Nucleoside reverse transcriptase inhibitors are the major class of HIV antiretroviral therapeutics that induce neuropathic pain in Mice

Abstract

AO_SCPLOWBSTRACTC_SCPLOWThe development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications that lead to decreased quality of life, one of the most significant of which is neuropathic pain and development of painful peripheral sensory neuropathy (PSN). Critically, although cART is thought to induce pain pathogenesis, the relative contribution of different classes of antiretrovirals has not been systematically investigated. In this study, we measured development of pathological pain and peripheral neuropathy in mice orally treated with distinct antiretrovirals at their translational dosages. Our results show that only nucleoside reverse transcriptases (NRTIs), but not other types of antiretrovirals, such as proteinase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and CCR5 antagonists, induce pathological pain and PSN. Thus, these findings suggest that NRTIs are the major class of antiretrovirals in cART that promote development of neuropathic pain. As NRTIs form the essential backbone of multiple different current cART regimens, it is of paramount clinical importance to better understand the underlying mechanism to facilitate design of less toxic forms of these drugs and or potential mitigation strategies.