TY - JOUR
T1 - HIV gp120 H375 is unique to HIV-1 subtype CRF01-AE and confers strong resistance to the entry inhibitor BMS-599793, a candidate microbicide drug
AU - Schader, Susan M.
AU - Colby-Germinario, Susan P.
AU - Quashie, Peter K.
AU - Oliveira, Maureen
AU - Ibanescu, Ruxandra Ilinca
AU - Moisi, Daniela
AU - Mespléde, Thibault
AU - Wainberg, Mark A.
PY - 2012/8
Y1 - 2012/8
N2 - BMS-599793 is a small molecule entry inhibitor that binds to human immunodeficiency virus type 1 (HIV-1) gp120, resulting in the inhibition of CD4-dependent entry into cells. Since BMS-599793 is currently considered a candidate microbicide drug, we evaluated its efficacy against a number of primary patient HIV isolates from different subtypes and circulating recombinant forms (CRFs) and showed that activity varied between ∼3 ρMand 7 μMat 50% effective concentrations (EC50s). Interestingly, CRF01-AE HIV-1 isolates consistently demonstrated natural resistance against this compound. Genotypic analysis of > 1,600 sequences (Los Alamos HIV sequence database) indicated that a single amino acid polymorphism in Env, H375, may account for the observed BMS-599793 resistance in CRF01-AE HIV-1. Results of site-directed mutagenesis experiments confirmed this hypothesis, and in silico drug docking simulations identified a drug resistance mechanism at the molecular level. In addition, CRF01-AE viruses were shown to be resistant to multiple broadly neutralizing monoclonal antibodies. Thus, our results not only provide insight into how Env polymorphisms may contribute to entry inhibitor resistance but also may help to elucidate how HIV can evade some broadly neutralizing antibodies. Furthermore, the high frequency of H375 in CRF01-AE HIV-1, and its apparent nonoccurrence in other subtypes, could serve as a means for rapid identification of CRF01-AE infections.
AB - BMS-599793 is a small molecule entry inhibitor that binds to human immunodeficiency virus type 1 (HIV-1) gp120, resulting in the inhibition of CD4-dependent entry into cells. Since BMS-599793 is currently considered a candidate microbicide drug, we evaluated its efficacy against a number of primary patient HIV isolates from different subtypes and circulating recombinant forms (CRFs) and showed that activity varied between ∼3 ρMand 7 μMat 50% effective concentrations (EC50s). Interestingly, CRF01-AE HIV-1 isolates consistently demonstrated natural resistance against this compound. Genotypic analysis of > 1,600 sequences (Los Alamos HIV sequence database) indicated that a single amino acid polymorphism in Env, H375, may account for the observed BMS-599793 resistance in CRF01-AE HIV-1. Results of site-directed mutagenesis experiments confirmed this hypothesis, and in silico drug docking simulations identified a drug resistance mechanism at the molecular level. In addition, CRF01-AE viruses were shown to be resistant to multiple broadly neutralizing monoclonal antibodies. Thus, our results not only provide insight into how Env polymorphisms may contribute to entry inhibitor resistance but also may help to elucidate how HIV can evade some broadly neutralizing antibodies. Furthermore, the high frequency of H375 in CRF01-AE HIV-1, and its apparent nonoccurrence in other subtypes, could serve as a means for rapid identification of CRF01-AE infections.
UR - http://www.scopus.com/inward/record.url?scp=84864386257&partnerID=8YFLogxK
U2 - 10.1128/AAC.00639-12
DO - 10.1128/AAC.00639-12
M3 - Article
C2 - 22615295
AN - SCOPUS:84864386257
SN - 0066-4804
VL - 56
SP - 4257
EP - 4267
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 8
ER -