Effect of nucleoside analogs and non-nucleoside inhibitors of HIV-1 reverse transcriptase on cell-free virions

Reverse transcription takes place in the cytoplasm of infected cells, altho ugh it has been demonstrated that retroviruses can also initiate reverse tr anscription prior to infection of target cells. In addition to partial reve rse transcripts, full-length proviral molecules have been detected in the p lasma and seminal fluid of HIV-I seropositive patients. Intravirion endogen ous reverse transcription appears to be directly correlated with an increas ed level of infectivity. Therefore, the ability of an inhibitor to reach an d inhibit the replication complex in the core of the free-virion may consti tute an important part of its capacity to suppress viral infection. In this work we tested the ability of some reverse transcriptase inhibitors to dec rease viral infectivity in pretreated highly purified virions. Our results showed that Curie pyridinone [Dolle et al. (1995), J Med Chem 38: 4679-4686 ], a non nucleoside RT inhibitor, strongly inhibited the infectivity of ext racellular HIV-1 particles. Other non nucleoside inhibitors (TIBO R82913, H EFT, nevirapine) tested in these conditions were unable to do so. Our data indicate that the effect of Curie pyridinone on intact virions may be relat ed to its capacity to tightly bind the target RT. This approach may lead to the design and synthesis of new drugs able to interact with the retroviral enzyme inside the viral core.