Kato Frank, Kapaata Anne, Galiwango Ronald, Nakyanzi Angella, Ndekezi Christian, Natwijuka Fortunate, Omara Denis, Obuku Andrew Ekii, Foley Brian, Kaleebu Pontiano, Nduati Eunice, Balinda Sheila Nina
MRC/UVRI & LSHTM Uganda Research Unit, Department of Viral Pathogens, Entebbe, Uganda.
Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda.
Front Microbiol. 2025 Aug 4;16:1632581. doi: 10.3389/fmicb.2025.1632581. eCollection 2025.
The envelope glycoprotein (Env) of HIV-1 Transmitted/Founder (T/F) viruses in subtypes B and C carries distinct genetic signatures that enhance transmission fitness, augment infectivity and immune evasion. However, there is limited data on such signatures in T/F subtypes A1, D and A1D recombinants that predominate East Africa's HIV epidemic.
We used phylogenetically corrected approaches to detect distinct genetic signatures by comparing 44 contemporary HIV-1 T/F Envs with 229 historical Envs of the same subtype in East Africa.
Subtype analysis based on the full-length Env gene of contemporary T/F viruses revealed a high proportion of subtype A1, followed by A1D recombinants, and fewer subtype D. Signature analysis revealed that the contemporary subtype A1 T/Fs were more likely to select distinct amino acids, including M22 in the signal peptide, R82 in gp120, A172 in the V2 loop, E230 in the glycosite 230, K275 in the D loop, Y317 in the V3 loop, K476 and N477 in the CD4 contact site, when compared with the historical Envs (q-value < 0.2). Conversely, the contemporary subtype A1 T/F Envs were less likely to carry the amino acids Q432 in the CD4 contact site, and the L784 signature within the LLP-2 (q-value < 0.2). The A1D recombinant T/Fs were more likely to select the D620 in the C-helix, but under selected the L34 in gp120, P299 in the V3 loop and Y643 in the Heptad repeat-2, compared to the historical Envs (q-value < 0.2). The distinct signature sites reported in this study may contribute to the successful establishment of acute infection as well as the persistence of long-term infection. Therefore, effective therapeutics and vaccines may target these distinct amino acid signatures especially for the East African region as it may be necessary to employ subtype-specific vaccines according to the subtype distribution.
B型和C型HIV-1传播/奠基者（T/F）病毒的包膜糖蛋白（Env）具有独特的基因特征，可增强传播适应性、提高感染性并实现免疫逃逸。然而，在东非HIV疫情中占主导地位的A1、D型和A1D重组T/F亚型中，关于此类特征的数据有限。
我们采用系统发育校正方法，通过比较44个当代HIV-1 T/F Env与东非229个相同亚型的历史Env，来检测独特的基因特征。
基于当代T/F病毒全长Env基因的亚型分析显示，A1亚型比例很高，其次是A1D重组体，D亚型较少。特征分析表明，与历史Env相比，当代A1亚型T/F更有可能选择独特的氨基酸，包括信号肽中的M22、gp120中的R82、V2环中的A172、糖基化位点230中的E230、D环中的K275、V3环中的Y317、CD4接触位点中的K476和N477（q值<0.2）。相反，当代A1亚型T/F Env携带CD4接触位点中氨基酸Q432和LLP-2内L784特征的可能性较小（q值<0.2）。与历史Env相比，A1D重组T/F更有可能选择C螺旋中的D620，但在gp120中选择L34、V3环中的P299和七肽重复序列2中的Y643的可能性较小（q值<0.2）。本研究报告的独特特征位点可能有助于急性感染的成功建立以及长期感染的持续存在。因此，有效的治疗方法和疫苗可能针对这些独特的氨基酸特征，特别是对于东非地区，因为可能需要根据亚型分布使用亚型特异性疫苗。
