HIV-1 Eradication: Early Trials (and Tribulations)

Abstract

Antiretroviral therapy (ART) has rendered HIV-1 infection a manageable illness for those with access to treatment. However, ART does not lead to viral eradication owing to the persistence of replication-competent, unexpressed proviruses in long-lived cellular reservoirs. The potential for long-term drug toxicities and the lack of access to ART for most people living with HIV-1 infection have fueled scientific interest in understanding the nature of this latent reservoir. Exploration of HIV-1 persistence at the cellular and molecular level in resting memory CD4(+) T cells, the predominant viral reservoir in patients on ART, has uncovered potential strategies to reverse latency. We review recent advances in pharmacologically based 'shock and kill' HIV-1 eradication strategies, including comparative analysis of early clinical trials.

Figure 1. Sources and kinetics of plasma viremia on antiretroviral therapy (ART)

The initiation of ART results in a biphasic decay in plasma viremia. The first phase reflects the death of productively infected CD4⁺ T lymphocytes. Infected cells with a longer half-life, such as tissue macrophages, are thought to produce the second phase of viral decay, during which the viral load falls below the detection limit of commercial assays (20-50 copies/mL). Patients maintain low-level viremia during ART that likely arises from spontaneous reactivation of latently infected resting CD4⁺ T cells. The contribution of non-T cell reservoirs including chronically infected tissue macrophages to residual viremia remains incompletely understood. Analytical treatment interruption (ATI) consists of study participants stopping ART with close monitoring for adverse effects of unchecked viral replication and quantifiable viral rebound. The time to viral rebound during ATI is thought to provide an estimate of the efficacy of the intervention in reducing reservoir size. Figure adapted from Durand C.M. et al. Trends in Immunology 2012 [ref 22]

Figure 2. Induction of proviral transcription in latently infected resting CD4⁺ T cells

In the latent state, the 5′LTR NF-κB and NFAT binding sites are occupied by inactive p50 homodimers, while the active p50/p65 NF-κB isoform is bound to IκB and sequestered in the cytoplasm. NFAT is phosphorylated and also remains in the cytoplasm. Histone deacetylases are recruited to the 5′LTR and repress transcriptional activity. Additional mechanisms of latency that are not pharmacologic targets in pilot clinical trials have been omitted for clarity. Disulfiram (green arrows) blocks the activity of the Akt-inhibitory protein PTEN. Akt signaling pathway activation results in release of the active positive transcription elongation factor b (p-TEFb, not shown) as well as phosphorylation of IKK and subsequent degradation of IκB, which allows the p50/p65 NF-κB isoform to enter the nucleus, bind to the 5′LTR and induce transcription. Cytoplasmic PKC isoforms are activated by PKC agonists and also target IκB for degradation (blue arrows), which leads to active NF-κB entry into the nucleus. Stimulation of the T cell receptor (TCR) leads to cellular activation (orange arrows), which results in translocation of both transcription factors NF-κB and NFAT into the nucleus. Histone deacetylase inhibitors (HDACi, brown arrows) block the activity of histone deacetylases and lead to acetylation of Nuc-0 and Nuc-1. Active NF-κB bound to the 5′LTR leads to the recruitment of histone acetyltransferases (HATs). Figure adapted from Xing S. et al Drug Discov. Today 2013 [ref 29] and Van Lint C. et al Retrovirology 2013 [ref 24]