Disparate effects of cytotoxic chemotherapy on the antiviral activity of antiretroviral therapy: Implications for treatments of HIV-infected cancer patients

• Type of Material: Article
• Authors: Sandra Medina-Moreno, University of Maryland; Juan C Zapata, University of Maryland; Mackenzie L. Cottrell, The University of North Carolina at Chapel Hill; Nhut M Le, University of Maryland; Sijia Tao, Emory University; Joseph Bryant, University of Maryland; Edward Sausville, University of Maryland; Raymond Schinazi, Emory University; Angela DM Kashuba, The University of North Carolina at Chapel Hill; Robert R Redfield, University of Maryland; Alonso Heredia, University of Maryland
• Language: English
• Date: 2019-01-01
• Publisher: International Medical Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 International Medical Press 1359-6535 (print) 2040-2058 (online)
• Final Published Version (URL): http://dx.doi.org/10.3851/IMP3285
• Title of Journal or Parent Work: Antiviral Therapy
• ISSN: 1359-6535
• Volume: 24
• Issue: 3
• Start Page: 177
• End Page: 186
• Grant/Funding Information: This work was supported by grants CFAR P30-AI-050410, CFAR 2P30-AI-050409, R01-CA-233441, and by additional research funds from the Institute of Human Virology.
• Keywords: Chemotherapy; Antiretroviral therapy (ART); HIV; Disparity; Cancer
• Research Categories: Health Sciences, Pharmacology; Chemistry, Biochemistry; Health Sciences, Oncology

Abstract

Background: Cancer is a leading cause of death in HIV-infected patients in the era of combination antiretroviral therapy (cART). Yet, there are no specific guidelines for the combined use of cART and chemotherapy in HIV-infected cancer patients. The cellular enzyme thymidylate synthase (TS) catalyses the conversion of dUMP to TMP, which is converted to TDP and ultimately to TTP, a building block in DNA synthesis. TS inhibitors are recommended in some cancers, particularly non-small cell lung cancer (NSCLC). Because TS inhibitors modulate intracellular concentrations of endogenous 2′-deoxynucleotides, we hypothesized that TS inhibitors could impact the anti-HIV activity of nucleoside analogue reverse transcriptase inhibitors (NRTIs). Methods: We evaluated gemcitabine and pemetrexed, two approved TS inhibitors, on the anti-HIV activities of NRTIs in infectivity assays using peripheral blood mononuclear cells (PBMCs) and in humanized mice. Results: Gemcitabine enhanced the anti-HIV activities of tenofovir, abacavir and emtricitabine (FTC) in PBMCs. In contrast, pemetrexed had no effect on tenofovir, enhanced abacavir and, unexpectedly, decreased FTC and lamivudine (3TC) activities. Pemetrexed inhibitory effects on FTC and 3TC may be due to lower concentrations of active metabolites (FTCtp and 3TCtp) relative to their competing endogenous nucleotide (dCTP), as shown by decreases in FTCtp/dCTP ratios. Gemcitabine enhanced tenofovir while pemetrexed abrogated FTC antiviral activity in humanized mice. Conclusions: Chemotherapy with TS inhibitors can have opposing effects on cART, potentially impacting control of HIV and thereby development of viral resistance and size of the reservoir in HIV-infected cancer patients. Combinations of cART and chemotherapy should be carefully selected.