Mechanism of HIV Resistance to the Drug AZT Sol M. Gruner, Cornell University, DMR 0936384

1. Mechanism of HIV Resistance to the Drug AZTSol M. Gruner, Cornell University, DMR 0936384 Intellectual Merit: Drugs which inhibit the activity of the reverse transcriptase of HIV-1 (HIV-RT) are effective in treating AIDS, since the virus cannot replicate without a working RT. Unfortunately, HIV is prone to mutations, some of which can render a formerly potent drug ineffective. The Arnold group (Rutgers) has now elucidated the mechanism by which a mutated form of HIV-RT resists the drug AZT. HIV-RT is able to remove the AZT, using the cellular energy source ATP; this process is usually quite inefficient, but mutations to HIV-RT can enhance it to the point that AZT becomes ineffective. The crystal structures they found also help elucidate the mechanism by which HIV-RT transfers AZT from the 3' end of a DNA primer to ATP, suggesting that drugs targeting the ATP binding site would inhibit this excision process and would be useful therapeutically when administered together with AZT to avoid drug resistance. Binding sites of ATP on the surface of HIV-RT. Site I exists in both wild-type and mutant protein, but site II is present only in the mutant. Structural basis of HIV-1 resistance to AZT by excision, X. Tu, K. Das, Q. Han, J. Bauman, A. Clark Jr., X. Hou, Y. Frenkel, B. Gaffney, R. Jones, P. Boyer, S. Hughes, S. Sarafianos, and E. Arnold , Nature Structural & Molecular Biology 17, 1202-1209 (2010) CHESS DMR-0936384 2011_1