Garcia-Lerma J G, Nidtha S, Blumoff K, Weinstock H, Heneine W
HIV and Retrovirology Branch, Division of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13907-12. doi: 10.1073/pnas.241300698. Epub 2001 Nov 6.
Transmission of HIV-1 with reduced susceptibility to antiretroviral drugs raises public health concerns. Through surveillance of drug-resistant HIV-1 in 603 treatment-naive, recently diagnosed HIV-1-infected persons, we identified a distinct group of viruses that have mutations at codon 215 of the reverse transcriptase (RT) gene that are different from either the wild-type (WT) T or the zidovudine (AZT)-selected T215Y/F. These mutations included 215D/C/S and were found in 20 patients (3.3%). The 215D, 215C, and 215S mutations differ from 215Y by a 1-nt change compared with 2 nt for the WT T215 and likely represent revertants of 215Y. These viruses all were found to have WT susceptibility to AZT, and all replicated efficiently as WT HIV-1(T215). However, differences in fitness among HIV-1(215D), HIV-1(215C), and HIV-1(215S) were seen when RT backgrounds were changed, demonstrating a role of the RT background in the selection of these revertants. In vitro selection with AZT showed that HIV-1(215D) and HIV-1(215C) acquired 215Y more rapidly than did WT HIV-1(T215), likely reflecting the need for only 1-nt change to evolve to 215Y. Our study demonstrates that HIV-1 with unusual mutations at codon 215 replicate efficiently, have WT susceptibility, and are commonly found in treatment-naive persons. The increased ability for selecting resistance mutations defines this class of WT HIV-1 and highlights the higher potential of these viruses to compromise the efficacy of antiretroviral therapy.
对抗逆转录病毒药物敏感性降低的HIV-1传播引发了公共卫生问题。通过对603名未经治疗、近期诊断为HIV-1感染的初治患者中耐药HIV-1的监测，我们鉴定出一组独特的病毒，其逆转录酶（RT）基因第215密码子发生的突变不同于野生型（WT）的T，也不同于齐多夫定（AZT）选择的T215Y/F。这些突变包括215D/C/S，在20名患者（3.3%）中被发现。与WT T215的2个核苷酸变化相比，215D、215C和215S突变与215Y仅相差1个核苷酸变化，可能代表215Y的回复突变体。这些病毒均对AZT具有野生型敏感性，并且都能像WT HIV-1（T215）一样高效复制。然而，当RT背景改变时，HIV-1（215D）、HIV-1（215C）和HIV-1（215S）之间出现了适应性差异，这表明RT背景在这些回复突变体的选择中起作用。用AZT进行体外选择表明，HIV-1（215D）和HIV-1（215C）比WT HIV-1（T215）更快获得215Y，这可能反映了只需1个核苷酸变化就能进化为215Y。我们的研究表明，在第215密码子处具有异常突变的HIV-1能高效复制，具有野生型敏感性，并且在初治患者中很常见。选择耐药突变能力的增强定义了这类WT HIV-1，并突出了这些病毒损害抗逆转录病毒疗法疗效的更高可能性。
