Detecting and understanding combinatorial mutation patterns responsible for HIV drug resistance.
We propose a systematic approach for a better understanding of how HIV viruses employ various combinations of mutations to resist drug treatments, which is critical to developing new drugs and optimizing the use of existing drugs. By probabilistically modeling mutations in the HIV-1 protease or reverse transcriptase (RT) isolated from drug-treated patients, we present a statistical procedure that first detects mutation combinations associated with drug resistance and then infers detailed interaction structures of these mutations. The molecular basis of our statistical predictions is further studied by using molecular dynamics simulations and free energy calculations. We have demonstrated the usefulness of this systematic procedure on three HIV drugs, (Indinavir, Zidovudine, and Nevirapine), discovered unique interaction features between viral mutations induced by these drugs, and revealed the structural basis of such interactions.
Zhang
Jing
J
Department of Statistics, Harvard University, Science Center, 1 Oxford St, Cambridge, MA 02138, USA.
Hou
Tingjun
T
Wang
Wei
W
Liu
Jun S
JS
D019380:Anti-HIV Agents / Q000737:chemistry / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D019469:Indinavir / Q000737:chemistry / Q000627:therapeutic use; D008958:Models, Molecular; D009154:Mutation; D019829:Nevirapine / Q000627:therapeutic use; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015215:Zidovudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; D015215:Zidovudine; D019469:Indinavir; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1