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Characterisation of HIV-1 transmission clusters and drug-resistant mutations in Denmark, 2004 to 2016.

ABSTRACT: This study describes the prevalence of human immunodeficiency virus (HIV) drug resistance mutations among 1,815 patients in Denmark from 2004 to 2016 and characterises transmission clusters. POL sequences were analysed for subtype, drug resistance mutations and phylogenetic relationship. The prevalence of surveillance drug resistance mutations (SDRM) was 6.7%, while the prevalence of drug resistance mutations (DRM) with a clinical impact was 12.3%. We identified 197 transmission clusters with 706 patients. Patients 40 years or older were less likely to be members of a transmission cluster and patients in transmission clusters were less likely to be infected abroad. The proportion of late presenters (LP) was lower in active compared with inactive clusters. Large active clusters consisted of more men who have sex with men (MSM), had members more frequently infected in Denmark and contained a significantly lower proportion of LP and significantly fewer patients with DRM than small active clusters. Subtyping demonstrated that the Danish HIV epidemic is gradually becoming more composed of non-B subtypes/circulating recombinant forms. This study shows that active HIV-1 transmission has become increasingly MSM-dominated and that the recent increase in SDRM and DRM prevalence is not associated with more sustained transmission within identified transmission networks or clusters.

SUBMITTER: Petersen A

PROVIDER: S-EPMC6337072 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Characterisation of HIV-1 transmission clusters and drug-resistant mutations in Denmark, 2004 to 2016.

Petersen Andreas A Cowan Susan A SA Nielsen Jens J Fischer Thea K TK Fonager Jannik J

Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 20181101 44

This study describes the prevalence of human immunodeficiency virus (HIV) drug resistance mutations among 1,815 patients in Denmark from 2004 to 2016 and characterises transmission clusters. POL sequences were analysed for subtype, drug resistance mutations and phylogenetic relationship. The prevalence of surveillance drug resistance mutations (SDRM) was 6.7%, while the prevalence of drug resistance mutations (DRM) with a clinical impact was 12.3%. We identified 197 transmission clusters with 70 ...[more]

PMID: 30401010

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Project description:Drug-resistance is a serious problem for treatment of the HIV/AIDS pandemic. Potent clinical inhibitors of HIV-1 protease show several orders of magnitude worse inhibition of highly drug-resistant variants. Hence, the structure and enzyme activities were analyzed for HIV protease mutant HIV-1 protease (EC 3.4.23.16) (PR) with 22 mutations (PRS5B) from a clinical isolate that was selected by machine learning to represent high-level drug-resistance. PRS5B has 22 mutations including only one (I84V) in the inhibitor binding site; however, clinical inhibitors had poor inhibition of PRS5B activity with kinetic inhibition value (Ki ) values of 4-1000 nm or 18- to 8000-fold worse than for wild-type PR. High-resolution crystal structures of PRS5B complexes with the best inhibitors, amprenavir (APV) and darunavir (DRV) (Ki ~ 4 nm), revealed only minor changes in protease-inhibitor interactions. Instead, two distinct clusters of mutations in distal regions induce coordinated conformational changes that decrease favorable internal interactions across the entire protein subunit. The largest structural rearrangements are described and compared to other characterized resistant mutants. In the protease hinge region, the N83D mutation eliminates a hydrogen bond connecting the hinge and core of the protease and increases disorder compared to highly resistant mutants PR with 17 mutations and PR with 20 mutations with similar hinge mutations. In a distal β-sheet, mutations G73T and A71V coordinate with accessory mutations to bring about shifts that propagate throughout the subunit. Molecular dynamics simulations of ligand-free dimers show differences consistent with loss of interactions in mutant compared to wild-type PR. Clusters of mutations exhibit both coordinated and antagonistic effects, suggesting PRS5B may represent an intermediate stage in the evolution of more highly resistant variants. DATABASES: Structural data are available in Protein Data Bank under the accession codes 6P9A and 6P9B for PRS5B/DRV and PRS5B/APV, respectively.

Project description:BackgroundThe HIV-1 epidemic in Ethiopia has been shown to be dominated by two phylogenetically distinct subtype C clades, the Ethiopian (C'-ET) and East African (C-EA) clades, however, little is known about the temporal dynamics of the HIV epidemic with respect to subtypes and distinct clades. Moreover, there is only limited information concerning transmission of HIV-1 drug resistance (TDR) in the country.MethodsA cross-sectional survey was conducted among young antiretroviral therapy (ART)-naïve individuals recently diagnosed with HIV infection, in Gondar, Ethiopia, 2011-2013 using the WHO recommended threshold survey. A total of 84 study participants with a median age of 22 years were enrolled. HIV-1 genotyping was performed and investigated for drug resistance in 67 individuals. Phylogenetic analyses were performed on all available HIV sequences obtained from Gondar (n = 301) which were used to define subtype C clades, temporal trends and local transmission clusters. Dating of transmission clusters was performed using BEAST.ResultFour of 67 individuals (6.0%) carried a HIV drug resistance mutation strain, all associated with non-nucleoside reverse transcriptase inhibitors (NNRTI). Strains of the C-EA clade were most prevalent as we found no evidence of temporal changes during this time period. However, strains of the C-SA clade, prevalent in Southern Africa, have been introduced in Ethiopia, and became more abundant during the study period. The oldest Gondar transmission clusters dated back to 1980 (C-EA), 1983 (C-SA) and 1990 (C'-ET) indicating the presence of strains of different subtype C clades at about the same time point in Gondar. Moreover, some of the larger clusters dated back to the 1980s but transmissions within clusters have been ongoing up till end of the study period. Besides being associated with more sequences and larger clusters, the C-EA clade sequences were also associated with clustering of HIVDR sequences. One cluster was associated with the G190A mutation and showed onward transmissions at high rate.ConclusionTDR was detected in 6.0% of the sequenced samples and confirmed pervious reports that the two subtype C clades, C-EA and C'-ET, are common in Ethiopia. Moreover, the findings indicated an increased diversity in the epidemic as well as differences in transmission clusters sizes of the different clades and association with resistance mutations. These findings provide epidemiological insights not directly available using standard surveillance and may inform the adjustment of public health strategies in HIV prevention in Ethiopia.

Dataset Information

Characterisation of HIV-1 transmission clusters and drug-resistant mutations in Denmark, 2004 to 2016.

Publications

Characterisation of HIV-1 transmission clusters and drug-resistant mutations in Denmark, 2004 to 2016.

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