Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. AIDS
INSERM, U802, Bicêtre, France. AIDS (London, England)
(Impact Factor: 5.55).
06/2008; 22(10):1125-9. DOI: 10.1097/QAD.0b013e3282fd6ddc
To investigate the impact of prolonged valproic acid treatment on the HIV reservoir in patients on highly active antiretroviral therapy.
In a single-center pilot study, the size of the HIV reservoir of 11 patients receiving valproic acid for seizures for more than 2 years was compared with 13 matched patients. In addition, the outcome of patients receiving valproic acid in the French clinical trials of scheduled treatment interruption was recorded.
Total and integrated HIV-1 DNA in, respectively, peripheral blood mononuclear cells and CD4 T cells of the patients were quantified by real-time PCR methods. The frequency of CD4 T cells carrying replication-competent virus was estimated by a quantitative limiting-dilution assay in which virus growth was detected by RT-PCR in culture supernatants of activated CD4 T cells. Clinical charts of the patients included in scheduled treatment interruption trials receiving valproic acid were reviewed.
Total and integrated HIV DNA were logarithmically more abundant than cells carrying replication-competent virus, but there was no significant difference in these three parameters between the two groups of matched patients. Three patients receiving valproic acid were included in scheduled treatment interruption trials. The rebound of viral replication was similar to that of the other patients of the trials.
Long-term valproic acid therapy seems to be insufficient to reduce the size of the HIV-1 reservoir.
Available from: embomolmed.embopress.org
- "This allowed us to determine for each HDACI an optimal concentration (outlined by an arrow in Fig 2A and B) in terms of both their HIV-1 reactivation potential and their C max (mentioned at the bottom of Fig 2A and B). In our next experiments, we selected the following HDACI concentrations for combinatory treatments with 5-AzadC: (i) MS-275 at a concentration of 0.5 lM in agreement with C max ; (ii) NaBut at 1.5 mM consistent with C max ; (iii) SAHA at 1.25 lM in agreement with C max ; (iv) VPA at 2.5 mM, which is higher than C max but allowed HIV reactivation as opposed to VPA reactivation incapacity at C max used in clinical trials (Lehrman et al, 2005; Siliciano et al, 2007; Archin et al, 2008, 2010; Sagot-Lerolle et al, 2008; Routy et al, 2012a,b); (v) belinostat at 1 lM consistent with C max ; (vi) panobinostat at 0.15 lM corresponding to the dose initiating the plateau phase; and (vii) romidepsin at 0.0175 lM corresponding to an intermediate dose between the concentration initiating the plateau phase and C max . "
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ABSTRACT: Reactivation of HIV gene expression in latently infected cells together with an efficient cART has been proposed as an adjuvant therapy aimed at eliminating/decreasing the reservoir size. Results from HIV clinical trials using deacetylase inhibitors (HDACIs) question the efficiency of these latency-reversing agents (LRAs) used alone and underline the need to evaluate other LRAs in combination with HDACIs. Here, we evaluated the therapeutic potential of a demethylating agent (5-AzadC) in combination with clinically tolerable HDACIs in reactivating HIV-1 from latency first in vitro and next ex vivo. We showed that a sequential treatment with 5-AzadC and HDACIs was more effective than the corresponding simultaneous treatment both in vitro and ex vivo. Interestingly, only two of the sequential LRA combinatory treatments tested induced HIV-1 particle recovery in a higher manner than the drugs alone ex vivo and at concentrations lower than the human tolerable plasmatic concentrations. Taken together, our data reveal the benefit of using combinations of 5-AzadC with an HDACI and, for the first time, the importance of treatment time schedule for LRA combinations in order to reactivate HIV.
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.
Available from: Ahmed Kabel
- "Recently, VPA is under investigation for treatment of HIV and various cancers . VPA not only suppresses tumor growth and metastasis, but also induces tumor differentiation in vitro and in vivo. "
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ABSTRACT: Solid Ehrlich carcinoma is an undifferentiated tumor used in tumor studies. Methotrexate is an antimetabolite used in treatment of cancer, autoimmune diseases and induction of abortion. Valproic acid is used as anticonvulsant and is under investigation for treatment of cancer. The aim of this work was to study the effect of each of methotrexate and valproic acid alone and in combination on solid Ehrlich tumor in mice. Fifty albino mice were divided into five equal groups: Control untreated group, solid Ehrlich carcinoma, solid Ehrlich carcinoma + methotrexate, solid Ehrlich carcinoma + valproic acid, solid Ehrlich carcinoma + methotrexate + valproic acid. Tumor volume, tissue catalase, glutathione reductase, malondialdehyde, cholesterol and tumor necrosis factor-α were determined. A part of the tumor was examined for histopathological and immunohistochemical study. Methotrexate or valproic acid alone or in combination induced significant increase in tissue catalase and glutathione reductase with significant decrease in tumor volume, tissue malondialdehyde, cholesterol and tumor necrosis factor-α and alleviated the histopathological changes with significant increase in p53 expression and apoptotic index compared to solid Ehrlich carcinoma group. The combination of methotrexate and valproic acid has a better effect than each of methotrexate or valproic acid alone against solid Ehrlich tumor in mice.
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