Exploiting the Anti-HIV-1 Activity of Acyclovir: Suppression of Primary and Drug-Resistant HIV Isolates and Potentiation of the Activity by Ribavirin

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Multiple clinical trials have demonstrated that herpes simplex virus 2 (HSV-2) suppressive therapy using acyclovir (ACV) or valacyclovir in HIV-1/HSV-2-infected persons increased the patient's survival and decreased the HIV-1 load. It has been shown that the incorporation of ACV-monophosphate into the nascent DNA chain instead of dGMP results in the termination of viral DNA elongation and directly inhibits laboratory strains of HIV-1. We evaluated here the anti-HIV activity of ACV against primary HIV-1 isolates of different clades and coreceptor specificity and against viral isolates resistant to currently used drugs, including zidovudine, lamivudine, nevirapine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs), a fusion inhibitor, and two protease inhibitors. We found that, at clinically relevant concentrations, ACV inhibits the replication of these isolates in human tissues infected<jats:italic>ex vivo</jats:italic>. Moreover, addition of ribavirin, an antiviral capable of depleting the pool of intracellular dGTP, potentiated the ACV-mediated HIV-1 suppression. These data warrant further clinical investigations of the benefits of using inexpensive and safe ACV alone or in combination with other drugs against HIV-1, especially to complement or delay highly active antiretroviral therapy (HAART) initiation in low-resource settings.</jats:p>

A common anti-cytomegalovirus drug, ganciclovir, inhibits HIV-1 replication in human tissues ex vivo

“…Indeed, the effect of ACV on HIV VL was initially attributed to the suppression of HSV-2 replication followed by the suppression of HSV-2-triggered inflammation [48, 49]. However, we and others [30, 50, 51] have found that ACV also has a direct effect on HIV-1 after the drug is phosphorylated by HHV. The direct inhibitory effect of ACV on HIV VL observed ex vivo was recently confirmed in vivo in a double-blind crossover clinical trial [52].…”

Standardization of a cytometric p24-capture bead-assay for the detection of main HIV-1 subtypes.

“…The assay developed by Biancotto et al (Biancotto et al, 2009) using mAb 4F6 as a C-Ab has demonstrated a great ability to measure concentrations of HIV-1 belonging to B subtypes (Balzarini et al, 2013; Introini et al, 2013; Merbah et al, 2012; Parrish et al, 2013; Saba et al, 2010; Vanpouille et al, 2012); however, its capacity to measure p24 from multiple non-B samples was more limited and opened the door for an assay using a more universal C-Ab. Biancotto et al .…”

“…As for all immunological assays, the success relies on the avidity and specificity of the C-Abs selected. Biancotto et al (Biancotto et al, 2009) developed a sensitive assay for the detection of p24 using the Luminex technology that has been used in many HIV-1 subtype B studies (Balzarini et al, 2013; Introini et al, 2013; Merbah et al, 2012; Parrish et al, 2013; Saba et al, 2010; Vanpouille et al, 2012). However, the C-Ab described by Biancotto et al lacks sensitivity for some HIV-1 non-B subtypes which account for almost 90% of HIV-1 infections worldwide (Hemelaar et al, 2011).…”

An ex vivo Model of HIV-1 Infection in Human Lymphoid Tissue and Cervico-vaginal Tissue

“…HIV-1 p24 gag concentrations were 49 ± 3 ng/ml and 53 ± 3 ng/ml for HIV-1 BaL and HIV-1 LAI.04 stock, respectively. For more viral preparations used in our experimental setting see References 3 and 4.…”