Transmission of antiretroviral-drug-resistant HIV-1 variants

Yerly, Sabine; Kaiser, Laurent; Race, Esther; Bru, J P; Clavel, François; Perrin, Luc

doi:10.1016/s0140-6736(98)12262-6

Cited by 392 publications

(242 citation statements)

References 20 publications

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“…However, the success of current therapies is limited by the emergence of drug-resistant strains, the need for sustained adherence to complex regimens, and the potential for drug toxicity (2,3). The two new antiretroviral classes of integrase and entry inhibitors may help overcome some of the current limitations of HAART (4,5).…”

mentioning

confidence: 99%

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

Heredia

Latinovic

Gallo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Vicriviroc (VCV) is a chemokine (C-C motif) receptor 5 (CCR5)antagonist with potent anti-HIV activity that currently is being evaluated in phase III clinical trials. In the present study, donor CCR5 density (CCR5 receptors/CD4 lymphocytes) inversely correlated with VCV antiviral activity (Spearman's correlation test; r ‫؍‬ 0.746, P ‫؍‬ 0.0034). Low doses of the transplant drug rapamycin (RAPA) reduced CCR5 density and enhanced VCV antiviral activity. In drug interaction studies, the RAPA/VCV combination had considerable antiviral synergy (combination indexes of 0.1-0.04) in both multicycle and single-cycle infection of lymphocytes. The synergy between RAPA and VCV translated into dose reduction indexes of 8-to 41-fold reductions for RAPA and 19-to 658-fold reductions for VCV. RAPA enhanced VCV antiviral activity against both B and non-B clade isolates, potently suppressing clade G viruses with reported reduced sensitivities to VCV and to the licensed CCR5 antagonist maraviroc. Importantly, RAPA reduction of CCR5 density in lymphocytes sensitized VCV-resistant strains to VCV, inhibiting virus production by ϳ 90%. We further demonstrated the role of CCR5 density on VCV activity against resistant virus in donor lymphocytes and in cell lines expressing varying CCR5 densities. Together, these results suggest that low doses of RAPA may increase the durability of VCV-containing regimens in patients by enhancing VCV viral suppression, by allowing the use of lower doses of VCV with reduced potential for toxicity, and by controlling emerging VCV-resistant variants.chemokine receptor 5 antagonists ͉ coreceptor density ͉ HIV resistance ͉ vicriviroc resistance ͉ maraviroc H ighly active antiretroviral therapy (HAART) has improved treatment of HIV-1 infected individuals considerably (1). However, the success of current therapies is limited by the emergence of drug-resistant strains, the need for sustained adherence to complex regimens, and the potential for drug toxicity (2, 3). The two new antiretroviral classes of integrase and entry inhibitors may help overcome some of the current limitations of HAART (4, 5). Entry inhibitors are especially attractive because they target HIV at the earliest step of the viral cycle and are effective against strains resistant to inhibitors of protease and reverse transcriptase. Entry inhibitors interfere with HIV binding to CD4 receptor (attachment inhibitors) or chemokine (C-C motif) receptor 5 (CCR5)/chemokine (C-X-C-motif) receptor 4 (CXCR4) coreceptors (coreceptor antagonists) or by preventing fusion between cellular and viral membranes (fusion inhibitors) (5). Currently, the fusion inhibitor T-20 (enfuvirtide) and the CCR5 antagonist maraviroc (Selzentry) are the only licensed entry inhibitors (6, 7). The CCR5 antagonist vicriviroc (VCV) presently is in phase III clinical trials (8). Coreceptor CCR5 antagonists inhibit CCR5-tropic HIV-1 (referred to as ''R5 HIV-1'') strains, which are responsible for most transmissions and generally are present throughout the course of infection. In nor...

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mentioning

confidence: 99%

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

Heredia

Latinovic

Gallo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The emergence of viral resistance to protease and reverse transcriptase inhibitors, combined with the difficulty of adhering to complicated dosing regimens that have associated side effects, has meant that an increasing number of patients are now failing to achieve sustained suppression of viral replication (1)(2)(3)(4).…”

mentioning

confidence: 99%

SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infectionin vitroandin vivo

Strizki

Wagner

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

297

186

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We describe here the identification and properties of SCH-C (SCH 351125), a small molecule inhibitor of HIV-1 entry via the CCR5 coreceptor. SCH-C, an oxime-piperidine compound, is a specific CCR5 antagonist as determined in multiple receptor binding and signal transduction assays. This compound specifically inhibits HIV-1 infection mediated by CCR5 in U-87 astroglioma cells but has no effect on infection of CXCR4-expressing cells. SCH-C has broad and potent antiviral activity in vitro against primary HIV-1 isolates that use CCR5 as their entry coreceptor, with mean 50% inhibitory concentrations ranging between 0.4 and 9 nM. Moreover, SCH-C strongly inhibits the replication of an R5-using HIV-1 isolate in SCID-hu Thy͞Liv mice. SCH-C has a favorable pharmacokinetic profile in rodents and primates with an oral bioavailability of 50 -60% and a serum half-life of 5-6 h. On the basis of its novel mechanism of action, potent antiviral activity, and in vivo pharmacokinetic profile, SCH-C is a promising new candidate for therapeutic intervention of HIV infection.

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“…Indeed, viremia-based studies have provided clear evidence that changes in HIV load during the different phases of this infection can be efficiently evaluated by measuring cell-free virus in plasma samples [YERLY et al, 1999] , and that substantial increases in viral load parallel or even predict the disease progression.…”

Section: Influences Virus Release P16 Vpumentioning

confidence: 99%

Assessment of HIV infection in cells of infected individuals

Aghajani¹,

Mirtajani²,

Kojuri³

et al. 2017

bjbabe

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Abstract. HIV is one of the most prevalent opportunistic pathogens in cells of infected individuals and can cause diseases such as: encephalitis, pneumonia and chorioretinitis. The aim of this study is to investigate HIV infection in cells infected persons. This study was performed on 50 blood samples from individuals infected with HIV. Studied patients in the two groups were consumer and nonconsumer of antiretroviral drugs (mention the name of the Antiviral drug). After separation of plasma from the blood samples to detect HIV in cell culture and PCR were examined. Of the 50 patients, 56 % (n = 28) were male and 44 percent (n = 22) were women. DNA antibodies in 16 % (8 cases) were identified in the population, the prevalence of HIV infection in men 21.4 % (6 cases) and in women 1.9% (2 cases). The high prevalence of HIV infection in patients treated with CMV (full form of CMV), the treatment of HIV infection should be considered.

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Transmission of antiretroviral-drug-resistant HIV-1 variants

Cited by 392 publications

References 20 publications

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infectionin vitroandin vivo

Assessment of HIV infection in cells of infected individuals

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