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.
Highlights
Despite nearly 36 years of intensive research investigating acquired immune deficiency syndrome (AIDS) and human immunodeficiency virus (HIV), mankind still faces major challenges in developing a cure for this disease
According to recent statistics released by the United Nations Programme on HIV/AIDS (UNAIDS), the number of HIV-infected individuals receiving antiretroviral treatment has increased considerably within the last decade, in African countries, which have the highest number of infected individuals
Despite the many benefits of this treatment, a cure cannot be achieved through Highly active antiretroviral therapy (HAART) and will require a clearer understanding of HIV-1 pathogenesis and the mechanisms contributing to provirus latency
Summary
Despite nearly 36 years of intensive research investigating acquired immune deficiency syndrome (AIDS) and human immunodeficiency virus (HIV), mankind still faces major challenges in developing a cure for this disease. A significant challenge is posed by the ability of the virus to form latent infections in the long-lived memory T-cell population. During replication in CD4+ T lymphocytes, a major target for HIV-1 infection, a small fraction of activated cells revert to a resting state, G0, in which transcription of chromosomally integrated provirus is repressed, causing the virus to become transcriptionally silenced or latent (Finzi et al, 1997). The highly stable and long-lived resting CD4+ T cells carrying integrated latent provirus are thought to represent a major barrier to an HIV-1 cure, because the immune system cannot recognize and eliminate these cells from patients (Palmer et al, 2011). The cessation of therapy results in rapid reappearance of the virus from reactivated latent reservoirs, which renders patients dependent on a lifetime of antiretroviral therapy (Shan & Siliciano, 2013). Without strategies for eliminating latently infected cells, HAART eventually becomes ineffective, because resistant viral strains emerge and side effects gradually accumulate through the prolonged use of antiretroviral drugs (Gunthard et al, 1998; Demeter et al, 2004; Lyons et al, 2005)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
