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High Degree of HIV-1 Group M (HIV-1M) Genetic Diversity within Circulating Recombinant Forms: Insight into the Early Events of HIV-1M Evolution.

ABSTRACT: The existence of various highly divergent HIV-1 lineages and of recombination-derived sequence tracts of indeterminate origin within established circulating recombinant forms (CRFs) strongly suggests that HIV-1 group M (HIV-1M) diversity is not fully represented under the current classification system. Here we used a fully exploratory screen for recombination on a set of 480 near-full-length genomes representing the full known diversity of HIV-1M. We decomposed recombinant sequences into their constituent parts and then used maximum-likelihood phylogenetic analyses of this mostly recombination-free data set to identify rare divergent sequence lineages that fall outside the major named HIV-1M taxonomic groupings. We found that many of the sequence fragments occurring within CRFs (including CRF04_cpx, CRF06_cpx, CRF11_cpx, CRF18_cpx, CRF25_cpx, CRF27_cpx, and CRF49_cpx) are in fact likely derived from divergent unclassified parental lineages that may predate the current subtypes, even though they are presently identified as derived from currently defined HIV-1M subtypes. Our evidence suggests that some of these CRFs are descended predominantly from what were or are major previously unidentified HIV-1M lineages that were likely epidemiologically relevant during the early stages of the HIV-1M epidemic. The restriction of these divergent lineages to the Congo basin suggests that they were less infectious and/or simply not present at the time and place of the initial migratory wave that triggered the global epidemic.IMPORTANCE HIV-1 group M (HIV-1M) likely spread to the rest of the world from the Congo basin in the mid-1900s (N. R. Faria et al., Science 346:56-61, 2014, http://dx.doi.org/10.1126/science.1256739) and is today the principal cause of the AIDS pandemic. Here, we show that large sequence fragments from several HIV-1M circulating recombinant forms (CRFs) are derived from divergent parental lineages that cannot reasonably be classified within the nine established HIV-1M subtypes. These lineages are likely to have been epidemiologically relevant in the Congo basin at the onset of the epidemic. Nonetheless, they appear not to have undergone the same explosive global spread as other HIV-1M subtypes, perhaps because they were less transmissible. Concerted efforts to characterize more of these divergent lineages could allow the accurate inference and chemical synthesis of epidemiologically key ancestral HIV-1M variants so as to directly test competing hypotheses relating to the viral genetic factors that enabled the present pandemic.

SUBMITTER: Tongo M

PROVIDER: S-EPMC4810712 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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High Degree of HIV-1 Group M (HIV-1M) Genetic Diversity within Circulating Recombinant Forms: Insight into the Early Events of HIV-1M Evolution.

Tongo Marcel M Dorfman Jeffrey R JR Martin Darren P DP

Journal of virology 20151209 5

The existence of various highly divergent HIV-1 lineages and of recombination-derived sequence tracts of indeterminate origin within established circulating recombinant forms (CRFs) strongly suggests that HIV-1 group M (HIV-1M) diversity is not fully represented under the current classification system. Here we used a fully exploratory screen for recombination on a set of 480 near-full-length genomes representing the full known diversity of HIV-1M. We decomposed recombinant sequences into their c ...[more]

PMID: 26656688

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Project description:Intersubtype recombinants classified as circulating recombinant forms (CRFs) or unique recombinant forms (URFs) have been shown to play an important role in the complex and dynamic Brazilian HIV/AIDS epidemic. Previous pol region studies (2003-2013) in 828 patients from six states from Central Western, Northern and Northeastern Brazil reported variable rates of BF1, F1CB, BC, and CF1 mosaics. In this study HIV-1 subtype diversity BF1, F1CB, BC, and CF1 recombinants in pol were analyzed. Full/near-full/partial genome sequences were generated from F1CB and BF1 recombinants. Genomic DNA extracted from whole blood was used in nested-PCR to amplify four overlapping fragments encompassing the full HIV-1 genome. Phylogenetic trees were generated using the neighbor-joining/NJ method (MEGA 6.0). The time of the most recent common ancestor (TMRCA) of F1CB and BF1 clades was estimated using a Bayesian Markov Chain Monte Carlo approach (BEAST v1.8; BEAGLE). Bootscanning was used for recombination analyses (Simplot v3.5.1); separate NJ phylogenetic analysis of fragments confirmed subtypes. The phylogenetic analyses of protease/reverse-transcriptase sequences in 828 patients revealed 76% subtype B (n = 629), 6.4% subtype C (n = 53), 4.2% subtype F1 (n = 35), 13.4% intersubtype recombinants: 10.5% BF1 (n = 87), 2.3% BC (n = 19), 0.4% F1CB (n = 3), and 0.2% CF1 (n = 2). Two full and one partial BF1C genomes allowed the characterization of the CRF81_cpx that has 9 breakpoints dividing the genome into 10 subregions. Basic Local Alignment Search Tool searches (Los Alamos HIV Sequence Database) identified six other sequences with the same recombination profile in pol, five from Brazil, and one from Italy. The estimated median TMRCA of CRF81_cpx was 1999 (1992-2003). CRF60_BC-like sequences, originally described in Italy, were also found. Two full and one near full-length BF1 genomes led to the characterization of the new CRF99_BF1 that has six recombination breakpoints dividing the genome into seven subregions. Two new URFs BF1, with six recombination breakpoints and seven subregions were also characterized. The description of the first Brazilian BF1C CRF81_cpx and of the new CRF99_BF1 corroborate the important role of CRFs in the HIV/AIDS epidemic throughout Brazil. Our data also highlight the value of HIV-1 full-genome sequence studies in order to fully reveal the complexity of the epidemic in a huge country as Brazil.

Project description:BACKGROUND: The HIV epidemic in Cameroon is characterized by a high degree of viral genetic diversity with circulating recombinant forms (CRFs) being predominant. The goal of our study was to determine recent trends in virus evolution and emergence of drug resistance in blood donors and HIV positive patients. METHODOLOGY: Blood specimens of 73 individuals were collected from three cities and a few villages in Cameroon and viruses were isolated by co-cultivation with PBMCs. Nested PCR was performed for gag p17 (670 bp) pol (840 bp) and Env gp41 (461 bp) genes. Sequences were phylogenetically analyzed using a reference set of sequences from the Los Alamos database. RESULTS: Phylogenetic analysis based on partial sequences revealed that 65% (n = 48) of strains were CRF02_AG, 4% (n = 3) subtype F2, 1% each belonged to CRF06 (n = 1), CRF11 (n = 1), subtype G (n = 1), subtype D (n = 1), CRF22_01A1 (n = 1), and 26% (n = 18) were Unique Recombinant Forms (URFs). Most URFs contained CRF02_AG in one or two HIV gene fragments analyzed. Furthermore, pol sequences of 61 viruses revealed drug resistance in 55.5% of patients on therapy and 44% of drug naïve individuals in the RT and protease regions. Overall URFs that had a primary HIV subtype designation in the pol region showed higher HIV-1 p24 levels than other recombinant forms in cell culture based replication kinetics studies. CONCLUSIONS: Our results indicate that although CRF02_AG continues to be the predominant strain in Cameroon, phylogenetically the HIV epidemic is continuing to evolve as multiple recombinants of CRF02_AG and URFs were identified in the individuals studied. CRF02_AG recombinants that contained the pol region of a primary subtype showed higher replicative advantage than other variants. Identification of drug resistant strains in drug-naïve patients suggests that these viruses are being transmitted in the population studied. Our findings support the need for continued molecular surveillance in this region of West Central Africa and investigating impact of variants on diagnostics, viral load and drug resistance assays on an ongoing basis.

Dataset Information

High Degree of HIV-1 Group M (HIV-1M) Genetic Diversity within Circulating Recombinant Forms: Insight into the Early Events of HIV-1M Evolution.

Publications

High Degree of HIV-1 Group M (HIV-1M) Genetic Diversity within Circulating Recombinant Forms: Insight into the Early Events of HIV-1M Evolution.

Similar Datasets

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