Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy

Prins, Jan M.; Jurriaans, Suzanne; Praag, van R.M.E.; Blaak, Hetty; Rij, van; Schellekens, P. T. A.; Berge, ten R.J.M.; Yong, S. L.; Fox, Cecil H.; Roos, M. T. L.; Wolf, de F; Goudsmit, Jaap; Schuitemaker, Hanneke; Lange, Joep M. A.

doi:10.1097/00002030-199912030-00012

Cited by 215 publications

(171 citation statements)

References 28 publications

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“…The strategy of purging the latent pool of HIV-1-infected CD4 + T cells was initially performed using interleukin (IL)-2 and other activators of T cells such as anti-CD3 antibodies (OKT3). However, although such agents caused a marked activation of the T cells, there were unacceptable toxicities and also an irreversible decrease in the amount of CD4 + T cells (15,16). Other studies using IL-2 did not reduce the pool (17,18), perhaps because of a paucity of cell surface receptors for IL-2 on the resting CD4 + T cells.…”

Section: Early Studies On Purging Hiv-1 From Latently Infected Cellsmentioning

confidence: 99%

Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir

Matalon

Rasmussen

Dinarello

2011

Mol Med

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A reservoir of latently infected memory CD4 + T cells is believed to be the source of HIV-1 reemergence after discontinuation of antiretroviral therapy. HIV-1 eradication may depend on depletion of this reservoir. Integrated HIV-1 is inaccessible for expression, in part because of histone deacetylases (HDACs). One approach is to exploit the ability of HDAC inhibitors to induce HIV-1 expression from an integrated virus. With effective antiretroviral therapy, newly expressed HIV-1 is incapable of reinfecting naive cells.With HIV-1 expression, one assumes the infected cell dies and there is a progressive reduction in the size of the reservoir. The concept was tested using the HDAC inhibitor valproic acid. However, valproic acid is weak in inducing HIV-1 from latency in vitro. As such, clinical trials revealed a small or no effect on reducing the number of latently infected T cells in the peripheral blood. However, the new HDAC inhibitors vorinostat, belinostat and givinostat are more effective at targeting specific HDACs for HIV-1 expression than valproic acid. Here, we review studies on HDAC inhibitor-induced expression of latent HIV-1, with an emphasis on new and specific HDAC inhibitors. With increased potency for HIV-1 expression as well as safety and ease of oral administration, new HDAC inhibitors offer a unique opportunity to deplete the latent reservoir. An additional benefit is the antiinflammatory properties of HDAC inhibitors, including downregulation of HIV-1 coreceptor expression.

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Section: Early Studies On Purging Hiv-1 From Latently Infected Cellsmentioning

confidence: 99%

Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir

Matalon

Rasmussen

Dinarello

2011

Mol Med

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“…One problem with potential therapies pursuing the goal of activating latent virus is that general T-cell activation produces cytotoxic effects [17]. Activated T-cells secrete cytokines such as IL-2, which plays a pivotal role in immune response.…”

Section: Chaetocin Does Not Cause Activation Of Jurkat T-cellsmentioning

confidence: 99%

The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response

et al. 2011

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Edited by Hans-Dieter KlenkKeywords: HIV-1 Latency Chaetocin SUV39H1 HDAC inhibitor a b s t r a c t Latent HIV-1 (human immunodeficiency virus-1) provirus is unaffected by current AIDS (acquired immunodeficiency syndrome) therapies. We show here that chaetocin, an SUV39H1 histone methyltransferase inhibitor, causes 25-fold induction of latent HIV-1 expression, while producing minimal toxicity and without causing T cell activation. Induction is associated with loss of histone H3 lysine 9 (H3K9) trimethylation at the long terminal repeat (LTR) promoter, and a corresponding increase in H3K9 acetylation. The effect of chaetocin is amplified synergistically in combination with histone deacetylase (HDAC) inhibitors. These results indicate that chaetocin may provide a therapy to purge cells of latent HIV-1, possibly in combination with other chromatin remodeling drugs. Crown

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“…Yet despite increased T-cell numbers, vaccination responses were unchanged in a cohort of patients treated with ART and IL-2 compared to results with ART alone (71), suggesting that acquired immunity is not enhanced by IL-2 cotherapy. Furthermore, despite initial optimism that IL-2 would activate HIV from its latent reservoir and thereby enhance the ability of ART to cause a decline in the size of the HIV latent pool (15), this effect has not translated to viral eradication, even after 2 years of intense ART plus IL-2 therapy (59,66,78). Other approaches towards enhancing HIVspecific immunity and enhancing viral clearance are therefore needed, especially for patients with chronic HIV infection.…”

mentioning

confidence: 99%

Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity

Lum

Schnepple

Nie

et al. 2004

J Virol

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Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy

Abstract: OKT3/IL-2 resulted in T cell activation and proliferation, and could stimulate HIV replication in patients having achieved prolonged suppression of plasma viremia. OKT3/IL-2 therapy was toxic and rapidly induced antibodies against OKT3.

Cited by 215 publications

References 28 publications

Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir

Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir

The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response

Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity

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