Patterns of genomic site inheritance in HIV-1M inter-subtype recombinants delineate the most likely genomic sites of subtype-specific adaptation

Abstract

Recombination between different HIV-1 group M (HIV-1M) subtypes is a major contributor to the ongoing genetic diversification of HIV-1M. However, it remains unclear whether the different genome regions of recombinants are randomly inherited from the different subtypes. To elucidate this, we analysed the distribution within 82 circulating and 201 unique recombinant forms (CRFs/URFs), of genome fragments derived from HIV-1M Subtypes A, B, C, D, F, and G and CRF01_AE. We found that viruses belonging to the analysed HIV-1M subtypes and CRF01_AE contributed certain genome fragments more frequently during recombination than other fragments. Furthermore, we identified statistically significant hot-spots of Subtype A sequence inheritance in genomic regions encoding portions of Gag and Nef, Subtype B in Pol, Tat and Env, Subtype C in Vif, Subtype D in Pol and Env, Subtype F in Gag, Subtype G in Vpu-Env and Nef, and CRF01_AE inheritance in Vpu and Env. The apparent non-randomness in the frequencies with which different subtypes have contributed specific genome regions to known HIV-1M recombinants is consistent with selection strongly impacting the survival of inter-subtype recombinants. We propose that hotspots of genomic region inheritance are likely to demarcate the locations of subtype-specific adaptive genetic variations.

Keywords: CRF/URF; HIV-1; permutation-based test; recombination; selection.

Figure 1.

The permutation test used to determine whether certain nucleotides within recombinant HIV genomes have been inherited from parental viruses from particular subtypes more or less frequently than can be accounted for by chance. The nucleotides derived from different subtypes are indicated by different colours. In this case we are interested in nucleotides derived from the orange subtype.

Figure 2.

Distribution of subtypes- and CRF01_AE-derived genome fragments within 283 different circulating and URFs. For each nucleotide position along the genome, the proportion of recombinants that inherited a nucleotide from a specific subtype and CRF01_AE parental virus is plotted. The grey line indicates the 95th percentile bounds on analogous proportions calculated with 1,000,000 permuted datasets containing the same numbers and sizes of subtypes or CRF01_AE attributed fragments as the real datasets (but where the positions and orderings of breakpoints were randomized). Solid vertical arrows indicate hot-spots of recombinationally acquired subtypes and CRF01_AE genome regions, while unfilled vertical arrows indicate cold-spots of recombinationally acquired subtypes and CRF01_AE genome regions.

Figure 3.

Distribution of subtypes-derived genome fragments within CRFs and URFs. The description is identical as in Figure 2. The left panel represent the URFs and right panel the CRFs. Shown here are data from Subtypes A, B, F, and G.