Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo

Beans, Elizabeth J.; Fournogerakis, Dennis N.; Gauntlett, Carolyn; Heumann, Lars V.; Kramer, Rainer; Marsden, Matthew D.; Murray, Danielle; Chun, Tae‐Wook; Zack, Jerome A.; Wender, Paul A.

doi:10.1073/pnas.1302634110

Cited by 137 publications

(110 citation statements)

References 28 publications

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“…Bryostatin-1 is a natural product available only in small amounts. Several synthetic analogs of both bryostatin-1 and prostratin have recently been developed (48,55). However, the clinical utility of these analogs remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Laird¹,

Bullen²,

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Laird¹,

Bullen²,

et al. 2015

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“…Various latencyreversing agents (LRAs) have been investigated, including drugs that trigger the NF-B activation pathway, such as prostratin (10) and bryostatin (11) analogues; BET inhibitors enhancing the binding of the viral Tat protein to the HIV TAR element (12); disulfiram (13,14); and histone deacetylase inhibitors (HDACi), like valproic acid (15,16), vorinostat (17,18), panobinostat (19), and romidepsin (20), that act as epigenetic modifiers. The HDACi were the first compounds to enter clinical trials, given the extensive data on their toxicity from studies in individuals with malignancy.…”

mentioning

confidence: 99%

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Petravic

Rasmussen

Lewin

et al. 2017

J Virol

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Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latencyreversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3-to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life Ͼ 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment.IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.KEYWORDS latency, reactivation, human immunodeficiency virus C ombination antiretroviral therapy (ART) suppresses plasma HIV RNA below the detection limit of laboratory assays and restores the immune systems of infected patients by preventing new rounds of productive infection. However, ART cannot eradicate the infection, and virus replication starts again within weeks of ART cessation

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“…Significantly, a potent lead analog also induced the expression of latent virus from PBMCs isolated from HAART-treated patients at the concentration at which prostratin lost its efficacy. These potent analogs will facilitate the research and preclinical advancement of HIV/AIDS eradication [64] .…”

Section: Histone Methyltransferase Inhibitors (Hmti)mentioning

confidence: 99%

Progress and challenges in the use of latent HIV-1 reactivating agents

Shang

Ding

et al. 2015

Acta Pharmacol Sin

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Highly active antiretroviral therapy (HAART) can effectively suppress the replication of human immunodeficiency virus-1 (HIV-1) and block disease progression. However, chronic HIV-1 infection remains incurable due to the persistence of a viral reservoir, including the transcriptionally silent provirus in CD4 + memory T cells and the sanctuary sites that are inaccessible to drugs. Reactivation and the subsequent elimination of latent virus through virus-specific cytotoxic effects or host immune responses are critical strategies for combating the disease. Indeed, a number of latency reactivating reagents have been identified through mechanism-directed approaches and large-scale screening, including: (1) histone deacetylase inhibitors (HDACi); (2) cytokines and chemokines; (3) DNA methyltransferase inhibitors (DNMTI); (4) histone methyltransferase inhibitors (HMTI); (5) protein kinase C (PKC) activators; (6) P-TEFb activators; and (7) unclassified agents, such as disulfram. They have proved to be efficacious in latent cell line models and CD4 + T lymphocytes from HIV-1-infected patients. This review comprehensively summarizes the recent progress and relative challenges in this field.

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Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo

Cited by 137 publications

References 28 publications

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Progress and challenges in the use of latent HIV-1 reactivating agents

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