HIV-1 Nef protein in the nucleus influences adipogenesis as well as viral transcription through the peroxisome proliferator-activated receptors

Otake, Kaori; Omoto, Shinya; Yamamoto, Takuya; Okuyama, Harumi; Okada, Hidechika; Okada, Noriko; Kawai, Masahiro; Saksena, Nitin K.; Fujii, Yoichi

doi:10.1097/00002030-200401230-00007

Cited by 51 publications

(27 citation statements)

References 30 publications

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“…Since Nef suppressed PPARγ expression and reduced fatty acid levels in vitro [29-32], we monitored the expression of PPARγ mRNA and body weights of mice. Significant PPARγ mRNA expression in intestinal adipose tissue of group 3, but not group 1 and 2, was detected on day 2 (Table 2).…”

Section: Resultsmentioning

confidence: 99%

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et al. 2004

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Section: Resultsmentioning

confidence: 99%

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“…Nef has also been shown to activate T cells, which increases expression of transcription factors required for viral transcription (31). Recent reports show that Nef directly acts as a positive modulator of HIV-1 LTR through different mechanisms (52,53) and also micro-RNA for nef may down-regulate HIV-1 transcription (54). In our previous study (30), we have shown that Nef enhances viral replication by interacting with its transactivator protein, Tat, and thereby modulates viral gene expression.…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Protein 40 Is Necessary for Human Immunodeficiency Virus-1 Nef-mediated Enhancement of Viral Gene Expression and Replication

Kumar¹,

Mitra

2005

Journal of Biological Chemistry

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The human immunodeficiency virus-1 (HIV-1) Nef protein, originally identified as a negative factor, has now emerged as one of the most important viral proteins necessary for viral pathogenesis and disease progression. Nef has been also implicated in viral infectivity and replication, however, the molecular mechanism of Nef-induced viral gene expression and replication is not clearly understood. Although involvement of heat shock proteins in viral pathogenesis has been reported earlier, a clear understanding of their role remains to be elucidated. Here we report for the first time that Nef not only interacts with heat shock protein 40 (Hsp40) but it also induces the expression of Hsp40 in HIV-1-infected cells. The interaction between Nef and Hsp40 is important for increased Hsp40 translocation into the nucleus of infected cells, which seems to facilitate viral gene expression by becoming part of the cyclin-dependent kinase 9-associated transcription complex regulating long terminal repeat-mediated gene expression. The finding is consistent with the failure of the nef-deleted virus to induce Hsp40, resulting in reduced virus production. Our data further shows that, whereas, Hsp40 overexpression induces viral gene expression, silencing of Hsp40 reduces the gene expression in a Nef-dependent manner. Thus our results clearly indicate that Hsp40 is crucial for Nef-mediated enhancement of viral gene expression and replication.Viruses are known to modulate cellular proteins for successful replication within the host cells. The sequence of events in the establishment of a productive infection by human immunodeficiency virus type 1 (HIV-1) 3 not only involves interaction between a number of viral and cellular factors but is also accompanied by complex and dynamic changes in the patterns of cellular gene expression. Nef, a 27-30-kDa myristoylated phosphoprotein, encoded by HIV-1 has been shown to play a crucial role in viral pathogenesis by modulating cellular gene expression and signaling pathways (1, 2). nef-deleted viruses fail to replicate efficiently in vivo, and do not develop symptoms of acquired immunodeficiency syndrome (AIDS) (3, 4). Nef is also thought to contribute to viral pathogenesis by down-regulation of CD4 and major histocompatibility complex class I surface molecules preventing viral superinfection and by helping the virus to evade host immune system. Nef has also been implicated in the activation of T cells, making the cells permissible to the virus (5, 6). All these functions of Nef are manifested by a number of important events such as activation of upstream signaling molecules, inhibition of apoptosis in the infected cell, activation and up-regulation of transcription factors, alleviation of repressors of transcription, as well as increase of the infectivity of newly produced virions (1, 7). Even though these functions of Nef have been well studied, controversy exists on its role in viral infectivity and replication as both negative (8, 9) and positive (10, 11) effects are available in the literature...

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“…Ties between resistin and HIV infection have been suggested to be due to the inhibition of PPAR␥ activity by nuclear HIV-1 nef. 39 Indeed, such a contribution by viral accessory proteins to resistin expression would provide a mechanism to explain the observed positive correlation between resistin and viral load. Increases in resistin have been reported in HIV-infected subjects with lipoatrophy, although a relationship between resistin and sTNF RII was not demonstrated.…”

Section: Figmentioning

confidence: 99%

Viral and Host Correlates of Serum Resistin in Simian AIDS

Wachtman

Gualtieri

Wanke

et al. 2008

AIDS Research and Human Retroviruses

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Resistin is an adipocytokine with a proposed dual role in metabolism and inflammation. In light of the ability to promote inflammatory responses, adipocytokines may prove key factors in modulating the host response to HIV. This study utilizes the simian immunodeficiency virus (SIV) model of HIV/AIDS to investigate changes in serum resistin levels following dietary intervention and SIV infection and determine associations with measures of body composition and disease severity. Resistin levels, body composition (n = 34), and insulin resistance (n = 16) were determined in healthy rhesus macaques. A subset of animals (n = 8) was placed on an atherogenic diet (AD) and subsequently inoculated with SIVmac239. Longitudinal measures of serum resistin, cytokines, viral load, lymphocyte subsets, and body composition were obtained. In healthy macaques consuming a standard diet, resistin levels correlated positively with total fat mass (r = 0.49; p < 0.01) and tissue fat percent (r = 0.53; p < 0.01) but failed to associate with measures of insulin resistance. In contrast, a negative correlation was noted between these measures of adiposity and resistin following SIV inoculation (r = -0.27; p < 0.05 and r = -0.24; p < 0.05, respectively). Viral load correlated positively with serum resistin (r = 0.32; p < 0.01). Serum levels of MCP-1 and sTNF RII demonstrated no correlation with resistin in normal animals on a standard diet, while a significant positive correlation was observed following SIV infection (r = 0.52; p < 0.0001 and r = 0.59; p < 0.0001, respectively). Findings indicate a fundamental difference in the relationship between resistin and body composition following SIV infection and suggest that elevations in resistin parallel measures of disease severity including loss of body fat and viral replication.

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HIV-1 Nef protein in the nucleus influences adipogenesis as well as viral transcription through the peroxisome proliferator-activated receptors

Abstract: Nef may be involved in both viral replication and the wasting syndrome associated with AIDS.

Cited by 51 publications

References 30 publications

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Heat Shock Protein 40 Is Necessary for Human Immunodeficiency Virus-1 Nef-mediated Enhancement of Viral Gene Expression and Replication

Viral and Host Correlates of Serum Resistin in Simian AIDS

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