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Romidepsin-induced HIV-1 viremia during effective antiretroviral therapy contains identical viral sequences with few deleterious mutations.

ABSTRACT: OBJECTIVE:To investigate the origin of the HIV-1 viremia induced by the latency-reversing agent romidepsin. DESIGN:Six individuals on suppressive antiretroviral therapy received romidepsin administered intravenously once weekly for 3 consecutive weeks. CD4 T cells were obtained at baseline, following the second and third romidepsin infusion, and 10 weeks after the final romidepsin treatment. Plasma samples were collected 24 and 72 h after romidepsin infusions. METHODS:Single-genome sequencing of the env and p24-RT region was used to genetically characterize the virus from proviral DNA, the transcribed cell-associated RNA and the plasma RNA pool. RESULTS:In three of six participants with available plasma samples we identified plasma HIV-1 RNA sequences that were identical to DNA and/or cell-associated RNA sequences from peripheral blood CD4 T cells. In two participants, plasma RNA sequences contained expansions of identical sequences, corresponding to 62 and 100% of the total sequences, respectively. Plasma HIV-1 RNA had very low amounts of defective viruses compared to cell-associated RNA (odds ratio 20.85, P?

SUBMITTER: Winckelmann A

PROVIDER: S-EPMC5345886 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Romidepsin-induced HIV-1 viremia during effective antiretroviral therapy contains identical viral sequences with few deleterious mutations.

Winckelmann Anni A Barton Kirston K Hiener Bonnie B Schlub Timothy E TE Shao Wei W Rasmussen Thomas A TA Østergaard Lars L Søgaard Ole S OS Tolstrup Martin M Palmer Sarah S

AIDS (London, England) 20170301 6

<h4>Objective</h4>To investigate the origin of the HIV-1 viremia induced by the latency-reversing agent romidepsin.<h4>Design</h4>Six individuals on suppressive antiretroviral therapy received romidepsin administered intravenously once weekly for 3 consecutive weeks. CD4 T cells were obtained at baseline, following the second and third romidepsin infusion, and 10 weeks after the final romidepsin treatment. Plasma samples were collected 24 and 72 h after romidepsin infusions.<h4>Methods</h4>Singl ...[more]

PMID: 28272134

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Project description:All sequenced genomes of representatives of the Francisella genus contain two rpoA genes, which encode non-identical RNA polymerase (RNAP) subunits, ?1 and ?2. In all other bacteria studied to date, a dimer of identical ? subunits initiates the assembly of the catalytically proficient RNAP core (subunit composition ?2??'). Based on an observation that both ?1 and ?2 are incorporated into Francisella RNAP, Charity et al. (2007) previously suggested that up to four different species of RNAP core enzyme might form in the same Francisella cell.By in vitro assembly from fully denatured state, we determined that both Francisella ? subunits are required for efficient dimerization; no homodimer formation was detected. Bacterial two-hybrid system analysis likewise indicated strong interactions between the ?1 and ?2 N-terminal domains (NTDs, responsible for dimerization). NTDs of ?2 did not interact detectably, while weak interaction between ?1 NTDs was observed. This weak homotypic interaction may explain low-level transcription activity observed in in vitro RNAP reconstitution reactions containing Francisella large subunits (?', ?) and ?1. No activity was observed with RNAP reconstitution reactions containing ?2, while robust transcription activity was detected in reactions containing ?1 and ?2. Phylogenetic analysis based on RpoA resulted in a tree compatible with standard bacterial taxonomy with both Francisella RpoA branches positioned within ?-proteobacteria. The observed phylogeny and analysis of constrained trees are compatible with Francisella lineage-specific rpoA duplication followed by acceleration of evolutionary rate and subfunctionalization.The results strongly suggest that most Francisella RNAP contains ? heterodimer with a minor subfraction possibly containing ?1 homodimer. Comparative sequence analysis suggests that this heterodimer is oriented, in a sense that only one monomer, ?1, interacts with the ? subunit during the ?2? RNAP subassembly formation. Most likely the two rpoA copies in Francisella have emerged through a lineage-specific duplication followed by subfunctionalization of interacting paralogs.

Dataset Information

Romidepsin-induced HIV-1 viremia during effective antiretroviral therapy contains identical viral sequences with few deleterious mutations.

Publications

Romidepsin-induced HIV-1 viremia during effective antiretroviral therapy contains identical viral sequences with few deleterious mutations.

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