New Findings in Cleavage Sites Variability across Groups, Subtypes and Recombinants of Human Immunodeficiency Virus Type 1

BACKGROUND: Polymorphisms at cleavage sites (CS) can influence Gag and Pol proteins processing by the viral protease (PR), restore viral fitness and influence the virological outcome of specific antiretroviral drugs. However, data of HIV-1 variant-associated CS variability is scarce. METHODS: In this descriptive research, we examine the effect of HIV-1 variants on CS conservation using all 9,028 gag and 3,906 pol HIV-1 sequences deposited in GenBank, focusing on the 110 residues (10 per site) involved at 11 CS: P17/P24, P24/P2, P2/P7, P7/P1, P1/P6(gag), NC/TFP, TFP/P6(pol), P6(pol)/PR, PR/RT(p51), RT(p51)/RT(p66) and RT(p66)/IN. CS consensus amino acid sequences across HIV-1 groups (M, O, N, P), group M 9 subtypes and 51 circulating recombinant forms (CRF) were inferred from our alignments and compared to the HIV-1 consensus-of-consensuses sequence provided by GenBank. RESULTS: In all HIV-1 variants, the most conserved CS were PR/RT(p51), RT(p51)/RT(p66), P24/P2 and RT(p66)/IN and the least P2/P7 and P6(pol)/PR. Conservation was significantly lower in subtypes vs. recombinants in P2/P7 and TFP/P6(pol) and higher in P17/P24. We found a significantly higher conservation rate among Group M vs. non-M Groups HIV-1. The late processing sites at Gag (P7/P1) and GagPol precursors (PR/RT(p51)) presented a significantly higher conservation vs. the first CS (P2/P7) in the 4 HIV-1 groups. Here we show 52 highly conserved residues across HIV-1 variants in 11 CS and the amino acid consensus sequence in each HIV-1 group and HIV-1 group M variant for each 11 CS. CONCLUSIONS: This is the first study to describe the CS conservation level across all HIV-1 variants and 11 sites in one of the largest available sequence HIV-1 dataset. These results could help other researchers for the future design of both novel antiretroviral agents acting as maturation inhibitors as well as for vaccine targeting CS.