A large population sample of African HIV genomes from the 1980s reveals a reduction in subtype D over time associated with propensity for CXCR4 tropism

Abstract

We present 109 near full-length HIV genomes amplified from blood serum samples obtained during early 1986 from across Uganda, which to our knowledge is the earliest and largest population sample from the initial phase of the HIV epidemic in Africa. Consensus sequences were made from paired-end Illumina reads with a target-capture approach to amplify HIV material following poor success with standard approaches. In comparisons with a smaller ‘intermediate’ genome dataset from 1998 to 1999 and a ‘modern’ genome dataset from 2007 to 2016, the proportion of subtype D was significantly higher initially, dropping from 67% (73/109), to 57% (26/46) to 17% (82/465) respectively (p < 0.0001). Subtype D has previously been shown to have a faster rate of disease progression than other subtypes in East African population studies, and to have a higher propensity to use the CXCR4 co-receptor (“X4 tropism”); associated with a decrease in time to AIDS. Here we find significant differences in predicted tropism between A1 and D subtypes in all three sample periods considered, which is particularly striking the 1986 sample: 66% (53/80) of subtype D env sequences were predicted to be X4 tropic compared with none of the 24 subtype A1. We also analysed the frequency of subtype in the envelope region of inter-subtype recombinants, and found that subtype A1 is over-represented in env, suggesting recombination and selection have acted to remove subtype D env from circulation. The reduction of subtype D frequency over three decades therefore appears to be a result of selective pressure against X4 tropism and its higher virulence. Lastly, we find a subtype D specific codon deletion at position 24 of the V3 loop, which may explain the higher propensity for subtype D to utilise X4 tropism.

HIV-1 subtype A1, D, and recombinant proviral genome landscapes during long-term suppressive therapy

“…Near-full-length HIV-1 genome sequencing identified a larger number of inter-subtype recombinant genomes when compared with subtyping based on short-range sequencing of RT and gp41. The high proportion of people with intra-subtype recombinant HIV-1 is consistent with our previous observations 25 and with data from previous Ugandan HIV-1 sequencing studies from the PANGEA consortium and the UARTO cohort 26 – 29 . Our results also further underscore the subtype complexity in this geographical region, as evidenced by the lack of any officially named circulating recombinant forms, and the lack of common inter-subtype recombination locations among the ten individuals with recombinant HIV-1.…”