Compounds producing an effective combinatorial regimen for disruption of HIV ‐1 latency

Abstract

Highly active antiretroviral therapy (HAART) has improved the outlook for the HIV epidemic, but does not provide a cure. The proposed “shock‐and‐kill” strategy is directed at inducing latent HIV reservoirs, which may then be purged via boosted immune response or targeting infected cells. We describe five novel compounds that are capable of reversing HIV latency without affecting the general T‐cell activation state. The new compounds exhibit synergy for reactivation of latent provirus with other latency‐reversing agents (LRAs), in particular ingenol‐3‐angelate/PEP005. One compound, designated PH02, was efficient at reactivating viral transcription in several cell lines bearing reporter HIV‐1 at different integration sites. Furthermore, it was capable of reversing latency in resting CD4+ T lymphocytes from latently infected aviremic patient cells on HAART, while producing minimal cellular toxicity. The combination of PH02 and PEP005 produces a strong synergistic effect for reactivation, as demonstrated through a quantitative viral outgrowth assay (qVOA), on CD4+ T lymphocytes from HIV‐1‐infected individuals. We propose that the PH02/PEP005 combination may represent an effective novel treatment for abrogating persistent HIV‐1 infection.

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

“…The LRAs MMQO, AV6, 57704, and PH03 were identified in four separate screens, but carry a common central quinoline structure, which we propose may represent a privileged structural motif. In chemical biology and medicinal chemistry, privileged structures are represented by a semirigid molecular scaffold that when modified by multiple hydrophobic residues or functional groups produce versatile binding properties that confer the capacity to interact with diverse biochemical targets .…”

“…Identification of novel compounds with HIV latency reversing activity is a relatively young endeavor; we describe results from 18 small molecule screens, but only two of which have involved extensive unbiased libraries of 100K compounds or more (Table ) . Considering that 100s of HTP screens involving very large libraries have been focused toward identification of novel cancer drugs over the past 20 years, efforts toward identification of novel HIV LRAs by comparable strategies appear to be in their infancy.…”

“…Additional important considerations include a requirement for minimal toxicity, and negligible effects on global T cell activation. Furthermore, there is increasing recognition that no single LRA is likely capable of inducing the full spectrum of latent provirus required to purge a sufficient fraction of infected cells, and therefore most recent efforts have focused on developing and characterizing combinations of compounds that produce synergistic effects on reactivation of individual provirus, and exert a broader effect on the latently infected population as a whole …”

Disruption of latent HIV in vivo during the clearance of actinic keratosis by ingenol mebutate

“…A short course of treatment with ingenol mebutate gel (US Food and Drug Administration-approved [FDA-approved] Picato) leads to effective clearance of AK lesions (1,2,6). We and others have previously shown that ingenol mebutate can reactivate latent HIV in the primary CD4 + T cells of HIV-infected patients under suppressive ART (7)(8)(9)(10)(11). Several families of compounds with PKC agonist activity can induce latent HIV expression by activating the PKC/NF-κB signaling pathway (12), but many of them have also been associated with systemic toxicities in animal studies (12).…”

HIV Latency Reversal Agents: Effective for Cure?

“…single agents, nevertheless the response seems modest for potential clinical use [20][21][22]. While the possibility of more potent candidates or combinations is perceivable, rationale suggests that most, if not all of these molecules induce clinical toxicity because of their dissemination into and thereby activation of bystander cells that do not harbor the virus.…”