Fast track — ArticlesDepletion of latent HIV-1 infection in vivo: a proof-of-concept study
Introduction
Antiretroviral therapy suppresses plasma HIV RNA concentrations below the limits of detection and restores immune function. However, latent replication-competent provirus in resting CD4+ T lymphocytes1, 2, 3 and persistent viral replication4, 5 prevent eradication of HIV infection. Nevertheless, since lifelong suppression of HIV infection with antiretroviral therapy is difficult, eradication should be the therapeutic aim. Approaches to deplete latent infection within resting CD4+ T cells are, therefore, needed.
Results of a long-term study,6 which followed-up patients for up to 7 years, confirm the stability of latent infection. Although a modest increase in the decay of the number of recoverable cells that contain replication-competent HIV has been reported after intensified antiretroviral therapy,7 the rate of decay of plasma HIV RNA8 or integrated HIV DNA decreases with time.9, 10 As such, a proportion of the pool of latently infected cells is probably highly stable and unlikely to be affected by potent inhibition of viral replication.
Intensive antiretroviral therapy in combination with T-cell activation does not eradicate HIV infection.11, 12, 13, 14 Activation can induce viral replication and increase the number of susceptible uninfected target cells beyond the threshold that can be contained by antiretroviral therapy.15 The discovery of reagents that selectively induce the expression of quiescent proviral genomes, but that have limited activating effects, might allow outgrowth of latent HIV and avoid the pitfalls of global T-cell activation.16, 17, 18, 19
Histone deacetylation is important for quiescence of HIV gene expression in infected resting CD4+ T lymphocytes. Histone deacetylase 1 (HDAC1) mediates chromatin remodeling, repression of viral gene expression, and virion production.20, 21, 22, 23 Blockade of HDAC activity ex vivo results in HIV outgrowth from the resting T cells of aviraemic patients.23, 24 Valproic acid, an anticonvulsant that inhibits HDAC, induces HIV expression ex vivo from the resting CD4+ T cells of aviraemic patients treated with highly-active antiretroviral therapy (HAART) as efficiently as activation with mitogen, but without upregulation of cell-surface markers of activation, or increased susceptibility to de-novo HIV infection.25
Our aim, therefore, was to test the ability of valproic acid to deplete HIV infection of resting CD4+ T cells in vivo.
Section snippets
Patients
Between July, 2002, and February, 2005, we did a proof-of-concept study to which we enrolled HIV-infected volunteers with long-term suppression of viraemia (<50 copies/mL for >2 years) who were taking HAART. Inclusion criteria were age 18 years or older, presence of documented HIV infection, ability to comply with protocol requirements and self-administer enfuvirtide for up to 18 weeks. Exclusion criteria were poor adherence to antiretroviral therapy, presence of contraindications to valproate
Results
The four patients enrolled tolerated the treatment regimen and adhered well to therapy, according to self-report, refill history, and enfuvirtide vial count (table 1). All had minor reactions at the injection site related to administration of enfuvirtide, as commonly reported.34 Patient 4, with a distant history of antiretroviral-related anaemia and baseline HAART that included zidovudine, developed grade 1 anaemia during the last 4 weeks of treatment with valproic acid. Anaemia resolved when
Discussion
Our findings show that 16–18 weeks' treatment with a standard clinical dose of valproic acid, in the setting of intensified HAART, produces a substantial decline in the frequency of replication-competent HIV in circulating resting CD4+ T cells.
We measured replication-competent HIV in resting CD4+ T cells under stringent conditions: our volunteers had been successfully treated with HAART for at least 2 years; we used an additional incubation step with reverse transcriptase and integrase
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