Efficient HIV-1 replication requires the expression of Vif (viral infectivity factor) protein to counter the activity of APOBEC3G (A3G), a DNA-editing cytidine deaminase expressed nonpermissive cells, which catalyzes critical hypermutations in the viral DNA and acts as an innate weapon against retroviruses. In contrast, HIV-1 replication is Vif-independent in host cells that do not express A3G (permissive cells). RN-18 is a small molecule HIV-1 Vif inhibitor with an IC50 of 6 μM in nonpermissive H9 cells. RN-18 also exhibits potent antiviral activity in the nonpermissive CEM cells with IC50 of 4.5 μM but not in permissive MT4 and CEM-SS cells [3]. In 293T cells treated with 50 μM RN-18 for 24 h, Vif protein levels were downregulated, and A3G expression increased, indicating that RN-18 inhibited Vif function and upregulated A3G levels. Similar to A3G, APOBEC3F and APOBEC3C, other members of APOBEC3 family, are also potent inhibitors of HIV-1 replication and is targeted by Vif. The levels of APOBEC3F and APOBEC3C were significantly and quantitatively enhanced in 293T cells treated with 50 μM RN-18 for 24 h [4].
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