why do hiv-1 and hiv-2 use different pathways to develop azt resistance为什么hiv - 1和hiv - 2使用不同的路径来开发azt阻力.pdf

Why Do HIV-1 and HIV-2 Use Different Pathways to Develop AZT Resistance? 1 2 3 2 1* Paul L. Boyer , Stefan G. Sarafianos , Patrick K. Clark , Eddy Arnold , Stephen H. Hughes 1 HIV Drug Resistance Program, NCI-Frederick, Frederick, Maryland, United States of America, 2 Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, United States of America, 3 Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, United States of America The human immunodeficiency virus type 1 (HIV-1) develops resistance to all available drugs, including the nucleoside analog reverse transcriptase inhibitors (NRTIs) such as AZT. ATP-mediated excision underlies the most common form of HIV-1 resistance to AZT. However, clinical data suggest that when HIV-2 is challenged with AZT, it usually accumulates resistance mutations that cause AZT resistance by reduced incorporation of AZTTP rather than selective excision of AZTMP. We compared the properties of HIV-1 and HIV-2 reverse transcriptase (RT) in vitro. Although both RTs have similar levels of polymerase activity, HIV-1 RT more readily incorporates, and is more susceptible to, inhibition by AZTTP than is HIV-2 RT. Differences in the region around the polymerase active site could explain why HIV-2 RT incorporates AZTTP less efficiently than HIV-1 RT. HIV-1 RT is markedly more efficient at carrying out the excision reaction with ATP as the pyrophosphate donor than is HIV-2 RT. This suggests that HIV-1 RT has a better nascent ATP binding site than HIV-2 RT, making it easier for HIV-1 RT to develop a more effective ATP binding site by mutation. A comparison of HIV-1 and HIV-2 RT shows that there are numerous differences