Host Genes Important to HIV Replication and Evolution

Telenti, Amalio; Johnson, Welkin E.

doi:10.1101/cshperspect.a007203

Cited by 24 publications

(17 citation statements)

References 137 publications

(147 reference statements)

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“…Consistent with most studies performed in HIV-1 host genetics over the past few years (reviewed in Telenti and Johnson (2012)), we did not identify previously unknown host genetic loci involved in host-viral interaction and HIV-1 restriction. The proposed approach can only detect polymorphic host factors that leave an imprint on the virus, which may exclude mediators of immunopathogenesis or genes involved in the establishment of tolerance (Medzhitov et al, 2012).…”

Section: Discussionsupporting

confidence: 86%

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

Bartha

Carlson

Brumme

et al. 2013

eLife

138

144

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HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p<2.4 × 10−12). All associated SNPs mapped to the HLA class I region. Clinical relevance of host and pathogen variation was assessed using VL results. We identified two critical advantages to the use of viral variation for identifying host factors: (1) association signals are much stronger for HIV-1 sequence variants than VL, reflecting the ‘intermediate phenotype’ nature of viral variation; (2) association testing can be run without any clinical data. The proposed genome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host–pathogen interaction.DOI: http://dx.doi.org/10.7554/eLife.01123.001

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Section: Discussionsupporting

confidence: 86%

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

Bartha

Carlson

Brumme

et al. 2013

eLife

138

144

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“…The apparent species specificity in G 2 /M arrest in SIV Vpr proteins initially seems to be more broad than the interactions that have been documented for lentiviral accessory genes and the restriction factors APOBEC3G, tetherin, and SAMHD1 (24). Guenon Vpr proteins can interact with the human SLX4 complex, whereas several SIVagm alleles, as well as those of SIVdeb, SIVolc, and SIVsyk, co-IP the complex from grivet cells.…”

Section: Discussionmentioning

confidence: 96%

G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

Berger

Lawrence

Hué

et al. 2015

J Virol

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V iral protein R (Vpr) is an accessory protein common to all primate lentiviruses whose role in viral replication remains unclear. It is packaged specifically into virions and is associated with the reverse-transcription complex during early steps of infection (1, 2). Although implicated in various virological processes, the major phenotype ascribed to Vpr is the induction of G 2 /M cell cycle arrest in dividing cells (3, 4). The importance of this phenotype in human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) replication has been notoriously difficult to define because of the minor effects of its deletion on viral replication in cell culture (5). However, reversion of inactivating mutations in both primates and humans highlights that Vpr plays an essential role for viral replication in vivo (6). In addition to cell cycle arrest, several SIV Vpr alleles are capable of targeting the host restriction factor SAMHD1 and that function became separated in the sooty mangabey SIV (SIVsm) lineage upon duplication to generate the vpx gene peculiar to this group (7). Importantly, at present HIV-1 Vpr is not known to retain any SAMHD1 counteractivity (7-10).Vpr-mediated cell cycle arrest depends on its localization to nuclear compartments and the ability to hijack a Cullin-4/DDB1/ Roc1 E3 ubiquitin ligase complex through the WD-containing DCAF-1 adaptor (11,12). For HIV-1 Vpr, this leads ultimately to the activation of the ataxia telangiectasia M and Rad3-related (ATR) and Chk1 kinases to prevent cell cycle progression into mitosis (13). Although several putative Vpr targets have been described, the identity of that which triggers this event has until recently remained elusive. The requirement for the ubiquitin-proteasome system and, in particular, K48-ubiquitin linkages supported a notion that the Vpr target is degraded (14). However, Laguette and colleagues recently found that Vpr interacts with the SLX4 complex, members of the Fanconi anemia DNA repair pathway (15). SLX4, also known as Fanconi anemia complementation group P (FANCP), is a large adaptor protein that acts as a scaffold for a heterodimeric structure-specific endonuclease comprised of MUS81 and EME1. This interaction directs this endonuclease and

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“…Studies have shown that the host cellular transcriptome is regulated by HIV-1 infection, as part of the cells’ response to pathogen insult [60,61]. HIV-1 infection results in differential regulation of specific cellular genes in target cells such as CD4+ T cells and monocytes/macrophages suggesting that virus infection alters host cellular proteins either to evade the immune system and/or for optimal viral replication.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA regulation and its effects on cellular transcriptome in Human Immunodeficiency Virus-1 (HIV-1) infected individuals with distinct viral load and CD4 cell counts

Duskova

Nagilla

et al. 2013

BMC Infect Dis

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BackgroundDisease progression in the absence of therapy varies significantly in HIV-1 infected individuals. Both viral and host cellular molecules are implicated; however, the exact role of these factors and/or the mechanism involved remains elusive. To understand how microRNAs (miRNAs), which are regulators of transcription and translation, influence host cellular gene expression (mRNA) during HIV-1 infection, we performed a comparative miRNA and mRNA microarray analysis using PBMCs obtained from infected individuals with distinct viral load and CD4 counts.MethodsRNA isolated from PBMCs obtained from HIV-1 seronegative and HIV-1 positive individuals with distinct viral load and CD4 counts were assessed for miRNA and mRNA profile. Selected miRNA and mRNA transcripts were validated using in vivo and in vitro infection model.ResultsOur results indicate that HIV-1 positive individuals with high viral load (HVL) showed a dysregulation of 191 miRNAs and 309 mRNA transcripts compared to the uninfected age and sex matched controls. The miRNAs miR-19b, 146a, 615-3p, 382, 34a, 144 and 155, that are known to target innate and inflammatory factors, were significantly upregulated in PBMCs with high viral load, as were the inflammatory molecules CXCL5, CCL2, IL6 and IL8, whereas defensin, CD4, ALDH1, and Neurogranin (NRGN) were significantly downregulated. Using the transcriptome profile and predicted target genes, we constructed the regulatory networks of miRNA-mRNA pairs that were differentially expressed between control, LVL and HVL subjects. The regulatory network revealed an inverse correlation of several miRNA-mRNA pair expression patterns, suggesting HIV-1 mediated transcriptional regulation is in part likely through miRNA regulation.ConclusionsResults from our studies indicate that gene expression is significantly altered in PBMCs in response to virus replication. It is interesting to note that the infected individuals with low or undetectable viral load exhibit a gene expression profile very similar to control or uninfected subjects. Importantly, we identified several new mRNA targets (Defensin, Neurogranin, AIF) as well as the miRNAs that could be involved in regulating their expression through the miRNA-mRNA interaction.

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Host Genes Important to HIV Replication and Evolution

Cited by 24 publications

References 137 publications

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

MicroRNA regulation and its effects on cellular transcriptome in Human Immunodeficiency Virus-1 (HIV-1) infected individuals with distinct viral load and CD4 cell counts

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Host Genes Important to HIV Replication and Evolution

Cited by 24 publications

References 137 publications

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

G 2 /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

MicroRNA regulation and its effects on cellular transcriptome in Human Immunodeficiency Virus-1 (HIV-1) infected individuals with distinct viral load and CD4 cell counts

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G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex