Troyano-Hernáez Paloma, Reinosa Roberto, Holguín África
HIV-1 Molecular Epidemiology Laboratory, Department of Microbiology, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, CIBER en Epidemiología y Salud Pública (CIBERESP), Red en Investigación Translacional en Infecciones Pediátricas (RITIP), Madrid, Spain.
Front Microbiol. 2022 Apr 12;13:854974. doi: 10.3389/fmicb.2022.854974. eCollection 2022.
The HIV p24 capsid protein has an essential, structural, and functional role in the viral replication cycle, being an interesting target for vaccine design, diagnostic tests, and new antiretroviral drugs (ARVs). The HIV-1 variability poses a challenge for the accuracy and efficiency of diagnostic and treatment tools. This study analyzes p24 diversity among HIV-1 variants and within its secondary structure in HIV-1 M, O, P, and N groups. All available HIV-1 p24 nucleotide sequences were downloaded from the Los Alamos HIV Sequence Database, selecting 23,671 sequences belonging to groups O, N, P, and M (9 subtypes, 7 sub-sub types, and 109 circulating recombinant forms or CRFs). Using a bioinformatics tool developed in our laboratory (EpiMolBio program), we analyzed the amino acid conservation compared to the HXB2 subtype B reference sequence and the V-markers, or amino acid changes that were specific for each variant with at least 10 available sequences. We inferred the p24 consensus sequence for HIV-1 and for each group to analyze the overall conservation in p24 main structural regions, reporting the percentage of substitutions per variant affecting the capsid assembly and molecule-binding, including those associated with resistance to the new capsid-inhibitor lenacapavir, and the key residues involved in lenacapavir-p24 interaction, according to the bibliography. Although the overall structure of p24 was highly conserved, the conservation in the secondary structure varied between HIV-1 variants and the type of secondary structure. All HIV-1 variants presented >80% amino acid conservation vs. HXB2 reference sequence, except for group M sub-subtype F1 (69.27%). Mutants affecting the capsid assembly or lenacapavir capsid-binding were found in <1% of the p24 consensus sequence. Our study reports the HIV-1 variants carrying 14 unique single V-markers in 9/38 group M variants and the level of p24 conservation in each secondary structure region among the 4 HIV-1 groups and group M variants, revealing no natural resistance to lenacapavir in any HIV-1 variant. We present a thorough analysis of p24 variability among all HIV-1 variants circulating to date. Since p24 genetic variability can impact the viral replication cycle and the efficacy of new p24-based diagnostic, therapeutic, and vaccine strategies, conservation studies must consider all HIV-1 variants circulating worldwide.
HIV p24衣壳蛋白在病毒复制周期中具有重要的结构和功能作用，是疫苗设计、诊断测试及新型抗逆转录病毒药物（ARV）的一个有吸引力的靶点。HIV-1的变异性对诊断和治疗工具的准确性和效率构成挑战。本研究分析了HIV-1 M、O、P和N组中HIV-1变体之间及其二级结构内的p24多样性。从洛斯阿拉莫斯HIV序列数据库下载了所有可用的HIV-1 p24核苷酸序列，选择了属于O、N、P和M组的23,671个序列（9个亚型、7个亚亚型和109种循环重组形式或CRF）。使用我们实验室开发的生物信息学工具（EpiMolBio程序），我们分析了与HXB2 B亚型参考序列相比的氨基酸保守性以及V标记，即每个至少有10个可用序列的变体特有的氨基酸变化。我们推断了HIV-1及每组的p24共有序列，以分析p24主要结构区域的总体保守性，报告每个变体中影响衣壳组装和分子结合的替换百分比，包括与对新型衣壳抑制剂伦那卡帕韦耐药相关的替换，以及根据文献，参与伦那卡帕韦-p24相互作用的关键残基。尽管p24的总体结构高度保守，但二级结构的保守性在HIV-1变体和二级结构类型之间有所不同。所有HIV-1变体与HXB2参考序列相比，氨基酸保守性均>80%，M组亚亚型F1除外（69.27%）。在p24共有序列中，发现影响衣壳组装或伦那卡帕韦衣壳结合的突变体<1%。我们的研究报告了9/38个M组变体中携带14个独特单V标记的HIV-1变体，以及4个HIV-1组和M组变体中每个二级结构区域的p24保守水平，揭示了任何HIV-1变体对伦那卡帕韦均无天然耐药性。我们对迄今流行的所有HIV-1变体中的p24变异性进行了全面分析。由于p24基因变异性会影响病毒复制周期以及基于p24的新型诊断、治疗和疫苗策略的疗效，保守性研究必须考虑全球流行的所有HIV-1变体。
