Extensive Intrasubtype Recombination in South African Human Immunodeficiency Virus Type 1 Subtype C Infections

Abstract

Recombinant human immunodeficiency virus type 1 (HIV-1) strains containing sequences from different viral genetic subtypes (intersubtype) and different lineages from within the same subtype (intrasubtype) have been observed. A consequence of recombination can be the distortion of the phylogenetic signal. Several intersubtype recombinants have been identified; however, less is known about the frequency of intrasubtype recombination. For this study, near-full-length HIV-1 subtype C genomes from 270 individuals were evaluated for the presence of intrasubtype recombination. A sliding window schema (window, 2 kb; step, 385 bp) was used to partition the aligned sequences. The Shimodaira-Hasegawa test detected significant topological incongruence in 99.6% of the comparisons of the maximum-likelihood trees generated from each sequence partition, a result that could be explained by recombination. Using RECOMBINE, we detected significant levels of recombination using five random subsets of the sequences. With a set of 23 topologically consistent sequences used as references, bootscanning followed by the interactive informative site test defined recombination breakpoints. Using two multiple-comparison correction methods, 47% of the sequences showed significant evidence of recombination in both analyses. Estimated evolutionary rates were revised from 0.51%/year (95% confidence interval [CI], 0.39 to 0.53%) with all sequences to 0.46%/year (95% CI, 0.38 to 0.48%) with the putative recombinants removed. The timing of the subtype C epidemic origin was revised from 1961 (95% CI, 1947 to 1962) with all sequences to 1958 (95% CI, 1949 to 1960) with the putative recombinants removed. Thus, intrasubtype recombinants are common within the subtype C epidemic and these impact analyses of HIV-1 evolution.Human immunodeficiency virus type 1 (HIV-1) genetic diversity is generated during viral replication and is caused by error-prone reverse transcription, host-mediated hypermutation, and recombination. Recombination has been estimated to occur approximately 2.8 times per genome per viral replication cycle (61). Detectable recombination requires simultaneous infection with more than one virus at the cellular level. In a previous report, an average of three to four distinct proviral genomes were found in infected spleen cells (21), indicating that conditions do exist for extensive recombination between different viral genomes. Indeed, numerous intersubtype recombinants resulting in both unique forms found in single individuals and circulating forms have been observed (http://hiv-web.lanl.gov/content/hiv-db /CRFs/CRFs.html). Furthermore, recombination among sequences from the same subtype, or intrasubtype recombination, has also been observed within individual patients (36,47,59).Recombination can distort the phylogenetic signal. In phylogenetic analyses, the variant sites in the recombinant portions of the genome will appear as parallel evolution (homoplasy) instead of a single lineage. This can cause longer branch lengths, overestimate th...

Temporal and Spatial Dynamics of Human Immunodeficiency Virus Type 1 Circulating Recombinant Forms 08_BC and 07_BC in Asia

“…Besides intersubtype recombination, recombination involving closely related lineages of the same subtype within a single individual has been reported (25,34,36), leading to possible quantitative discrepancies on linkage disequilibrium, including the loss of phylogenetic correlation between different loci and biases in the genealogical characteristics (i.e., overestimation of the tMRCA) along the HIV genome (35,46). Our study, however, showed that intrasubtype recombination has no significant impact on the estimated coalescence dates (Fig.…”

Importance of Viral Sequence Length and Number of Variable and Informative Sites in Analysis of HIV Clustering

“…It has been suggested that intrasubtype recombination in HIV-1C could be extensive. 68 While we reported frequent intrasubtype recombination in intrapatient viral quasispecies, 69 reliable identification of recombination between patients infected with the same HIV-1 subtype is still challenging due to a lack of a straightforward and unambiguous methodology. Assuming that intrasubtype recombinants are identified with improved technology in future studies, the specifics and nature of intrasubtype recombination could either complicate or assist in the analysis of HIV clustering.…”

Sequence Insertions in the HIV Type 1 Subtype C Viral Promoter Predominantly Generate an Additional NF-κB Binding Site

“…The major subtypes of HIV-1 are believed to have evolved into the distinct genetic forms as they are known today in the late 1950s or early 1960s. 13 The subsequent years witnessed the emergence of a large number of diverse recombinant forms although only a small minority of these strains appear to have survival competence. Of the several HIV-1 major subtypes and the plethora of the recombinant forms, viral strains belonging to subtype C dominate the global epidemics and cause half of the global infections.…”