Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony-stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): a single-arm, phase 1B/2A trial

Leth, Steffen; Schleimann, Mariane H.; Nissen, Sara Konstantin; Højen, Jesper Falkesgaard; Olesen, Rikke; Graversen, Mette E.; Jørgensen, Sofie E.; Kjær, Andreas; Denton, Paul W.; Mørk, Alejandra; Sommerfelt, Maja A.; Krogsgaard, Kim; Østergaard, Lars; Rasmussen, Thomas A; Tolstrup, Martin; Søgaard, Ole Schmeltz

doi:10.1016/s2352-3018(16)30055-8

Cited by 158 publications

(168 citation statements)

References 24 publications

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“…In these clinical studies, all LRAs except bryostatin increased HIV RNA transcription when administered alone, but there was no decline in the number of infected cells (Archin et al, 2012; Elliott et al, 2015; Elliott et al, 2014; Gutierrez et al, 2016; Rasmussen et al, 2014; Sogaard et al, 2015). In one clinical trial, the combination of the HDACi romidepsin with a T-cell vaccine led to a modest reduction in HIV DNA, although the mechanism for this reduction was not explored (Leth et al, 2016). More recently, in studies of SIV-infected rhesus macaques on ART and HIV-infected individuals on ART, the administration of TLR7 and TLR9 agonists led to significant increases in plasma SIV and HIV RNA respectively, consistent with latency reversal (Vibholm et al, 2017; Whitney et al, 2016; Whitney et al, 2015).…”

Section: Latency Reversing Agentsmentioning

confidence: 99%

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Kim

Anderson

Lewin

2018

Cell Host & Microbe

298

351

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Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is lifelong. HIV persists during ART due to long lived and proliferating latently infected CD4+ T-cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection.

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Section: Latency Reversing Agentsmentioning

confidence: 99%

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Kim

Anderson

Lewin

2018

Cell Host & Microbe

298

351

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“…A recent clinical trial administering romidepsin in combination with therapeutic vaccine Vacc-4x and recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) demonstrated a non-significant decline in PCR-based measures of proviral DNA and was generally well-tolerated by participants(100). Additional trials testing romidepsin with a different vaccine candidate, MVA.HIVconsv (NCT02616874) and with the promising HIV-1 broadly neutralizing antibody 3BNC117 (NCT03041012) are actively recruiting participants at present.…”

Section: Kill Phase Considerationsmentioning

confidence: 99%

Novel Latency Reversal Agents for HIV-1 Cure

2018

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Antiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness, however ART is not curative due to the persistence of replication-competent, latent proviruses in long-lived resting T cells. Strategies that target these latently infected cells and allow for immune recognition and clearance of this reservoir will be necessary to eradicate HIV-1 in infected individuals. This review describes current pharmacologic approaches to reactivate the latent reservoir in a manner that infected cells can be recognized and targeted, with the ultimate goal of achieving an HIV-1 cure.

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“…For example, combined treatment with Vacc-4x (a four-HIV-1-specific peptide vaccine), recombinant GM-CSF, and romidepsin (a histone deacetylase inhibitor) resulted in decrease of total HIV-1 DNA by nearly 40%, virus reactivation, and significant decrease of the size of latent HIV-1 reservoir (46). Administration of the peptide vaccine and GM-CSF before treatment with romidepsin was directed to recover DC-mediated anti-viral immune response.…”

Section: The Immunization With Dcs Also Resulted In Enhanced Productimentioning

confidence: 99%