Divergent HIV-1 strains (CRF92_C2U and CRF93_cpx) co-circulating in the Democratic Republic of the Congo: Phylogenetic insights on the early evolutionary history of subtype C

Abstract

Molecular epidemiological studies revealed that the epicenter of the HIV pandemic was Kinshasa, the capital city of the Democratic Republic of the Congo (DRC) in Central Africa. All known subtypes and numerous complex recombinant strains co-circulate in the DRC. Moreover, high intra-subtype diversity has been also documented. During two previous surveys on HIV-1 antiretroviral drug resistance in the DRC, we identified two divergent subtype C lineages in the protease and partial reverse transcriptase gene regions. We sequenced eight near full-length genomes and classified them using bootscanning and likelihood-based phylogenetic analyses. Four strains are more closely related to subtype C although within the range of inter sub-subtype distances. However, these strains also have small unclassified fragments and thus were named CRF92_C2U. Another strain is a unique recombinant of CRF92_C2U with an additional small unclassified fragment and a small divergent subtype A fragment. The three remaining strains represent a complex mosaic named CRF93_cpx. CRF93_cpx have two fragments of divergent subtype C sequences, which are not conventional subtype C nor the above described C2, and multiple divergent subtype A-like fragments. We then inferred the time-scaled evolutionary history of subtype C following a Bayesian approach and a partitioned analysis using major genomic regions. CRF92_C2U and CRF93_cpx had the most recent common ancestor with conventional subtype C around 1932 and 1928, respectively. A Bayesian demographic reconstruction corroborated that the subtype C transition to a faster phase of exponential growth occurred during the 1950s. Our analysis showed considerable differences between the newly discovered early-divergent strains and the conventional subtype C and therefore suggested that this virus has been diverging in humans for several decades before the HIV/M diversity boom in the 1950s.

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“…The exponential growth coupled with a strict molecular clock suggests steady transmission and diversification of viral lineages over time. The estimated growth rates were similar for the two genetic regions and were in the same order of magnitude as those of HIV group M in the prepandemic period (Faria et al., ; Villabona Arenas et al., ). The upper bound of the tMRCA for SIVgor in this particular region was around the late 1930s in line with the idea that SIVs are in general young lentiviral lineages (Wertheim & Worobey, ).…”

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“…The DRC66 sequence represents a sister lineage to the subtype C clade, and quite divergent: we estimate it shared a common ancestor with subtype C some 20 to 30 years before the time of the common ancestor of conventional subtype C. Parts of gag and pol from three recently described recombinant genomes from Kinshasa and Mbuji-Mayi sampled in 2008 are the only contemporary sequences that also belong to this lineage in part of their genomes. Villabona et al and Rodgers et al describe two additional so-called "divergent C lineages" sampled between 2001-2012 that are monophyletic with conventional C with respect to the DRC66 lineage, yet form separate sister lineages to subtype C (15,17). Similarly, for most other HIV-1 subtypes more divergent lineages can be found in DRC (in particular Kinshasa) and other central African countries than in other regions where the more restricted within-subtype diversity arose in a relatively short time after founder events.…”

“…Extensive BLAST searches and searches via neighbor-joining trees of downloaded HIV-1 sequences revealed that DRC66 is the only reported near-complete genome from this lineage. However, the subtype-C like portions of the genomes of three recently described circulating-recombinant-forms (designated CRF93_CPX) from Kinshasa and Mbuji-Mayi, DRC, sampled in 2008 (15), formed a monophyletic group with DRC66 in a maximum likelihood tree of a partial pol alignment ( Figure 1C). Partial pol sequences of other so-called "divergent C lineages" from CRF92_CU, described in Villabona et al (15) and Rodgers et al (17), were also included in this tree.…”

“…However, the subtype-C like portions of the genomes of three recently described circulating-recombinant-forms (designated CRF93_CPX) from Kinshasa and Mbuji-Mayi, DRC, sampled in 2008 (15), formed a monophyletic group with DRC66 in a maximum likelihood tree of a partial pol alignment ( Figure 1C). Partial pol sequences of other so-called "divergent C lineages" from CRF92_CU, described in Villabona et al (15) and Rodgers et al (17), were also included in this tree. The DRC66-CRF93_CPX clade is well supported, and as shown in Figure 1C, constitutes a sister clade to the rest of subtype C-like sequences.…”

“…Early divergence events that resulted in the diversity of HIV-1 group M we see today likely took place in the major-and at that time massively growing-cities on the banks of the Congo river in what is now Republic of Congo (ROC) and Democratic Republic of Congo (DRC) (10,11). This is also apparent from the much higher diversity of HIV-1 group M in DRC, ROC and Cameroon, with divergent lineages and circulating recombinant forms (CRFs) still being described from that region (15)(16)(17)(18).…”