild-type and vpx-defective human immunodeficiency virus type 2 (HIV-2) clones to synthesize viral DNA in human monocyte-derived macrophages (MDMs) and lymphocytic cells were comparatively and quantitatively evaluated. While the vpx-defective mutant directed the synthesis of viral DNA comparably to the wild-type virus and normally in lymphocytic cells, no appreciable viral DNA was detected in MDMs infected with the mutant. To substantiate this finding and to determine whether th ...[more]

PMID: 18495778

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Project description:Several steps of HIV-1 replication critically depend on cholesterol. HIV infection is associated with profound changes in lipid and lipoprotein metabolism and an increased risk of coronary artery disease. Whereas numerous studies have investigated the role of anti-HIV drugs in lipodystrophy and dyslipidemia, the effects of HIV infection on cellular cholesterol metabolism remain uncharacterized. Here, we demonstrate that HIV-1 impairs ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux from human macrophages, a condition previously shown to be highly atherogenic. In HIV-1-infected cells, this effect was mediated by Nef. Transfection of murine macrophages with Nef impaired cholesterol efflux from these cells. At least two mechanisms were found to be responsible for this phenomenon: first, HIV infection and transfection with Nef induced post-transcriptional down-regulation of ABCA1; and second, Nef caused redistribution of ABCA1 to the plasma membrane and inhibited internalization of apolipoprotein A-I. Binding of Nef to ABCA1 was required for down-regulation and redistribution of ABCA1. HIV-infected and Nef-transfected macrophages accumulated substantial amounts of lipids, thus resembling foam cells. The contribution of HIV-infected macrophages to the pathogenesis of atherosclerosis was supported by the presence of HIV-positive foam cells in atherosclerotic plaques of HIV-infected patients. Stimulation of cholesterol efflux from macrophages significantly reduced infectivity of the virions produced by these cells, and this effect correlated with a decreased amount of virion-associated cholesterol, suggesting that impairment of cholesterol efflux is essential to ensure proper cholesterol content in nascent HIV particles. These results reveal a previously unrecognized dysregulation of intracellular lipid metabolism in HIV-infected macrophages and identify Nef and ABCA1 as the key players responsible for this effect. Our findings have implications for pathogenesis of both HIV disease and atherosclerosis, because they reveal the role of cholesterol efflux impairment in HIV infectivity and suggest a possible mechanism by which HIV infection of macrophages may contribute to increased risk of atherosclerosis in HIV-infected patients.

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Vpx is critical for reverse transcription of the human immunodeficiency virus type 2 genome in macrophages.

Publications

Vpx is critical for reverse transcription of the human immunodeficiency virus type 2 genome in macrophages.

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