Epidemiological studies have demonstrated that the human immunodeficiency virus (HIV)-1 drug-resistant rate among injecting drug users is higher than that in other HIV-1-positive populations, which is generally believed to be largely due to clinical nonadherence. Little is known, however, about whether heroin abuse has a direct impact on the generation of HIV-1 drug-resistant mutations. In this study, we investigated the impacts of morphine, the active metabolite of heroin, on HIV-1 infection/replication and HIV-1 drug-resistant mutations through an in vitro HIV-1-CD4+ T cell system under selective pressure from two typical antiviral drugs, Lamivudine and Nevirapine. We found that morphine treatment of MT4 cells (a CD4+ T cell line) significantly increased HIV-1 III B (a T-tropic viral strain) infection and replication in MT4 cells, and the effect of morphine on HIV-1 was mediated through an opioid receptor. More importantly, our results showed that morphine treatment not only induced more drug-resistant mutations under selective pressure from antiretroviral drugs but also shortened the mutations' generation time, compared with the control groups that were treated with antiretroviral drugs alone. Although the in vivo relevance remains to be determined, these findings provide direct in vitro evidence to support the possibility that heroin abuse itself can act as an independent factor contributing to the generation of HIV-1 drug resistance during clinical antiretroviral therapy. Therapeutic guidelines should consider this issue for heroin users with HIV infection.
Keywords: HIV-1; Lamivudine; Nevirapine; drug resistance; morphine.