β5 Integrin Is the Major Contributor to the αv Integrin-Mediated Blockade of HIV-1 Replication

Ballana, Ester; Pauls, Eduardo; Clotet, Bonaventura; Perron-Sierra, Françoise; Tucker, Gordon C.; Esté, José A.

doi:10.4049/jimmunol.1002693

Cited by 22 publications

(16 citation statements)

References 41 publications

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“…With two RGD (arginine-glycine-aspartic acid) and 12 CSPG (chondroitin sulfate proteoglycan) domains, FREM1 variants can potentially exert different functions by differentially interacting with integrin, collagen, and fibronectin through variations in functional domains (26). These are important components of the genital mucosal barrier and play an important role in HIV-1 infection (4,6,7,10,13,14,33,43,51). The C-type lectin and Calx-beta domain of FREM1 suggest the ability of this protein to bind sugar and calcium and modify biological function.…”

Section: Discussionmentioning

confidence: 99%

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

Luo

Sainsbury

Tuff

et al. 2012

J Virol

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A subgroup of women enrolled in the Pumwani sex worker cohort remain seronegative and PCR negative for human immunodeficiency virus type 1 despite repeated exposure through high-risk sex work. Studies have shown that polymorphisms of genes involved in antigen presentation and viral restriction factors are associated with resistance to HIV infection. To discover other possible genetic factors underlying this HIV-resistant phenotype, we conducted an exploratory nonbiased, low-resolution, genome-wide single-nucleotide polymorphism (SNP) analysis comparing 60 HIV-resistant women to 48 HIV-infected controls. The SNP minor allele rs1552896, in an intron of FREM1, was significantly associated with the resistant phenotype (P ‫؍‬ 1.68 ؋ 10 ؊5 ; adjusted P ‫؍‬ 2.37 ؋ 10 ؊4 ; odds ratio [OR], 9.51; 95% confidence interval [CI], 2.82 to 32.05). We expanded the sample size by genotyping rs1552896 in the Pumwani cohort and comparing 114 HIV-resistant women to 609 HIV-infected controls and confirmed the association (P ‫؍‬ 1.7 ؋ 10 ؊4 ; OR, 2.67; 95% CI, 1.47 to 4.84). To validate the association in a second cohort, we genotyped 783 women enrolled in a mother-child health study and observed the minor allele of rs1552896 enriched in HIV-uninfected women (n ‫؍‬ 488) compared to HIV-infected enrollees (n ‫؍‬ 295) (P ‫؍‬ 0.036; OR, 1.69; 95% CI, 0.98 to 2.93). Quantitative reverse transcription-PCR showed that FREM1 mRNA was highly expressed in tissues relevant for HIV-1 infection, and immunohistochemical analysis revealed that FREM1 protein is expressed in the ectocervical mucosa of HIV-resistant women. The significant association of rs1552896 with an HIV-resistant phenotype, together with the expression profile of FREM1 in tissues relevant to HIV infection, suggests that FREM1 is a potentially novel candidate gene for resistance to HIV infection.

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Section: Discussionmentioning

confidence: 99%

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

Luo

Sainsbury

Tuff

et al. 2012

J Virol

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“…Activated CD4 ϩ T lymphocytes and CD3/CD8-stimulated PBMCs were spinoculated in the presence of the corresponding virus (HIV-1*GFP or HIV-2 for CD4 ϩ T lymphocytes and PBMCs, respectively) for 90 min at 1,200 ϫ g. Viral replication was measured in all cases 2 days later by flow cytometry. Measurement of cell cytotoxicity was performed by a methyl tetrazolium-based colorimetric assay (MTT method) as described before (13) or, in the case of lymphocytes, by relative quantification of the gate of live cells by flow cytometry.…”

Section: Cellsmentioning

confidence: 99%

SAMHD1 Specifically Affects the Antiviral Potency of Thymidine Analog HIV Reverse Transcriptase Inhibitors

Ballana

Badía

Terradas

et al. 2014

Antimicrob Agents Chemother

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bSterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase recently recognized as an antiviral factor that acts by depleting dNTP availability for viral reverse transcriptase (RT). SAMHD1 restriction is counteracted by the human immunodeficiency virus type 2 (HIV-2) accessory protein Vpx, which targets SAMHD1 for proteosomal degradation, resulting in an increased availability of dNTPs and consequently enhanced viral replication. Nucleoside reverse transcriptase inhibitors (NRTI), one of the most common agents used in antiretroviral therapy, compete with intracellular dNTPs as the substrate for viral RT. Consequently, SAMHD1 activity may be influencing NRTI efficacy in inhibiting viral replication. Here, a panel of different RT inhibitors was analyzed for their different antiviral efficacy depending on SAMHD1. Antiviral potency was measured for all the inhibitors in transformed cell lines and primary monocytederived macrophages and CD4؉ T cells infected with HIV-1 with or without Vpx. No changes in sensitivity to non-NRTI or the integrase inhibitor raltegravir were observed, but for NRTI, sensitivity significantly changed only in the case of the thymidine analogs (AZT and d4T). The addition of exogenous thymidine mimicked the change in viral sensitivity observed after Vpx-mediated SAMHD1 degradation, pointing toward a differential effect of SAMHD1 activity on thymidine. Accordingly, sensitivity to AZT was also reduced in CD4؉ T cells infected with HIV-2 compared to infection with the HIV-2⌬Vpx strain. In conclusion, reduction of SAMHD1 levels significantly decreases HIV sensitivity to thymidine but not other nucleotide RT analog inhibitors in both macrophages and lymphocytes. Sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) is a recently identified human immunodeficiency virus type 1 (HIV-1) host restriction factor that limits retroviral replication at the reverse transcription stage of the viral life cycle (1-5). SAMHD1 functions as a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that regulates the intracellular pool of dNTPs (6). It restricts HIV-1 infection in immune cells of myeloid lineage and in quiescent CD4-positive T lymphocytes (1, 2, 4). SAMHD1 reduces cellular dNTP levels to concentrations below the threshold required for reverse transcription of the viral RNA genome into DNA (4, 5). SAMHD1 is counteracted by the retroviral Vpx protein that is encoded by simian immunodeficiency virus (SIV) and HIV-2, but this gene is lacking from the HIV-1 and feline immunodeficiency virus (FIV) genomes (7). However, and despite the lack of Vpx function, HIV-1 is still able to replicate in noncycling myeloid cells, albeit at low levels (7).Most current standard three-drug antiretroviral regimens involve RT inhibitors combined with a protease inhibitor. [EFV], and etravirine). NRTI are phosphorylated to their triphosphate form to act as competitive inhibitors of HIV RT. In contrast, NNRTI bind at...

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“…Viability Assays-For measurement of cell toxicity or viability, methyl tetrazolium-based colorimetric assay (MTT method) was performed in transfected TZM-bl cells as described (24).…”

Section: Cells-tzm-bl and Hek293t Cells (Aidsmentioning

confidence: 99%

Characterization of the Influence of Mediator Complex in HIV-1 Transcription

Ruiz

Pauls

Badía

et al. 2014

Journal of Biological Chemistry

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β5 Integrin Is the Major Contributor to the αv Integrin-Mediated Blockade of HIV-1 Replication

Cited by 22 publications

References 41 publications

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

SAMHD1 Specifically Affects the Antiviral Potency of Thymidine Analog HIV Reverse Transcriptase Inhibitors

Characterization of the Influence of Mediator Complex in HIV-1 Transcription

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