HIV-1 transcriptional activity during frequent longitudinal sampling in aviremic patients on antiretroviral therapy

Leth, Steffen; Nymann, Rasmus; Jørgensen, Sofie E.; Olesen, Rikke; Rasmussen, Thomas A; Østergaard, Lars; Denton, Paul W.; Tolstrup, Martin; Søgaard, Ole Schmeltz

doi:10.1097/qad.0000000000000974

Cited by 18 publications

(15 citation statements)

References 61 publications

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“…Alternatively, this decline could have been driven by another unknown cause of assay variation, as the rca-RNA assay has not been extensively characterized in longitudinal studies 33 . Given the small sample size and lack of a control group, we cannot completely dismissed that some of the increase or decrease in caRNA is perhaps due to longitudinal variation in cRNA expression 34 . However, of note, VV-02 also had a decline in single-copy assay plasma viremia (SCA) from 4 copies/µl to <1.0 copies µl at all post-AGS-004 timepoints, but SCA levels were too low to assess in 3 other participants and were unaffected in a fourth (VV-06).…”

Section: Discussionmentioning

confidence: 99%

Assessing the impact of AGS-004, a dendritic cell-based immunotherapy, and vorinostat on persistent HIV-1 Infection

Kuruc

Falcinelli

Warren

et al. 2020

Sci Rep

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Approaches to deplete persistent HIV infection are needed. We investigated the combined impact of the latency reversing agent vorinostat (VOR) and AGS-004, an autologous dendritic cell immunotherapeutic, on the HIV reservoir. HIV+, stably treated participants in whom resting CD4 + t cell-associated HIV RNA (rca-RNA) increased after VOR exposure ex vivo and in vivo received 4 doses of AGS-004 every 3 weeks, followed by VOR every 72 hours for 30 days, and then the cycle repeated. Change in VOR-responsive host gene expression, HIV-specific T cell responses, low-level HIV viremia, rca-RNA, and the frequency of resting CD4 + T-cell infection (RCI) was measured at baseline and after each cycle. No serious treatment-related adverse events were observed among five participants. As predicted, VOR-responsive host genes responded uniformly to VOR dosing. Following cycles of AGS-004 and VOR, rca-RNA decreased significantly in only two participants, with a significant decrease in SCA observed in one of these participants. However, unlike other cohorts dosed with AGS-004, no uniform increase in HIV-specific immune responses following vaccination was observed. Finally, no reproducible decline of RCI, defined as a decrease of >50%, was observed. AGS-004 and VOR were safe and well-tolerated, but no substantial impact on RCI was measured. In contrast to previous clinical data, AGS-004 did not induce HIV-specific immune responses greater than those measured at baseline. More efficacious antiviral immune interventions, perhaps paired with more effective latency reversal, must be developed to clear persistent HIV infection.

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Section: Discussionmentioning

confidence: 99%

Assessing the impact of AGS-004, a dendritic cell-based immunotherapy, and vorinostat on persistent HIV-1 Infection

Kuruc

Falcinelli

Warren

et al. 2020

Sci Rep

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“…Consequently, these mild effects seen when a single factor is knocked down seem to suggest that the silencing of HIV-1 transcription for latency establishment requires the cooperation of multiple host factors and machineries. Furthermore, a two-fold increase is considered to be clinically significant for the “shock and kill” strategy to cure HIV [38]. Interestingly, most TAPs (NAT10, TINP1, XRCC5) showed beneficial effects when their depletion was coupled with LRAs (JQ1, SAHA), except for SIN3A as compared to the shNT control (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Identification of HIV-1 Tat-Associated Proteins Contributing to HIV-1 Transcription and Latency

Jean

Power

Kong

et al. 2017

Viruses

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Human immunodeficiency virus type 1 (HIV-1) Tat is a virus-encoded trans-activator that plays a central role in viral transcription. We used our recently developed parallel analysis of in vitro translated open reading frames (ORFs) (PLATO) approach to identify host proteins that associate with HIV-1 Tat. From this proteomic assay, we identify 89 Tat-associated proteins (TAPs). We combine our results with other datasets of Tat or long terminal repeat (LTR)-associated proteins. For some of these proteins (NAT10, TINP1, XRCC5, SIN3A), we confirm their strong association with Tat. These TAPs also suppress Tat-mediated HIV-1 transcription. Removing suppression of HIV-1 transcription benefits the reversal of post-integrated, latent HIV-1 proviruses. We demonstrate that these transcriptionally suppressing TAPs contribute to HIV-1 latency in Jurkat latency (J-LAT) cells. Therefore, our proteomic analysis highlights the previously unappreciated TAPs that play a role in maintaining HIV-1 latency and can be further studied as potential pharmacological targets for the “shock and kill” HIV-1 cure strategy.

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“…For total HIV-1 DNA, we used the ddPCR assay [25] and for integrated HIV-1 DNA, we performed an Alu-PCR analysis [26]. All assays were performed on total CD4 + T cells.…”

Section: No Detectable Change In the Size Of The Latent Hiv-1 Reservoirmentioning

confidence: 99%

Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection

Vibholm

Schleimann

Højen

et al. 2017

Clinical Infectious Diseases

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145

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HIV-1 transcriptional activity during frequent longitudinal sampling in aviremic patients on antiretroviral therapy

Abstract: The individual CA-US HIV-1 RNA levels are remarkably stable during ART. Importantly, the observed variations were less than the reported changes for latency-reactivating agent trials. These data will serve as a foundation for planning and interpreting future eradication trials.

Cited by 18 publications

References 61 publications

Assessing the impact of AGS-004, a dendritic cell-based immunotherapy, and vorinostat on persistent HIV-1 Infection

Assessing the impact of AGS-004, a dendritic cell-based immunotherapy, and vorinostat on persistent HIV-1 Infection

Identification of HIV-1 Tat-Associated Proteins Contributing to HIV-1 Transcription and Latency

Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection

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