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Functional bottlenecks for generation of HIV-1 intersubtype Env recombinants.

ABSTRACT: Intersubtype recombination is a powerful driving force for HIV evolution, impacting both HIV-1 diversity within an infected individual and within the global epidemic. This study examines if viral protein function/fitness is the major constraint shaping selection of recombination hotspots in replication-competent HIV-1 progeny. A better understanding of the interplay between viral protein structure-function and recombination may provide insights into both vaccine design and drug development.In vitro HIV-1 dual infections were used to recombine subtypes A and D isolates and examine breakpoints in the Env glycoproteins. The entire env genes of 21 A/D recombinants with breakpoints in gp120 were non-functional when cloned into the laboratory strain, NL4-3. Likewise, cloning of A/D gp120 coding regions also produced dead viruses with non-functional Envs. 4/9 replication-competent viruses with functional Env's were obtained when just the V1-V5 regions of these same A/D recombinants (i.e. same A/D breakpoints as above) were cloned into NL4-3.These findings on functional A/D Env recombinants combined with structural models of Env suggest a conserved interplay between the C1 domain with C5 domain of gp120 and extracellular domain of gp41. Models also reveal a co-evolution within C1, C5, and ecto-gp41 domains which might explain the paucity of intersubtype recombination in the gp120 V1-V5 regions, despite their hypervariability. At least HIV-1 A/D intersubtype recombination in gp120 may result in a C1 from one subtype incompatible with a C5/gp41 from another subtype.

SUBMITTER: Bagaya BS

PROVIDER: S-EPMC4445978 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Functional bottlenecks for generation of HIV-1 intersubtype Env recombinants.

Bagaya Bernard S BS Vega José F JF Tian Meijuan M Nickel Gabrielle C GC Li Yuejin Y Krebs Kendall C KC Arts Eric J EJ Gao Yong Y

Retrovirology 20150523

<h4>Background</h4>Intersubtype recombination is a powerful driving force for HIV evolution, impacting both HIV-1 diversity within an infected individual and within the global epidemic. This study examines if viral protein function/fitness is the major constraint shaping selection of recombination hotspots in replication-competent HIV-1 progeny. A better understanding of the interplay between viral protein structure-function and recombination may provide insights into both vaccine design and dru ...[more]

PMID: 25997955

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Project description:BackgroundHIV-1 is a retrovirus with high rate of recombination. Increasing experimental studies in vitro indicated that local hairpin structure of RNA was associated with recombination by favoring RT pausing and promoting strand transfer. A method to estimate the potential to form stem-loop structure by calculating the folding of randomized sequence difference (FORS-D) has been used to investigate the relationship between secondary structure and evolutionary pressure in some genome. It showed that gene regions under strong positive "Darwinian" selection were associated with positive FORS-D values. In the present study, the sequences of HIV-1 subtypes B' and C, both of which represent the parent strains of CRF07_BC, CRF08_BC and China URFs, were selected to investigate the relationship between natural recombination and secondary structure by calculating the FORS-D values.ResultsThe apparent higher negative FORS-D value region appeared in the gag-pol gene region (nucleotide 0-3000) of HIV-1 subtypes B' and C. Thirteen (86.7%) of 15 mosaic fragments and 17 (81%) of 21 recombination breakpoints occurred in this higher negative FORS-D region. This strongly suggested that natural recombination did not occur randomly throughout the HIV genome, and that there might be preferred (or hot) regions or sites for recombination. The FORS-D analysis of breakpoints showed that most breakpoints of recombinants were located in regions with higher negative FORS-D values (P = 0.0053), and appeared to have a higher negative average FORS-D value than the whole genome (P = 0.0007). The regression analysis also indicated that FORS-D values correlated negatively with breakpoint overlap.ConclusionHigh negative FORS-D values represent high, base order determined stem-loop potentials and influence mainly the formation of stem-loop structures. Therefore, the present results suggested for the first time that occurrence of natural recombination was associated with high base order-determined stem-loop potential, and that local base order might play a key role in the initiation of natural recombination by favoring the formation of stable stem-loop structures.

Project description:Human immunodeficiency virus type 1 (HIV-1) recombinants in the world are believed to be generated through recombination between distinct HIV-1 strains among coinfection or superinfection cases. However, direct evidence to support transmission of HIV-1 recombinants from a coinfected/superinfected donor to putative recipient is lacking. Here, we report on the origin and evolutionary relationship between a set of recombinants from a CRF01_AE/CRF07_BC superinfected putative donor and diverse CRF01_AE/CRF07_BC recombinants from five putative recipients. Interviews on sociodemographic characteristics and sexual behaviors for these six HIV-1-infected men who have sex with men showed that they had similar ways of partner seeking: online dating sites and social circles. Phylogenetic and recombination analyses demonstrated that the near-full-length genome sequences from six patients formed a monophyletic cluster different from known HIV-1 genotypes in maximum likelihood phylogenetic trees, were all composed of CRF01_AE and CRF07_BC fragments with two common breakpoints on env, and shared 4-7 breakpoints with each other. Moreover, 3' half-genomes of recombinant strains from five recipients had identical/similar recombinant structures with strains at longitudinal samples from the superinfected donor. Recombinants from the donor were paraphyletic, whereas five recipients were monophyletic or polyphyletic in the maximum clade credibility tree. Bayesian analyses confirmed that the estimated time to the most recent common ancestor (tMRCA) of CRF01_AE and CRF07_BC strains of the donor was 2009.2 and 2010.7, respectively, and all were earlier than the emergence of recombinants from five recipients. Our results demonstrated that the closely related unique recombinant forms of HIV-1 might be the descendent of a series of recombinants generated gradually in a superinfected patient. This finding highlights the importance of early initiation of antiretroviral therapy as well as tracing and testing of partners in patients with multiple HIV-1 infection.

Dataset Information

Functional bottlenecks for generation of HIV-1 intersubtype Env recombinants.

Publications

Functional bottlenecks for generation of HIV-1 intersubtype Env recombinants.

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