Unique Genetic Signatures in HIV-1 Subtype A1 and A1D recombinant Envelope Glycoprotein distinguish Contemporary Transmitted/Founder Viruses from Historical Strains in East Africa

Frank Kato^1,2*Anne Kapaata¹Ronald Galiwango³Angella Nakyanzi⁴Christian Ndekezi^1,2Fortunate Natwijuka^1,2Denis Omara^1,2Andrew Ekii Obuku¹Brian T Foley⁵Pontiano Kaleebu^1,4Eunice Nduati⁶Sheila Balinda^1,4

• ¹Viral Pathogens, London School of Hygiene and Tropical Medicine Uganda Research Unit, Medical Research Council (Uganda), Entebbe, Uganda
• ²College of Health Sciences, Makerere University, Kampala, Uganda
• ³Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda
• ⁴Uganda Virus Research Institute (UVRI), Entebbe, Uganda
• ⁵Theoretical Division, Los Alamos National Laboratory (DOE), Los Alamos, New Mexico, United States
• ⁶Kenya Medical Research Institute (KEMRI), Nairobi, Kenya

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.