HIV-1 TAT Interactions with Opioids are Modulated by Progesterone and Estradiol

HIV infection and combined substance abuse are comorbid epidemics. Previous studies show that concurrent opioid drug use may potentiate HIV-1-mediated neurotoxicity partly via interactions with opioids. Preclinical studies suggest that the HIV-1 trans-activator of transcription (Tat), an HIV regulatory protein, can synergize with opioids to exacerbate its already neurotoxic effects. However, its interactions with clinical opioids, such as oxycodone, have yet to be elucidated. Additionally, Tat disrupts a number of systems including the dopaminergic system, which contribute to its capacity to potentiate the rewarding effects of abused drugs. Although the neurotoxic effects of Tat may be inhibited by gonadal steroids in vitro, such as estradiol (E2) and progesterone (P4), preclinical work suggests that estradiol may also potentiate drug reward/reinforcement as well. Little is known about the behavioral interactions between Tat and E2. In a 2-bottle choice task, we found that Tat expression in mice significantly increased morphine preference on the first day of morphine presentation. E2 (0.09 mg/kg, s.c., QOD) significantly increased morphine consumption, irrespective of Tat expression. Following naloxone-precipitated withdrawal, Tat or E2 increased jumping behavior. In complementary in vitro experiments, Tat increased cell death in SH-SY5Y human neuroblastoma cells and oxycodone did not further potentiate this effect. Irrespective of whether cells were treated with Tat alone or in combination with oxycodone, any concentration of E2 (1 or 10 nM), or the highest concentration of P4 (100 nM, but not 10 nM) significantly attenuated Tat-mediated cell death. These data suggest that E2 may display parallel protective qualities over Tat’s capacity to potentiate withdrawal and promote cell death. However, caution is warranted given E2’s capacity to increase opioid self-administration. These data lend further evidence to support the potential neuroprotective efficacy of gonadal steroid hormone-based therapeutics and further our understanding of their interactions with HIV-1 and the clinically-prescribed opioid, oxycodone