ABSTRACT
OBJECTIVES: We aim to identify long-term trends in HIV drug resistance before and after combined antiretroviral therapy (cART) initiation. METHODS: IAS-USA (2015) mutations were identified in 23 271 HIV protease-reverse transcriptase sequences from 6543 treatment naïve adults in British Columbia. Participants who started cART between 1996 and 2014 were followed until April 2016. Equality of proportions test was used to compare the percentage of participants with acquired drug resistance (ADR) or transmitted drug resistance (TDR) in 1996, to those in 2014. Kaplan-Meier was used to estimate time to ADR in four drug resistance categories. Multivariable regression odds ratios (OR) of ADR for select clinical variables were determined by 5-year eras of cART initiation. RESULTS: The proportion of individuals with ADR declined from 39% (51/132) to 3% (8/322) in 1996-2014 (p <0.0001), while the proportion with TDR increased from 12% (16/132) to 18% (59/322) (p 0.14). The estimated proportions of individuals with ADR rose to 29% (NNRTI), 28% (3TC/FTC), 14% (other nRTI), and 7% (PI) after >16 years of therapy. After 5 years on therapy, participants initiating cART in 1996-2000 had 5.5-times more 3TC/FTC ADR, 5.3-times more other nRTI ADR, 4.7-times more NNRTI ADR, and 24-times more PI ADR than those starting in 2011-2014. The individuals with highest odds of developing ADR in 1996-2010 were adherent to regimens at levels between 60% and 80%, which shifted to <40% adherent in 2011-2014. CONCLUSIONS: HIV drug resistance transitioned from being primarily selected de-novo to being driven by TDR. Among those who started treatment in the past 5 years, ADR is rare and observed mostly in the lowest adherence strata.
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , Adult , British Columbia/epidemiology , Drug Resistance, Viral/genetics , Female , HIV/drug effects , HIV/genetics , Humans , Kaplan-Meier Estimate , Longitudinal Studies , Male , Medication Adherence , Middle AgedABSTRACT
We undertake a detailed study of the one-locus two-allele partial selfing selection model. We show that a polymorphic equilibrium can exist only in the cases of overdominance and underdominance and only for a certain range of selfing rates. Furthermore, when it exists, we show that the polymorphic equilibrium is unique. The local stability of the polymorphic equilibrium is investigated and exact analytical conditions are presented. We also carry out an analysis of local stability of the fixation states and then conclude that only overdominance can maintain polymorphism in the population. When the linear local analysis is inconclusive, a quadratic analysis is performed. For some sets of selective values, we demonstrate global convergence. Finally, we compare and discuss results under the partial selfing model and the random mating model.
Subject(s)
Genetic Variation/genetics , Models, Biological , Polymorphism, Genetic/genetics , Selection, Genetic , Alleles , Gene Frequency , Genes, Dominant , Genes, Recessive , HomozygoteABSTRACT
The third group I intron of Physarum polycephalum is found at the same site in the large subunit rRNA as the well-characterized intron from Tetrahymena thermophila. Formation of alternative structures in the rRNA can inhibit self-splicing of the Tetrahymena intron. We report that splicing of Physarum intron 3 is also influenced by adjacent sequences. In this case, however, splicing is stimulated by the presence of a second group I intron 24 nucleotides downstream. In vitro, intron 3 self-splices 10-25-fold faster in transcripts containing both introns. In vivo, intron 3 is excised from pre-rRNA before intron 2 in the majority of transcripts, as judged by PCR amplification of processing intermediates. This is an unusual example in which self-splicing is enhanced by the juxtaposition of two group I introns. This cooperative effect may be mediated by a conformational change in the rRNA.
Subject(s)
Genes, Protozoan , Physarum polycephalum/genetics , RNA, Catalytic/metabolism , RNA, Protozoan/metabolism , RNA, Ribosomal/metabolism , Animals , Base Sequence , DNA Primers , Introns , Molecular Sequence Data , Nucleic Acid Conformation , RNA Precursors/metabolismABSTRACT
The third intron from Physarum polycephalum (Pp LSU 3) is one of the closest known relatives to the well-studied Tetrahymena group I intron. Both introns are located at the same position in the 26S rRNA gene, and with the exception of an open reading frame in Pp LSU 3, are highly homologous. While Pp LSU 3 has been shown to self splice, little is known about its activity in vitro. We have examined the requirements for self splicing in greater detail. Despite its similarity to the Tetrahymena intron, Pp LSU 3 is 1500-fold less reactive, demonstrates a preference for high salt, and exhibits a low Km for GTP. Removal of the open reading frame results in a modest increase of activity. This system provides an opportunity to understand how sequence variations in two related introns alter the efficiency of autoexcision, and how this relates to adaptation of group I introns to their particular sequence context.
