| dc.description.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. | en_US |
