Role of the Matrix-Capsid Cleavage Site Polymorphism S124V of HIV-1 Sub-subtype A2 in Gag Polyprotein Processing

Abstract

Subtype C and A HIV-1 strains dominate the epidemic in Africa and Asia, while sub-subtype A2 is found at low frequency only in West Africa. To relate Gag processing in vitro with viral fitness, viral protease (PR) enzymatic activity and in vitro Gag processing were evaluated. The rate of sub-subtype A2 Gag polyprotein processing, as production of the p24 protein, was reduced compared to subtype B or C independent of PR subtype, indicating that subtype A2 Gag qualitatively differed from other subtypes. Introduction of subtype B matrix-capsid cleavage site in sub-subtype A2 Gag only partially restored the processing rate. Unique amino acid polymorphism V124S at the matrix-capsid cleavage site, together with other polymorphisms at non-cleavage sites, are differentially influencing the processing of Gag polyproteins. This genetic polymorphisms landscape defining HIV-1 sub-subtypes, subtypes and recombinant forms are determinants of viral fitness and frequency in the HIV-1 infected population. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/382879v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@eb2312org.highwire.dtl.DTLVardef@14ba88eorg.highwire.dtl.DTLVardef@2715c3org.highwire.dtl.DTLVardef@5ba6a_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe polymorphism at matrix-capsid cleavage site, together with non-cleavage sites polymorphisms, direct the processing rate of the substrate, not the intrinsic activity of the enzyme. C_LIO_LIThe less prevalent and less infectious sub-subtype A2 harbors the matrix-capsid cleavage site polymorphism that we report as a limiting factor for gag processing. C_LIO_LISub-subtype A2 Gag polyprotein processing rate is independent of the PR subtype. C_LI