PDF《Article》

Immunity Article Stimulation of HIV-1-Speci?c Cytolytic T Lymphocytes Facilitates Elimination of Latent Viral Reservoir after Virus Reactivation Liang Shan,1,2 Kai Deng,1 Neeta S.

Shroff,1 Christine M. Durand,1 S. Alireza. Rabi,1 Hung-Chih Yang,3 Hao Zhang,4 Joseph B. Margolick,4 Joel N. Blankson,1 and Robert F. Siliciano1,5,* 1Department of Medicine 2Department of Pharmacology and Molecular Sciences Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 3Department of Microbiology, National Taiwan University College of Medicine, Taipei 100, Taiwan 4Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA 5Howard Hughes Medical Institute, Baltimore, MD 21205, USA *Correspondence: [email protected] DOI 10.1016/j.immuni.2012.01.014 SUMMARY Highly active antiretroviral therapy (HAART) sup- presses HIV-1 replication but cannot eliminate the virus because HIV-1 establishes latent infection. Interruption of HAART leads to a rapid rebound of viremia, so life-long treatment is required. Efforts to purge the latent reservoir have focused on reactivat- ing latent proviruses without inducing global T cell activation. However, the killing of the infected cells after virus reactivation, which is essential for elimina- tion of the reservoir, has not been assessed. Here we show that after reversal of latency in an in vitro model, infected resting CD4+ T cells survived despite viral cytopathic effects, even in the presence of autol- ogous cytolytic T lymphocytes (CTLs) from most patients on HAART. Antigen-speci?c stimulation of patient CTLs led to ef?cient killing of infected cells. These results demonstrate that stimulating HIV-1- speci?c CTLs prior to reactivating latent HIV-1 may be essential for successful eradication efforts and should be considered in future clinical trials. INTRODUCTION The extremely stable latent reservoir for HIV-1 in resting memory CD4+ T cells (Chun et al., 1995, 1997a, 1997b;

Finzi et al., 1997;

Wong et al., 1997) is a major barrier to viral eradication. In latently infected cells, the integrated provirus is transcriptionally silent (Hermankova et al., 2003;

Chun et al., 2003) but is able to produce replication-competent virus after cellular activation (Finzi et al., 1997;

Wong et al., 1997;

Chun et al., 1997b). Because of the stability of the reservoir (Siliciano et al., 2003;

Strain et al., 2003), life-long antiretroviral therapy is required, raising concerns about adverse effects over decades of therapy, the evolution of resistance, and the ?nancial burden of treatment. Strategies to eradicate HIV-1 from infected individuals are there- fore urgently needed. Efforts to eradicate HIV-1 have focused on reactivating latent proviruses. Early studies with IL-2 or IL-2 plus CD3 antibodies to reactivate latent HIV-1 failed to eliminate the reservoir and caused signi?cant toxicity as a result of global T cell activation (Chun et al., 1999;

Prins et al., 1999;

van Praag et al., 2001;

Stell- brink et al., 2002;

Kulkosky et al., 2002). More recent studies have focused on identifying small molecules that reactivate latent virus without inducing host cell activation (Richman et al., 2009). Three FDA-approved drugs, valproic acid (Ylisasti- gui et al., 2004), suberoylanilide hydroxamic acid (SAHA) (Contreras et al., 2009;

Archin et al., 2009;

Edelstein et al., 2009), and disul?ram (Xing et al., 2011), can reactivate latent virus in primary cell models and/or cells from infected individ- uals. Clinical studies of valproic acid, which has histone deace- tylase (HDAC) inhibitor activity, have not shown a consistent decrease in the latent reservoir (Lehrman et al., 2005;