Stratov Ivan, Dale C Jane, Chea Socheata, McCluskey James, Kent Stephen J
Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
J Virol. 2005 Jun;79(12):7728-37. doi: 10.1128/JVI.79.12.7728-7737.2005.
Antiretroviral drug-resistant human immunodeficiency virus type 1 (HIV-1) is a major, growing, public health problem. Immune responses targeting epitopes spanning drug resistance sites could ameliorate development of drug resistance. We studied 25 individuals harboring multidrug-resistant HIV-1 for T-cell immunity to HIV-1 proteins and peptides spanning all common drug resistance mutations. CD8 T cells targeting epitopes spanning drug-induced mutations were detected but only in the 3 individuals with robust HIV-specific T-cell activity. Novel CD8 T-cell responses were detected against the common L63P and L10I protease inhibitor fitness mutations. Induction of T-cell immunity to drug-resistant variants was demonstrated in simian human immunodeficiency virus-infected macaques, where both CD8 and CD4 T-cell immune responses to reverse transcriptase and protease antiretroviral mutations were elicited using a novel peptide-based immunotherapy. T-cell responses to antiretroviral resistance mutations were strongest in the most immunocompetent animals. This study suggests feasible strategies to further evaluate the potential of limiting antiretroviral drug resistance through induction of T-cell immunity.
抗逆转录病毒药物耐药的1型人类免疫缺陷病毒（HIV-1）是一个日益严重的重大公共卫生问题。针对跨越耐药位点表位的免疫反应可能会改善耐药性的发展。我们研究了25名携带多药耐药HIV-1的个体，以了解其针对涵盖所有常见耐药突变的HIV-1蛋白和肽的T细胞免疫情况。检测到了针对跨越药物诱导突变表位的CD8 T细胞，但仅在3名具有强大HIV特异性T细胞活性的个体中检测到。检测到了针对常见的L63P和L10I蛋白酶抑制剂适应性突变的新型CD8 T细胞反应。在感染猿猴免疫缺陷病毒的猕猴中证实了对耐药变体的T细胞免疫诱导，在那里，使用一种新型的基于肽的免疫疗法引发了针对逆转录酶和蛋白酶抗逆转录病毒突变的CD8和CD4 T细胞免疫反应。在免疫功能最强的动物中，T细胞对抗逆转录病毒耐药突变的反应最强。这项研究提出了可行的策略，以进一步评估通过诱导T细胞免疫来限制抗逆转录病毒药物耐药性的潜力。
