Abstract Body

The NNRTIs dapivirine (DAP), rilpivirine (RPV) and the phenylethylthiazolylthiourea analog MIV-150 are in development as pre-exposure prophylaxis (PrEP) modalities to prevent the acquisition of HIV-1 infection. Currently, there is a paucity of information in regard to the resistance and cross-resistance profiles of DAP and MIV-150, which we addressed in this study.

Twenty-eight subtype B HIV-1LAI infectious viruses containing single NNRTI resistance mutations spanning 17 different codons (V90I; L100I/V; K101E/P; K103N/S; V106I; V108I; E138A/K; V179D/F, G190A/S; I181C/I/V; Y188C/H/L; H221Y; P225H; F227C/L; M230L; P236L; N348I) were constructed by site-directed mutagenesis. Drug susceptibility in a single cycle assay using TZM-bl cells was determined for RPV, DAP and MIV-150. Low-, intermediate- and high-level resistance was defined as 2-8, 8-20, and >20-fold changes in drug susceptibility compared to the wild type virus.

Of the 3 NNRTIs studied, RPV exhibited the best antiviral activity across the panel of HIV-1 variants tested. RPV was found to be active against 19 of 28 variants, with low-level resistance conferred by the E138A/K, F227C, K101E, Y188L and M230L mutant viruses, and high-level resistance conferred by Y181I/V and K101P. DAP was active against only 15 of the 28 viruses. The K101E, E138K, K103N/S, F227C, Y181C and L100V viruses conferred low resistance to RPV; whereas the L100I and M230L and Y188L, K101P and Y181I/V viruses were found to confer intermediate and high-level resistance, respectively. MIV-150 was also active against only 15 of the HIV-1 variants tested: K101E and L100I/V; F227C and Y181C; and M230L, K103N/S, Y181I/V, Y188L and K101P mutations conferred low-, intermediate and high-level resistance, respectively.

DAP and MIV-150 activity is compromised by many HIV-1 variants containing a single NNRTI resistance mutation. Both NNRTIs exhibit decreased susceptibility toward the K101E, K103N and Y181C mutations which are major NNRTI transmitted drug resistance mutations in all geographic regions and HIV-1 subtypes.