Characterization of Human Endogenous Retroviral Elements in the Blood of HIV-1-Infected Individuals

Contreras-Galindo, Rafael; Kaplan, Mark H.; Contreras-Galindo, Angie C.; Gonzalez-Hernandez, Marta J.; Ferlenghi, Ilaria; Giusti, Fabiola; Lorenzo, Eric; Gitlin, Scott D.; Dosik, Michael; Yamamura, Yuichi; Markovitz, David M.

doi:10.1128/jvi.00602-11

Cited by 88 publications

(147 citation statements)

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“…Furthermore, upregulation of HERV-K RNA was detected (14-17, 19, 40) in plasma samples of HIV-1-infected individuals, in HIV-1-infected T cells (17,38), and in HIV-1 Tat-transfected T cells (23). In addition to RNA, HERV-K Gag proteins were also observed to increase upon HIV-1 infection (15,17) and HIV-1 Tat transfection (23). These reports collectively suggest that HIV-1 infection enhances the HERV-K expression in T cells.…”

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confidence: 87%

Human Endogenous Retrovirus K Gag Coassembles with HIV-1 Gag and Reduces the Release Efficiency and Infectivity of HIV-1

Monde

Contreras-Galindo

Kaplan

et al. 2012

J Virol

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Human endogenous retroviruses (HERVs), which are remnants of ancestral retroviruses integrated into the human genome, are defective in viral replication. Because activation of HERV-K and coexpression of this virus with HIV-1 have been observed during HIV-1 infection, it is conceivable that HERV-K could affect HIV-1 replication, either by competition or by cooperation, in cells expressing both viruses. In this study, we found that the release efficiency of HIV-1 Gag was 3-fold reduced upon overexpression of HERV-K CON Gag. In addition, we observed that in cells expressing Gag proteins of both viruses, HERV-K CON Gag colocalized with HIV-1 Gag at the plasma membrane. Furthermore, HERV-K CON Gag was found to coassemble with HIV-1 Gag, as demonstrated by (i) processing of HERV-K CON Gag by HIV-1 protease in virions, (ii) coimmunoprecipitation of virion-associated HERV-K CON Gag with HIV-1 Gag, and (iii) rescue of a late-domain-defective HERV-K CON Gag by wild-type (WT) HIV-1 Gag. Myristylation-deficient HERV-K CON Gag localized to nuclei, suggesting cryptic nuclear trafficking of HERV-K Gag. Notably, unlike WT HERV-K CON Gag, HIV-1 Gag failed to rescue myristylation-deficient HERV-K CON Gag to the plasma membrane. Efficient colocalization and coassembly of HIV-1 Gag and HERV-K Gag also required nucleocapsid (NC). These results provide evidence that HIV-1 Gag heteromultimerizes with HERV-K Gag at the plasma membrane, presumably through NC-RNA interaction. Intriguingly, HERV-K Gag overexpression reduced not only HIV-1 release efficiency but also HIV-1 infectivity in a myristylation- and NC-dependent manner. Altogether, these results indicate that Gag proteins of endogenous retroviruses can coassemble with HIV-1 Gag and modulate the late phase of HIV-1 replication.

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confidence: 87%

Human Endogenous Retrovirus K Gag Coassembles with HIV-1 Gag and Reduces the Release Efficiency and Infectivity of HIV-1

Monde

Contreras-Galindo

Kaplan

et al. 2012

J Virol

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“…Analysis of the HERV-K (HML-2) long terminal repeats (LTRs) for mutations and deletions was performed using published sequences (9,45). Potential transcription factor binding sites were analyzed using the online prediction software tools ALGGEN PROMO and version 8.3 of TRANSFAC (BioBase Co., Beverly, MA) (71,72).…”

Section: Addition Of Exogenous Tat Proteinmentioning

confidence: 99%

“…It appears that expression depends upon individual host factors, like ethnicity (10,21,22,24), cell populations (18,25,26), and tissue types (27)(28)(29). Additionally, external stimuli, such as infections, viral transactivators, chemical exposures, cytokines, hormones, and inflammation, can induce expression of these proviruses (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). We and others have shown that HIV-1 infection is associated with increased HERV-K (HML-2) expression in vitro and in vivo (33,(45)(46)(47)(48)(49)(50)(51)(52)(53).…”

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confidence: 99%

“…We and others have shown that HIV-1 infection is associated with increased HERV-K (HML-2) expression in vitro and in vivo (33,(45)(46)(47)(48)(49)(50)(51)(52)(53). Compared to healthy individuals, HIV-1-infected individuals show high levels of HERV-K (HML-2) RNA, DNA, protein, and viral particles in their plasma (45,47,48,50). This HIV-1-mediated activation of HERV-K (HML-2) is partially due to the HIV-1 Tat protein activating the NF-B and NF-AT transcription factors, which then interact with the HERV-K (HML-2) LTR promoter to stimulate transcription (46).…”

mentioning

confidence: 99%

“…Additionally, external stimuli, such as infections, viral transactivators, chemical exposures, cytokines, hormones, and inflammation, can induce expression of these proviruses (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). We and others have shown that HIV-1 infection is associated with increased HERV-K (HML-2) expression in vitro and in vivo (33,(45)(46)(47)(48)(49)(50)(51)(52)(53). Compared to healthy individuals, HIV-1-infected individuals show high levels of HERV-K (HML-2) RNA, DNA, protein, and viral particles in their plasma (45,47,48,50).…”

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confidence: 99%

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Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

Gonzalez-Hernandez

Cavalcoli

Sartor

et al. 2014

J Virol

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Approximately 8% of the human genome is made up of endogenous retroviral sequences. As the HIV-1 Tat protein activates the overall expression of the human endogenous retrovirus type K (HERV-K) (HML-2), we used next-generation sequencing to determine which of the 91 currently annotated HERV-K (HML-2) proviruses are regulated by Tat. Transcriptome sequencing of total RNA isolated from Tat-and vehicle-treated peripheral blood lymphocytes from a healthy donor showed that Tat significantly activates expression of 26 unique HERV-K (HML-2) proviruses, silences 12, and does not significantly alter the expression of the remaining proviruses. Quantitative reverse transcription-PCR validation of the sequencing data was performed on Tattreated PBLs of seven donors using provirus-specific primers and corroborated the results with a substantial degree of quantitative similarity. IMPORTANCEThe expression of HERV-K (HML-2) is tightly regulated but becomes markedly increased following infection with HIV-1, in part due to the HIV-1 Tat protein.The findings reported here demonstrate the complexity of the genome-wide regulation of HERV-K (HML-2) expression by Tat. This work also demonstrates that although HERV-K (HML-2) proviruses in the human genome are highly similar in terms of DNA sequence, modulation of the expression of specific proviruses in a given biological situation can be ascertained using next-generation sequencing and bioinformatics analysis.

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Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis

Young¹,

Stoye²,

Kassiotis³

2013

BioEssays

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A number of observations have led researchers to postulate that, despite being replication-defective, human endogenous retroviruses (HERVs) may have retained the potential to cause or contribute to disease. However, mechanisms of HERV pathogenicity might differ substantially from those of modern infectious retroviruses or of the infectious precursors of HERVs. Therefore, novel pathways of HERV involvement in disease pathogenesis should be investigated. Recent technological advances in sequencing and bioinformatics are making this task increasingly feasible. The accumulating knowledge of HERV biology may also facilitate the definition and general acceptance of criteria that establish HERV pathogenicity. Here, we explore possible mechanisms whereby HERVs may cause disease and examine the evidence that either has been or should be obtained in order to decisively address the pathogenic potential of HERVs.

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Characterization of Human Endogenous Retroviral Elements in the Blood of HIV-1-Infected Individuals

Cited by 88 publications

References 46 publications

Human Endogenous Retrovirus K Gag Coassembles with HIV-1 Gag and Reduces the Release Efficiency and Infectivity of HIV-1

Human Endogenous Retrovirus K Gag Coassembles with HIV-1 Gag and Reduces the Release Efficiency and Infectivity of HIV-1

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis

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