Intracellular Interactions Between Nucleos(t)ide Inhibitors of HIV Reverse Transcriptase

Current standard-of-care regimens recommended for the treatment of HIV infection include two ormore nucleos(t)ide reverse transcriptase inhibitors (NRTI) in combination with a protease or nonnucleosidereverse transcriptase inhibitor. NRTIs are activated through interactions with the cellularmachinery for regulating endogenous nucleoside triphosphate (NTP) pools. Once activated to theirtriphosphate form, NRTIs compete with natural 2’- deoxynucleoside triphosphates (dNTP) for incorporationby the virally encoded reverse transcriptase and host polymerases. Competitive inhibition,changes in enzyme expression, or allosteric modulation of cellular metabolizing enzymes maytherefore alter NRTI activation or perturb cellular dNTP levels causing changes in NRTI antiviralactivity and toxicity. This paper reviews the unique metabolic profiles of NRTIs and discusses methodologiesfor understanding the effects of combining them. Cell culture experiments assessing theantiviral synergy and intracellular metabolism of NRTI combinations have yielded valuable insightsinto the behavior of treatment regimens in vivo. The development of more reliable and convenientmethods for detecting nucleotides, including those applying mass spectrometry, are helping tofurther elucidate the intracellular pharmacology of NRTIs. Studies assessing the potential for intracellularNRTI drug-drug interactions will facilitate a better understanding of the efficacy of currenttherapies, as well as the design of combination therapies with optimal activity and toxicity profiles.