HIV-1 and Vaccine: Analysis of gp41 Target Sequences

Despite extensive efforts by scientists, academic institutions, and pharmaceutical companies, a safe and effective HIV/AIDS vaccine remains elusive. Most HIV-1 envelope peptide vaccine strategies have concentrated on Gp120, gp140, or gp160. HIV-1 Env trimer binding to the CD4-receptor initiates structural changes promoting the envelope's transition from a closed to an open state via an intermediate step. Broadly neutralizing antibodies target the state-1 Env conformation, while less effective antibodies typically recognize open states. However, due to virus variability, an optimal vaccine has not yet been successfully developed. In this study, focusing on the pivotal role of Gp41 in various vaccine strategies, a very large sequence dataset was utilized. These sequences were obtained from drug-naïve individuals or those undergoing antiretroviral therapy (ART). Gp41 amino acid variability was characterized genetically using a starting pool dataset of 24,505 full-length Env sequences from HIV-1 Subtype-B infected individuals. The dataset underwent hydropathy analysis, genetic distance evaluation, non-synonymous/synonymous substitution rate estimation, Shannon-Entropy calculation, and N-linked glycosylation (NLG) analysis. Similar variability between viral sequences retrieved from drug-naïve and antiretroviral-treated individuals was observed. In our dataset, ART selection pressures observed at gp41 level are minimal: 7 positions with dN/dS > 1, significant increases in entropy values, and a comparable value of glycosylation sites were highlighted. This study reinforces the importance of identifying specific single sensitizing mutations in HIV control. Gp41 remains an important vaccine target for understanding virus-host immunological interactions. Further analyses may reveal specific mechanisms related to host antiviral responses and viral regions with strong masking activity.