Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: Results from a multicentre randomized clinical study
Division of Hematology, Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada. HIV Medicine
(Impact Factor: 3.99).
01/2012; 13(5):291-6. DOI: 10.1111/j.1468-1293.2011.00975.x
Conflicting results have been reported regarding the ability of valproic acid (VPA) to reduce the size of HIV reservoirs in patients receiving suppressive highly active antiretroviral therapy (HAART). In a randomized multicentre, cross-over study, we assessed whether adding VPA to stable HAART could potentially reduce the size of the latent viral reservoir in CD4 T cells of chronically infected patients.
A total of 56 virologically suppressed patients were randomly assigned either to receive VPA plus HAART for 16 weeks followed by HAART alone for 32 weeks (arm 1; n = 27) or to receive HAART alone for 16 weeks and then VPA plus HAART for 32 weeks (arm 2; n = 29). VPA was administered at a dose of 500 mg twice a day (bid) and was adjusted to the therapeutic range. A quantitative culture assay was used to assess HIV reservoirs in CD4 T cells at baseline and at weeks 16 and 48.
No significant reductions in the frequency of CD4 T cells harbouring replication-competent HIV after 16 and 32 weeks of VPA therapy were observed. In arm 1, median (range) values of IU per log(10) billion (IUPB) cells were 2.55 (range 1.20-4.20), 1.80 (range 1.0-4.70) and 2.70 (range 1.0-3.90; P = 0.87) for baseline, week 16 and week 48, respectively. In arm 2, median values of IUPB were 2.55 (range 1.20-4.65), 1.64 (range 1.0-3.94) and 2.51 (range 1.0-4.48; P = 0.50) for baseline, week 16 and week 48, respectively.
Our study demonstrates that adding VPA to stable HAART does not reduce the latent HIV reservoir in virally suppressed patients.
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Available from: Lech Dudycz
- "SAHA (suberoylanilide hydroxamic acid) is a histone deacetylases inhibitor that can disrupt HIV-1 latency in vitro (Archin et al., 2012, 2009; Liu et al., 2006) and in HIV positive patients submitted to HAART combined with 400 mg of SAHA (Archin et al., 2012). Introduction of yet another HDACi; valproic acid (VPA), was envisioned to flush out the latent virus from these reservoirs within few years, but VPA in combination with HAART failed to deplete latent HIV reservoir sufficiently (Routy et al., 2012). Some compounds are able to disrupt HIV latency activating the transcriptional elongation factor b (P-TEFb). "
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ABSTRACT: The ability of HIV to establish long-lived latent infection is mainly due to transcriptional silencing of viral genome in resting memory T lymphocytes. Here, we show that new semi-synthetic ingenol esters reactivate latent HIV reservoirs. Amongst the tested compounds, 3-caproyl-ingenol (ING B) was more potent in reactivating latent HIV than known activators such as SAHA, ingenol 3,20-dibenzoate, TNF-α, PMA and HMBA. ING B activated PKC isoforms followed by NF-κB nuclear translocation. As virus reactivation is dependent on intact NF-κB binding sites in the LTR promoter region ING B, we have shown that. ING B was able to reactivate virus transcription in primary HIV-infected resting cells up to 12 fold and up to 25 fold in combination with SAHA. Additionally, ING B promoted up-regulation of P-TEFb subunits CDK9/Cyclin T1. The role of ING B on promoting both transcription initiation and elongation makes this compound a strong candidate for an anti-HIV latency drug combined with suppressive HAART.
Virology 07/2014; 462-463C:328-339. DOI:10.1016/j.virol.2014.05.033 · 3.32 Impact Factor
Available from: Asier Sáez-Cirión
- "A first study reported a decrease in the frequency of circulating resting CD4þ T cells carrying replication competent HIV-1 in four patients receiving cART after 16 weeks of additional treatment with VPA (Lehrman et al., 2005). However, subsequent randomized clinical studies could not confirm these results and no significant effects of VPA were evidenced (Archin et al., 2010; Routy et al., 2012; Sagot-Lerolle et al., 2008; Steel et al., 2006). Failure of VPA was eventually associated to a poor capacity of this molecule to inhibit HDAC3, the HDAC isoform that is thought to play a preponderant role in HIV latency (Huber et al., 2011). "
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ABSTRACT: Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy (cART) in recent years have transformed HIV infection into a chronic disease when treatment is available. However, in spite of the favorable outcomes provided by the newer therapies, cART is not curative and patients are at risk of developing HIV-associated disorders. Moreover, universal access to antiretroviral treatment is restricted by financial obstacles. This review discusses the most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV.
Virology 04/2014; 454-455(1). DOI:10.1016/j.virol.2014.02.021 · 3.32 Impact Factor
Available from: PubMed Central
- "To this end, a number of small molecule activators have been shown to stimulate HIV transcription in latently infected cells (1,2). However, these compounds are toxic, mutagenic (positive in Ames tests) or ineffective in trials involving enlarged sample size and prolonged treatment (3–5). Thus, better and more specific latency activators are urgently needed, which can only be achieved through the identification of the most relevant molecular mechanism and factors that contribute to viral latency. "
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ABSTRACT: Latent HIV reservoirs are the primary hurdle to eradication of infection. Identification of agents, pathways and molecular mechanisms that activate latent provirus may, in the presence of highly active antiretroviral therapy, permit clearance of infected cells by the immune system. Promoter-proximal pausing of RNA polymerase (Pol) II is a major rate-limiting step in HIV gene expression. The viral Tat protein recruits human Super Elongation Complex (SEC) to paused Pol II to overcome this limitation. Here, we identify the bromodomain protein Brd4 and its inhibition of Tat-transactivation as a major impediment to latency reactivation. Brd4 competitively blocks the Tat-SEC interaction on HIV promoter. The BET bromodomain inhibitor JQ1 dissociates Brd4 from the HIV promoter to allow Tat recruitment of SEC to stimulate HIV elongation. JQ1 synergizes with another latency activator prostratin, which promotes Pol II loading onto the viral promoter. Because JQ1 activates viral latency without inducing global T cell activation, this and other closely related compounds and their antagonization of Brd4 to promote Tat-SEC interaction merit further investigations as effective agents/strategies for eliminating latent HIV.
Nucleic Acids Research 10/2012; 41(1). DOI:10.1093/nar/gks976 · 9.11 Impact Factor
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