Anti-HIV Activity and Resistance Profile of the CXC Chemokine Receptor 4 Antagonist POL3026

Moncunill, Gemma; Armand‐Ugón, Mercedes; Clotet‐Codina, Imma; Pauls, Eduardo; Ballana, Ester; Llano, Anuska; Romagnoli, Bárbara; Vrijbloed, Jan W.; Gombert, Frank O.; Clotet, Bonaventura; Marco, Steve De; Esté, José A.

doi:10.1124/mol.107.042911

Cited by 50 publications

(42 citation statements)

References 36 publications

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“…CD4 ϩ T lymphocytes were immediately purified (Ͼ95%) from PBMCs by negative selection using the CD4 ϩ T cell enrichment kit (Stem Cell Technologies, Vancouver, Canada) and grown in RPMI 1640 -L-glutamine medium (Gibco, Madrid, Spain). Chronically HIV-1-infected MOLT cells were generated after infection of the MOLT-4/CCR5 lymphoid cell line (AIDS Research and Reference Reagent Program, National Institutes of Health, Bethesda, MD) with an NL4-3 X4 HIV-1 strain (HIV-1 NL4-3 ) constructed in an HIV HXB2 backbone (29). After the infection peak, the persistently infected culture was grown and characterized for Env expression and virus production (5).…”

Section: Cellsmentioning

confidence: 99%

Antiretroviral Agents Effectively Block HIV Replication after Cell-to-Cell Transfer

Permanyer

Ballana

Ruiz

et al. 2012

J Virol

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Cell-to-cell transmission of HIV has been proposed as a mechanism contributing to virus escape to the action of antiretrovirals and a mode of HIV persistence during antiretroviral therapy. Here, cocultures of infected HIV-1 cells with primary CD4+T cells or lymphoid cells were used to evaluate virus transmission and the effect of known antiretrovirals. Transfer of HIV antigen from infected to uninfected cells was resistant to the reverse transcriptase inhibitors (RTIs) zidovudine (AZT) and tenofovir, but was blocked by the attachment inhibitor IgGb12. However, quantitative measurement of viral DNA production demonstrated that all anti-HIV agents blocked virus replication with similar potency to cell-free virus infections. Cell-free and cell-associated infections were equally sensitive to inhibition of viral replication when HIV-1 long terminal repeat (LTR)-driven green fluorescent protein (GFP) expression in target cells was measured. However, detection of GFP by flow cytometry may incorrectly estimate the efficacy of antiretrovirals in cell-associated virus transmission, due to replication-independent Tat-mediated LTR transactivation as a consequence of cell-to-cell events that did not occur in short-term (48-h) cell-free virus infections. In conclusion, common markers of virus replication may not accurately correlate and measure infectivity or drug efficacy in cell-to-cell virus transmission. When accurately quantified, active drugs blocked proviral DNA and virus replication in cell-to-cell transmission, recapitulating the efficacy of antiretrovirals in cell-free virus infections andin vivo.

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Section: Cellsmentioning

confidence: 99%

Antiretroviral Agents Effectively Block HIV Replication after Cell-to-Cell Transfer

Permanyer

Ballana

Ruiz

et al. 2012

J Virol

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“…HIV-1 stocks of NL4-3 and clinical isolate 92UG024 were grown in lymphoid MT-4 cells, as described elsewhere [24,25]. The R5 HIV-1 strain BaL was grown in peripheral blood mononuclear cells stimulated with phytohemagglutinin and interleukin 12.…”

Section: Patients and Samplesmentioning

confidence: 99%

ZNRD1 (Zinc Ribbon Domain–Containing 1) Is a Host Cellular Factor That Influences HIV‐1 Replication and Disease Progression

et al. 2010

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“…Impact of mutations in the V3 region on CXCR4 antagonist and neutralization sensitivity As previously reported (Kanbara et al, 2001;Moncunill et al, 2008;Schols et al, 1998;de Vreese et al, 1996), all of the mutant viruses had several mutations in V3-coding region. To examine whether the V3 mutations were responsible for the loss of viral sensitivity to CXCR4 antagonists, we generated V3 chimeric clones from each env chimeric clone.…”

Section: Susceptibility Of the Cxcr4 Antagonist-resistant Viruses To mentioning

confidence: 48%

“…Prior studies have only considered the first possibility because T-cell lines that express low levels of CCR5, such as MT-4, were used (Kanbara et al, 2001;Moncunill et al, 2008;Schols et al, 1998;de Vreese et al, 1996). In the current study, NL4-3 virus was passaged in the presence of CXCR4 antagonists using PM1/CCR5 cells which express high levels of CCR5 to examine the second possibility.…”

Section: Discussionmentioning

confidence: 99%

Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists

Hikichi

Yokoyama

Takemura

et al. 2016

Journal of General Virology

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HIV-1 passage in cell culture in the presence of chemokine receptor antagonists can result in selection of viruses with env mutations that confer resistance to these inhibitors. In the present study, we examined the effect of HIV-1 env mutations that confer resistance to CXCR4 antagonists on envelope (Env) sensitivity to neutralizing antibodies (NAbs). Serial passage of CXCR4-tropic HIV-1 NL4-3 in PM1/CCR5 cells under CXCR4 antagonists KRH-3955, AMD3100 and AMD070 yielded two KRH-3955-resistant, one AMD3100-resistant and one AMD070-resistant viruses. These viruses had multiple env mutations including the Env gp120 V3 region. The majority of viruses having these CXCR4 antagonist-resistant Envs showed higher sensitivity to NAbs 447-52D, b12 and 2F5 targeting the V3 region, the gp120 CD4-binding site and the gp41 membrane proximal region, respectively, compared to NL4-3 WT virus. Recombinant NL4-3 viruses with the V3-coding region replaced with those derived from the CXCR4 antagonist-resistant viruses showed increased sensitivity to NAbs b12, 2F5 and 447-52D. Molecular dynamics simulations of Env gp120 outer domains predicted that the V3 mutations increased levels of fluctuations at the tip and stem of the V3 loop. These results indicate that mutations in the V3-coding region that result in loss of viral sensitivity to CXCR4 antagonists increase viral sensitivity to NAbs, providing insights into our understanding of the interplay of viral Env accessibility to chemokine receptors and sensitivity to NAbs.

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Anti-HIV Activity and Resistance Profile of the CXC Chemokine Receptor 4 Antagonist POL3026

Cited by 50 publications

References 36 publications

Antiretroviral Agents Effectively Block HIV Replication after Cell-to-Cell Transfer

Antiretroviral Agents Effectively Block HIV Replication after Cell-to-Cell Transfer

ZNRD1 (Zinc Ribbon Domain–Containing 1) Is a Host Cellular Factor That Influences HIV‐1 Replication and Disease Progression

Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists

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