Christophe Vanpouille1, Jean A Bernatchez, Andrea Lisco, Anush Arakelyan, Elisa Saba, Matthias Götte, Leonid Margolis. 1. aEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland bDepartment of Biochemistry, McGill University, Montreal, Quebec cDepartment of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, Katz Group Centre for Health Research, University of Alberta, Edmonton, Alberta, Canada. *Christophe Vanpouille and Jean A. Bernatchez contributed equally to this article. †Current address: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. ‡Current address: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA.
Abstract
BACKGROUND: Cytomegalovirus (CMV) is a common HIV-1 copathogen. Since CMV infection is an important contributor to immune activation, the driving force of HIV disease, an anti-CMV strategy might be beneficial to HIV-infected patients. Shin et al. (J Acquir Immune Defic Syndr 2014; 65:251-258) reported that anti-CMV therapy with valganciclovir in coinfected individuals results in a decrease of HIV viral load that is not accompanied by a decrease of immune activation. This suggests an alternative mechanism for HIV inhibition other than suppression of CMV-mediated inflammation. METHOD: We evaluated the anti-HIV activity of ganciclovir (GCV), the active form of valganciclovir, on HIV replication in human tissues ex vivo. RESULTS: We show that GCV has a direct suppressive activity on HIV replication in human tissues ex vivo, including laboratory strains, drug-resistant and primate HIV-1 isolates. We deciphered the mechanism of this inhibition and showed that GCV-TP is incorporated in the nascent DNA chain and acts as a delayed chain terminator. CONCLUSION: Our results suggest that anti-CMV strategy using valganciclovir in HIV-1-infected individuals may reduce HIV-1 viral load not only indirectly by decreasing CMV-mediated immune activation but also directly by inhibiting HIV-1 reverse transcriptase.
BACKGROUND:Cytomegalovirus (CMV) is a common HIV-1 copathogen. Since CMV infection is an important contributor to immune activation, the driving force of HIV disease, an anti-CMV strategy might be beneficial to HIV-infectedpatients. Shin et al. (J Acquir Immune Defic Syndr 2014; 65:251-258) reported that anti-CMV therapy with valganciclovir in coinfected individuals results in a decrease of HIV viral load that is not accompanied by a decrease of immune activation. This suggests an alternative mechanism for HIV inhibition other than suppression of CMV-mediated inflammation. METHOD: We evaluated the anti-HIV activity of ganciclovir (GCV), the active form of valganciclovir, on HIV replication in human tissues ex vivo. RESULTS: We show that GCV has a direct suppressive activity on HIV replication in human tissues ex vivo, including laboratory strains, drug-resistant and primate HIV-1 isolates. We deciphered the mechanism of this inhibition and showed that GCV-TP is incorporated in the nascent DNA chain and acts as a delayed chain terminator. CONCLUSION: Our results suggest that anti-CMV strategy using valganciclovir in HIV-1-infected individuals may reduce HIV-1 viral load not only indirectly by decreasing CMV-mediated immune activation but also directly by inhibiting HIV-1 reverse transcriptase.
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