Efavirenz is a potent nonnucleoside reverse transcriptase inhibitor of HIVtype 1 replication in microglia in vitro

The objective of this study was to determine whether reverse transcriptase inhibitors (RTIs) could decrease viral replication in microglia. Human micr oglia obtained from individuals undergoing temporal lobectomy were cultured and infected with HIV-1 isolates from the central nervous system (CNS) as previously described (Strizki JM, et al. J Virol 1996; 70:7654-7662). These microglial cultures were treated with one of three nucleoside RTIs (NRTIs) or with efavirenz, a nonnucleoside RTI (NNRTI), at various time points bef ore and during HIV-1 infection. The drug levels sufficient to provide > 90% inhibition of microglial HIV replication (IC90) were determined by compari son of p24(gag) release in the cultures among treated and untreated microgl ia. Infectious virus released from the infected cultures was also measured with U373-MAGI-CCR5 cells. Efavirenz, an NNRTI, blocked HIV-1(DS-br) infect ion of microglia with an IC90 of 0.7-7 nM. This value is similar to the efa virenz IC90 values for inhibition of laboratory and clinical isolates in ly mphocytes, is 2-3 logs lower than the IC90 values of AZT and d4T, and is 1- 2 logs lower than that of ddC in microglia. Efavirenz also inhibited infect ion with other neurotropic isolates, and with viruses isolated from other c ompartments that also replicated well in microglia. Thus, efavirenz is a po tent inhibitor of HIV-1 infection in microglia. Furthermore, efavirenz IC90 drug levels are present in the cerebrospinal fluid (CSF) of patients takin g this once daily NNRTI.