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

Romidepsin-induced HIV-1 viremia during effective antiretroviral therapy contains identical viral sequences with few deleterious mutations.
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Winckelmann A, Barton K, Hiener B, Schlub TE, Shao W, Rasmussen TA, Østergaard L, Søgaard OS, Tolstrup M, Palmer S,


Winckelmann A, Barton K, Hiener B, Schlub TE, Shao W, Rasmussen TA, Østergaard L, Søgaard OS, Tolstrup M, Palmer S, (click to view)

Winckelmann A, Barton K, Hiener B, Schlub TE, Shao W, Rasmussen TA, Østergaard L, Søgaard OS, Tolstrup M, Palmer S,

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AIDS (London, England) 31(6) 771-779 doi 10.1097/QAD.0000000000001400

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 < 0.001) and to DNA (odds ratio 7.07, P = 0.011) during romidepsin therapy. CONCLUSIONS
Romidepsin induced transcription from proviruses in peripheral blood cells, which contributed to viremia in patients on suppressive therapy. The intermingling of these cell-associated HIV-1 RNA with DNA sequences indicates transcription from a diverse range of proviruses, but the expansions of identical viral plasma sequences with few defects indicate that the romidepsin-induced viremia arises from intact proviruses with highly similar or identical genetic backgrounds.

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