Neutralizing antibodies directed against the V3 loop select for different escape variants in a virus with mutated reverse transcriptase (M184V) than in wild-type human immunodeficiency virus type 1

ABSTRACT The M184V substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) encodes high-level resistance to the (−)-enantiomer of 2′,3′-dideoxy-3′-thiacytidine (3TC) and low-level resistance to each of 2′,3′-dideoxycytidine (ddC) and 2′,3′-dideoxyinosine (ddI). This mutation also results in decreased HIV replication fitness in primary cells, diminished RT processivity, and increased RT fidelity. To assess the effect of this substitution on genetic variation in the HIV env region, we cultured both M184V-containing and wild-type BH10 in MT-4 cells in the presence of the neutralizing monoclonal antibody 447-52D, targeted to the GPGR epitope within the V3 loop of gp 120. Outgrowth of viruses resistant to neutralization was followed by sequence analysis of the V3 loop by standard methodology. Wild-type HIV first showed escape after 15–22 days in culture. Sequence analysis revealed an arginine-to-lysine change within the GPGR epitope in the V3 loop (R20K, AGA → AAA) in six of six ...