根据初治个体中的病毒进化枝评估HIV-1衣壳基因变异性和与来那卡帕韦（GS-6207）耐药相关的突变。

Evaluation of HIV-1 capsid genetic variability and lenacapavir (GS-6207) drug resistance-associated mutations according to viral clades among drug-naive individuals.

作者信息

Nka Alex Durand, Bouba Yagai, Teto Georges, Semengue Ezéchiel Ngoufack Jagni, Takou Désiré Komego, Ngueko Aurelie Minelle Kengni, Fabeni Lavinia, Carioti Luca, Armenia Daniele, Pabo Willy, Dambaya Béatrice, Sosso Samuel Martin, Colizzi Vittorio, Perno Carlo-Federico, Ceccherini-Silberstein Francesca, Santoro Maria Mercedes, Fokam Joseph, Ndjolo Alexis

机构信息

Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management (CIRCB), Yaoundé, Cameroon.

University of Rome 'Tor Vergata', Rome, Italy.

出版信息

J Antimicrob Chemother. 2022 Dec 23;78(1):272-275. doi: 10.1093/jac/dkac388.

DOI:10.1093/jac/dkac388

PMID:36411257

Abstract

OBJECTIVES

We evaluated the HIV-1 capsid genetic variability and lenacapavir drug resistance-associated mutations (DRMs) among drug-naive individuals across HIV-1 clades.

METHODS

A total of 2031 HIV-1 sequences from drug-naive patients were analysed for capsid amino acid modification and the prevalence of lenacapavir DRMs. Amino acid positions with <5% variability were considered as conserved and variability was analysed by HIV-1 clades.

RESULTS

Overall, 63% (148/232) of amino acid positions were conserved in the capsid protein. Of note, conservation was consistent in specific binding residues of cellular factors involved in viral replication [CypA (G89, P90), CPSF6 (Q4, N57, N74, A77, K182) and TRIM-NUP153 (R143)], while N183 (12.31%) was the only non-conserved lenacapavir binding residue. The overall prevalence (95% CI) of lenacapavir DRMs was 0.14% (0.05-0.44) (3/2031), with M66I (0.05%) and Q67H (0.05%) observed in subtype C, and T107N (0.05%) observed in CRF01_AE. Moreover, polymorphic mutations M66C (n = 85; 4.18%), Q67K (n = 78; 3.84%), K70R (n = 7; 0.34%), N74R (n = 57; 2.81%) and T107L (n = 82; 4.03%) were observed at lenacapavir resistance-associated positions.

CONCLUSIONS

The low level of lenacapavir DRMs (<1%) supports its predicted effectiveness for treatment and prevention, regardless of HIV-1 clades. The established conserved regions hence serve as a hallmark for the surveillance of novel mutations potentially relevant for lenacapavir resistance.

摘要

目的

我们评估了初治个体中HIV-1衣壳的基因变异性以及不同HIV-1进化枝中与来那卡帕韦耐药相关的突变（DRMs）。

方法

对来自初治患者的总共2031条HIV-1序列进行分析，以检测衣壳氨基酸修饰情况以及来那卡帕韦DRMs的流行率。变异率低于5%的氨基酸位置被视为保守位置，并按HIV-1进化枝分析变异性。

结果

总体而言，衣壳蛋白中63%（148/232）的氨基酸位置是保守的。值得注意的是，参与病毒复制的细胞因子的特定结合残基（CypA的G89、P90，CPSF6的Q4、N57、N74、A77、K182以及TRIM-NUP153的R143）的保守性是一致的，而N183（12.31%）是唯一不保守的来那卡帕韦结合残基。来那卡帕韦DRMs的总体流行率（95%CI）为0.14%（0.05 - 0.44）（3/2031），在C亚型中观察到M66I（0.05%）和Q67H（0.05%），在CRF01_AE中观察到T107N（0.05%）。此外，在与来那卡帕韦耐药相关的位置观察到多态性突变M66C（n = 85；4.18%）、Q67K（n = 78；3.84%）、K70R（n = 7；0.34%）、N74R（n = 57；2.81%）和T107L（n = 82；4.03%）。