Identification of unique molecular signatures in the envelope Glycoproteins of HIV-1 transmitted/founder viruses from East Africa

Abstract

Background: HIV-1 mucosal transmission undergoes a genetic bottleneck that allows a single virus termed HIV-1 Transmitted/Founder (T/F) virus to establish a productive clinical infection in most heterosexual transmission incidents. Studies emphasize that the presence of unique molecular signatures in the envelope glycoproteins (Env) of HIV-1 T/F subtypes B and C enhances transmission fitness, including, higher infectivity of target cells, and immune evasion. However, there is limited evidence on the unique molecular signatures in the Envs of HIV-1 T/F subtype A1, D and A1/D recombinants predominant in East Africa. To bridge the gap, we detected the T/F Env sequences, their subtypes, and unique molecular signatures associated with them compared to the chronics of the same subtype. We also explored the association between the molecular signatures and HIV-1 T/F Env structural characteristics. Methods: Single genome amplification (SGA), Sanger sequencing, highlighter plots and maximum likelihood trees identified HIV-1 T/F Env sequences. The Entropy, GenSig and HIV genome browser tools were deployed for the unique molecular signature analysis where 90 HIV-1 T/F Envs from acutely infected individuals were compared to 118 HIV-1 chronic Envs. Results: Subtype analysis based on the complete HIV-1 Env (gp160) gene revealed a high proportion of subtype A1 T/Fs, followed by A1D recombinants, and fewer subtype D T/Fs in East Africa, from 2006 to 2021. The same subtype trend was consistent among HIV-1 chronic infection in the same period. Signature analysis revealed that HIV-1 T/F subtype A1 viruses (85.37%) are less likely to have a robust Leucine signature at position 22 (L22) in the signal peptide domain compared to subtype A1 chronic viruses (100%) (Fisher's exact test, p-value = 0.00235, q-value = 0.12). Additionally, the HIV-1 T/F subtype A1 viruses (84.62%) are less likely to carry a robust Leucine signature at position 784 (L784) in the lentiviral lytic peptide 2 in the gp41 region compared to subtype A1 chronics (100%) (p-value = 0.00228, q-value = 0.12). Notably, both the robust L22 and L784 are sensitivity signatures to bnAbs in subtype C early viruses. In addition, the HIV-1 A1D recombinant chronics (100%) are more likely to select the robust Glutamate signature at position 734 (E734) in the gp41 cytoplasmic tail compared to the A1D T/F viruses (75%) (p-value = 0.00122, q-value = 0.146). The E734 signature is an HXB2 site of interest associated with extraordinary immunogenicity. Conclusion: The presence of the robust L22 and L784 signature sites in subtype A1 T/F viruses and the robust E734 signature site in A1D recombinant T/F viruses may contribute to the successful establishment of acute infection as well as maintenance of chronic infection. Therefore, effective therapeutics should target these principal amino acid signatures pattern.