Expression Level of HIV-1 Vif Can Be Fluctuated by Natural Nucleotide Variations in the -Coding and Regulatory SA1D2prox Sequences of the Proviral Genome

Vif is required for HIV-1 replication in natural target cells by counteracting host restriction factors, APOBEC3 (A3) proteins. We recently demonstrated that Vif expression level can be changed by naturally occurring single-nucleotide variations within SA1D2prox of the HIV-1 genome. We also found that levels for / mRNAs are inversely correlated. While amino acid sequence per se is critical for functionality, Vif expression level modulated by signal sequences in its coding region is likely to be important as well. There are two splicing sites in the region involved in expression. To reveal possible fluctuations of Vif-expression level, we examined SA1D2prox and gene by chimeric approaches using HIV-1 subtypes B and C with distinct anti-A3 activity. In this report, recombinant clones in subtype B backbone carrying chimeric sequences with respect to SA1D2prox/ and those within the -coding region were generated. Of these, clones containing -coding sequence of subtype C, especially its 3' region, expressed /Vif at a decreased level but did at an increased level for /Vpr. Clones with reduced /Vif level grew similarly or slightly better than a parental clone in weakly A3G-positive cells but more poorly in highly A3G-expressing cells. Three clones with this property were also tested for their A3-degrading activity. One of the clones appeared to have some defect in addition to the poor ability to express Vif. Taken all together, our results show that natural variations in the SA1D2prox and -coding region can change the Vif-expression level and affect the HIV-1 replication potential.