Sonawane Aanand, Selvam Deepak, Yue Ling, Nesakumar Manohar, Vivekanandan Sandhya, Ashokkumar Manickam, Hunter Eric, Hanna Luke Elizabeth
Department of Virology & Biotechnology, ICMR-National Institute for Research in Tuberculosis, Chennai 600031, India.
Department of Immunology, University of Madras, Chennai 600005, India.
Viruses. 2024 Nov 29;16(12):1854. doi: 10.3390/v16121854.
The biological characteristics of early transmitted/founder (T/F) variants are crucial factors for viral transmission and constitute key determinants for the development of better therapeutics and vaccine strategies. The present study aimed to generate T/F viruses and to characterize their biological properties. For this purpose, we constructed 18 full-length infectious molecular clones (IMCs) of HIV from recently infected infants. All the clones were characterized genotypically through whole genome sequencing and phenotypically for infectivity, replication kinetics, co-receptor usage, as well as their susceptibility to neutralizing antibodies and entry inhibitors using standard virological assays. Genotypic analysis revealed that all the T/F clones were of non-recombinant subtype C, but some of them harboured the Y181C drug resistance mutation associated with resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretroviral drugs. In vitro studies showed that while all the IMCs were capable of replicating in PBMCs and utilized the CCR5 co-receptor for cellular entry, the drug-resistant variants had significantly lower replicative capacity and per particle infectivity than the drug-sensitive viruses. Both exhibited similar sensitivities to a standard panel of broadly neutralizing monoclonal antibodies and viral entry inhibitors. These findings suggest that despite their diminished replicative fitness, the drug-resistant T/F variants retain transmission fitness and remain susceptible to neutralizing antibody-based interventions and viral entry inhibitors.
早期传播/奠基者（T/F）变异株的生物学特性是病毒传播的关键因素，也是开发更好的治疗方法和疫苗策略的关键决定因素。本研究旨在构建T/F病毒并表征其生物学特性。为此，我们从近期感染的婴儿中构建了18个HIV全长感染性分子克隆（IMC）。所有克隆均通过全基因组测序进行基因分型，并使用标准病毒学检测方法对其感染性、复制动力学、共受体使用情况以及对中和抗体和进入抑制剂的敏感性进行表型分析。基因分型分析显示，所有T/F克隆均为非重组C亚型，但其中一些携带与对非核苷类逆转录酶抑制剂（NNRTI）类抗逆转录病毒药物耐药相关的Y181C耐药突变。体外研究表明，虽然所有IMC都能够在PBMC中复制并利用CCR5共受体进入细胞，但耐药变异株的复制能力和每颗粒感染性明显低于药物敏感病毒。两者对一组标准的广泛中和单克隆抗体和病毒进入抑制剂表现出相似的敏感性。这些发现表明，尽管耐药T/F变异株的复制适应性有所降低，但它们仍保留传播适应性，并且对基于中和抗体的干预措施和病毒进入抑制剂仍敏感。
