Dataset Information

Genotypic and phenotypic heterogeneity in the U3R region of HIV type 1 subtype C.

ABSTRACT: Approximately 20% of all HIV-1 mother-to-child transmission (MTCT) occurs in utero (IU). In a chronic HIV infection, HIV-1 exists as a complex swarm of genetic variants, and following IU MTCT, viral genomic diversity is restricted through a mechanism that remains to be described. The 5' U3R region of the HIV-1 long terminal repeat (LTR) contains multiple transcription factor (TF) binding sites and regulates viral transcription. In this study, we tested the hypothesis that sequence polymorphisms in the U3R region of LTR are associated with IU MTCT. To this end, we used single template amplification to isolate 517 U3R sequences from maternal, placental, and infant plasma derived from 17 HIV-infected Malawian women: eight whose infants remained HIV uninfected (NT) and nine whose infants became HIV infected IU. U3R sequences show pairwise diversities ranging from 0.2% to 2.3%. U3R sequences from one participant contained two, three, or four putative NF-?B binding sites. Phylogenetic reconstructions indicated that U3R sequences from eight of nine IU participants were consistent with placental compartmentalization of HIV-1 while only one of eight NT cases was consistent with such compartmentalization. Specific TF sequence polymorphisms were not significantly associated with IU MTCT. To determine if replication efficiency of the U3R sequences was associated with IU MTCT, we cloned 90 U3R sequences and assayed promoter activity in multiple cell lines. Although we observed significant, yet highly variable promoter activity and TAT induction of promoter activity in the cell lines tested, there was no association between measured promoter activity and MTCT status. Thus, we were unable to detect a promoter genotype or phenotype associated with IU MTCT.

SUBMITTER: Mates JM

PROVIDER: S-EPMC3887403 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genotypic and phenotypic heterogeneity in the U3R region of HIV type 1 subtype C.

Mates Jessica M JM Kumar Surender B SB Bazan Jose J Mefford Megan M Voronkin Igor I Handelman Samuel S Mwapasa Victor V Ackerman William W Janies Daniel D Kwiek Jesse J JJ

AIDS research and human retroviruses 20130812 1

Approximately 20% of all HIV-1 mother-to-child transmission (MTCT) occurs in utero (IU). In a chronic HIV infection, HIV-1 exists as a complex swarm of genetic variants, and following IU MTCT, viral genomic diversity is restricted through a mechanism that remains to be described. The 5' U3R region of the HIV-1 long terminal repeat (LTR) contains multiple transcription factor (TF) binding sites and regulates viral transcription. In this study, we tested the hypothesis that sequence polymorphisms ...[more]

PMID: 23826737

Similar Datasets

Project description:Health-associated oral Streptococcus species are promising probiotic candidates to protect against dental caries. Ammonia production through the arginine deiminase system (ADS), which can increase the pH of oral biofilms, and direct antagonism of caries-associated bacterial species are desirable properties for oral probiotic strains. ADS and antagonistic activities can vary dramatically among individuals, but the genetic basis for these differences is unknown. We sequenced whole genomes of a diverse set of clinical oral Streptococcus isolates and examined the genetic basis of variability in ADS and antagonistic activities. A total of 113 isolates were included and represented 10 species: Streptococcus australis, A12-like, S. cristatus, S. gordonii, S. intermedius, S. mitis, S. oralis including S. oralis subsp. dentisani, S. parasanguinis, S. salivarius, and S. sanguinis. Mean ADS activity and antagonism on Streptococcus mutans UA159 were measured for each isolate, and each isolate was whole genome shotgun sequenced on an Illumina MiSeq. Phylogenies were built of genes known to be involved in ADS activity and antagonism. Several approaches to correlate the pan-genome with phenotypes were performed. Phylogenies of genes previously identified in ADS activity and antagonism grouped isolates by species, but not by phenotype. A genome-wide association study (GWAS) identified additional genes potentially involved in ADS activity or antagonism across all the isolates we sequenced as well as within several species. Phenotypic heterogeneity in oral streptococci is not necessarily reflected by genotype and is not species specific. Probiotic strains must be carefully selected based on characterization of each strain and not based on inclusion within a certain species. IMPORTANCE Representative type strains are commonly used to characterize bacterial species, yet species are phenotypically and genotypically heterogeneous. Conclusions about strain physiology and activity based on a single strain therefore may be inappropriate and misleading. When selecting strains for probiotic use, the assumption that all strains within a species share the same desired probiotic characteristics may result in selection of a strain that lacks the desired traits, and therefore makes a minimally effective or ineffective probiotic. Health-associated oral streptococci are promising candidates for anticaries probiotics, but strains need to be carefully selected based on observed phenotypes. We characterized the genotypes and anticaries phenotypes of strains from 10 species of oral streptococci and demonstrate poor correlation between genotype and phenotype across all species.

Project description:The extent to which viral genetic context influences HIV adaptation to human leukocyte antigen (HLA) class I-restricted immune pressures remains incompletely understood. The Ugandan HIV epidemic, where major pandemic group M subtypes A1 and D cocirculate in a single host population, provides an opportunity to investigate this question. We characterized plasma HIV RNA gag, pol, and nef sequences, along with host HLA genotypes, in 464 antiretroviral-naive individuals chronically infected with HIV subtype A1 or D. Using phylogenetically informed statistical approaches, we identified HLA-associated polymorphisms and formally compared their strengths of selection between viral subtypes. A substantial number (32%) of HLA-associated polymorphisms identified in subtype A1 and/or D had previously been reported in subtype B, C, and/or circulating recombinant form 01_AE (CRF01_AE), confirming the shared nature of many HLA-driven escape pathways regardless of viral genetic context. Nevertheless, 34% of the identified HLA-associated polymorphisms were significantly differentially selected between subtypes A1 and D. Experimental investigation of select examples of subtype-specific escape revealed distinct underlying mechanisms with important implications for vaccine design: whereas some were attributable to subtype-specific sequence variation that influenced epitope-HLA binding, others were attributable to differential mutational barriers to immune escape. Overall, our results confirm that HIV genetic context is a key modulator of viral adaptation to host cellular immunity and highlight the power of combined bioinformatic and mechanistic studies, paired with knowledge of epitope immunogenicity, to identify appropriate viral regions for inclusion in subtype-specific and universal HIV vaccine strategies.IMPORTANCE The identification of HIV polymorphisms reproducibly selected under pressure by specific HLA alleles and the elucidation of their impact on viral function can help identify immunogenic viral regions where immune escape incurs a fitness cost. However, our knowledge of HLA-driven escape pathways and their functional costs is largely limited to HIV subtype B and, to a lesser extent, subtype C. Our study represents the first characterization of HLA-driven adaptation pathways in HIV subtypes A1 and D, which dominate in East Africa, and the first statistically rigorous characterization of differential HLA-driven escape across viral subtypes. The results support a considerable impact of viral genetic context on HIV adaptation to host HLA, where HIV subtype-specific sequence variation influences both epitope-HLA binding and the fitness costs of escape. Integrated bioinformatic and mechanistic characterization of these and other instances of differential escape could aid rational cytotoxic T-lymphocyte-based vaccine immunogen selection for both subtype-specific and universal HIV vaccines.

Dataset Information

Genotypic and phenotypic heterogeneity in the U3R region of HIV type 1 subtype C.

Publications

Genotypic and phenotypic heterogeneity in the U3R region of HIV type 1 subtype C.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets