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Upon infection of its host cell, human immunodeficiency virus (HIV) establishes a quiescent and non-productive state capable of spontaneous reactivation. Diverse cell types harboring the provirus form a latent reservoir, constituting a major obstacle to curing HIV. Here, we investigate the effects of latency reversal agents (LRAs) in an HIV-infected THP-1 monocyte cell line in vitro. We demonstrate that leading drug treatments synergize activation of the HIV long terminal repeat (LTR) promoter. We establish a latency model in THP-1 monocytes using a replication incompetent HIV reporter vector with functional Tat, and show that chromatin modifiers synergize with a potent transcriptional activator to enhance HIV reactivation, similar to T-cells. Furthermore, leading reactivation cocktails are shown to differentially affect latency reactivation and surface expression of chemokine receptor type 4 (CXCR4), leading to altered host cell migration. This study investigates the effect of chromatin-modifying LRA treatments on HIV latent reactivation and cell migration in monocytes. As previously reported in T-cells, epigenetic mechanisms in monocytes contribute to controlling the relationship between latent reactivation and cell migration. Ultimately, advanced “Shock and Kill” therapy needs to successfully target and account for all host cell types represented in a complex and composite latency milieu.
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This content will become publicly available on November 19, 2025
Croton oligandrus Pierre & Hutch (Euphorbiaceae) Extracts and Isolated Compounds Reverse HIV-1 Latency
Background: Croton oligandrus Pierre & Hutch is a tropical tree that grows in West and Central Africa, used in ethnomedicine to treat cancer, diabetes, headaches, convulsions, urinary diseases, and inflammatory diseases. As other Croton species have been observed to possess chemical compounds that target HIV latency-reversal, we hypothesized that this species may have similar properties. Aim of the study: The identification of extracts and compounds of this species, which have HIV-1 latency-reversing activity in J-Lat T cell lines. Methods: The stem bark was obtained, air-dried, powdered, and extracted using dichloromethane. In vitro flow cytometry was used to monitor GFP expression, a marker of HIV latency reversal, following treatment of J-Lat T cells with extracts and compounds. Results: Four extracts were found to reverse HIV latency, the most active extract showing better activity (ie, latency reversal in 69.7 ± 7.1% [mean ± s.e.m.] of J-Lat 10.6 cells at 1 µg/mL) than control agents prostratin (46.2 ± 9.5% at 1.2 µg.mL) and the "Mukungulu" (Croton megalobotrys) extract (34.9 ± 24.2% at 1 µg/mL). Extracts reversed HIV latency through mechanisms over and above protein kinase C (PKC) activation and distinct from histone deacetylase (HDAC) inhibition. The most active extract also synergized with the control HDAC inhibitor romidepsin but did not synergize with other extracts. Isolated compounds (β-Stigmasterol and lupeol) had limited but consistent latency reversal on their own. Conclusion: The plant extracts and compounds reverse HIV latency through mechanisms additional to PKC activation and/or synergize with romidepsin in vitro. Extracts and compounds from this plant may enhance the activity of current HIV latency-reversing agents being assessed in HIV cure studies.
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- PAR ID:
- 10586186
- Publisher / Repository:
- Dovepress
- Date Published:
- Journal Name:
- Journal of Experimental Pharmacology
- Volume:
- Volume 16
- ISSN:
- 1179-1454
- Page Range / eLocation ID:
- 413 to 425
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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