Evaluation of capsid inhibitor resistance profiles and HIV-1 subtype distribution via near-full-length genome NGS in ART-naive HIV-1 patients in Guangxi, China
Peijiang Pan, Caichang Mo, Rongfeng Chen, Yanyan Liao, Bingyu Liang, Xiaomei Li, Qisi Su, Yuanting Li, Feirong Chen, Yifeng Huang, Hailong Wang, Lijuan Zhou, Xu Li, Junjun Jiang, Li Ye, Hao LiangAbstract
Objectives
Lenacapavir, a first-in-class, long-acting capsid inhibitor (CAI), has been approved for HIV-1 treatment and prevention. However, naturally occurring resistance to the HIV-1 CAI at the quasi-species level is rarely reported.
Methods
Using next-generation sequencing (NGS), we obtained 495 HIV-1 near-full-length genome (NFLG) sequences derived from plasma specimens of ART-naive individuals in Guangxi, China. Drug resistance mutations (DRMs) conferring resistance to CAIs, as well as to NNRTIs, NRTIs, PIs and INSTIs, were detected at a 5% frequency threshold for variant calling using the HIVdb program. To analyse naturally occurring polymorphisms, the gag sequences of CRF08_Bc subtype were retrieved from two public sequence databases, followed by CAI-related DRM detection. Subtype-specific capsid polymorphism was analysed with a 0.5% prevalence cut-off.
Results
Of the 495 individuals, 16.77% (83/495) were infected with unique recombinant forms (URFs). Overall, 4.44% (22/495) of the sequences were carrying at least DRMs to CAIs, including one major DRM (Q67H, 0.80%) and two accessory DRMs (T107A, 2.22%; T107S, 1.81%). No cross-resistance to other classes of drugs, including PIs, NRTIs, NNRTIs or INSTIs, was observed in individuals with CAI-related DRMs. According to the definition of subtype-specific polymorphism (>0.5% prevalence), Q67H (1.60%, 3/188) and T107S (1.60%, 3/188) were CRF01_AE-specific polymorphisms, whereas T107A (5.05%, 11/218) and T107S (3.03%, 5/218) were CRF08_Bc-specific polymorphisms.
Conclusions
HIV URFs are commonly misclassified by conventional partial pol gene subtyping among treatment-naive patients in Guangxi, indicating a need for enhanced full-genome genotyping surveillance locally. Subtype-specific capsid polymorphisms that have not been identified in previous studies further highlight the value of geographically diverse cohorts in future CAI research to improve real-world applicability.