Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro

DeChristopher, Brian A.; Loy, Brian A.; Marsden, Matthew D.; Schrier, Adam J.; Zack, Jerome A.; Wender, Paul A.

doi:10.1038/nchem.1395

Cited by 151 publications

(141 citation statements)

References 51 publications

(59 reference statements)

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“…We then asked whether robust induction of latent HIV-1 by treatments containing a PKC agonist was coupled with T cell activation or toxicity. rCD4s stimulated with PKC agonists alone or in combination with another LRA exhibited increased surface expression of the early activation marker CD69 ( Figure 6A), consistent with previous studies (14,48). While some induction of CD25 surface expression on rCD4s occurred after treatment with PKC agonists alone, this expression was reduced with the addition of another LRA ( Figure 6A).…”

Section: Resultssupporting

confidence: 80%

See 1 more Smart Citation

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

Laird¹,

Bullen²,

et al. 2015

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Section: Resultssupporting

confidence: 80%

“…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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“…Collectively called latencyreversing agents (LRAs), these drugs include histone deacetylase inhibitors (12)(13)(14), PKC activators (15)(16)(17)(18), and the bromodomain inhibitor JQ1 (19)(20)(21). Although LRAs are the subject of intense research, it is unclear how much the LR must be reduced to enable patients to safely discontinue ART.…”

mentioning

confidence: 99%

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

Hill

Rosenbloom

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

254

313

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Significance HIV infection cannot be cured by current antiretroviral drugs, due to the presence of long-lived latently infected cells. New antilatency drugs are being tested in clinical trials, but major unknowns remain. It is unclear how much latent virus must be eliminated for a cure, which remains difficult to answer empirically due to few case studies and limited sensitivity of viral reservoir assays. In this paper, we introduce a mathematical model of HIV dynamics to calculate the likelihood and timing of viral rebound following antilatency treatment. We derive predictions for the required efficacy of antilatency drugs, and demonstrate that rebound times may be highly variable and occur after years of remission. These results will aid in designing and interpreting HIV cure studies.

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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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Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro

Cited by 151 publications

References 51 publications

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

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

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

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

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