Biology subjects

Rice, A. P.

Publications and source records attributed to Rice, A. P..

2 recordsLinked to original sources

bioRxiv2024

Sirtuin2 blockade inhibits replication of Human Immunodeficiency Virus-1 and 1 Mycobacterium tuberculosis in macrophages and humanized mice

Coinfections with Mycobacterium tuberculosis (Mtb) and HIV-1 present a critical health challenge and require treatment for survival. We found that human M1 macrophages inhibit Mtb growth, while M2 macrophages, characterized by elevated Sirt2 expression, permit Mtb growth. Further, we found that HIV-1 augmented Sirt2 gene expression in M[FE]s. Therefore, we explored the therapeutic potential of sirtuin-modulating drugs in M[FE]s. Sirtinol, a Sirt2 inhibitor, significantly reduced HIV-1 growth in M0, M1, and M2-M[FE]s by >1 log10 over 7 days. Conversely, individual doses of resveratrol and SRT1460, which activate Sirt1, did not affect HIV-1. However, their combination showed a strong synergistic inhibition of HIV-1. The combination of sirtinol with resveratrol was neither synergistic nor antagonistic. Sirtinol upregulated iNOS and ATG5 mRNA in HIV-1 infected M[FE]s in a phenotype-dependent manner. In a humanized mouse model (Hu-NSG-SGM3) co-infected with Mtb H37Rv and the HIV-1 BAL strain, treatment with sirtinol alone, or in combination with combination antiretroviral therapy (cART), showed promising results; Sirtinol alone reduced Mtb growth, while its combination with cART effectively inhibited HIV-1 replication in the organs. We propose that Sirt2 blockade and Sirt1-activation represent a novel dual therapeutic strategy for treating HIV-1 and Mtb coinfections.

immunology↗

bioRxiv2020

Identification of Celastrol as a novel HIV-1 Latency Reversal Agent by an Image-Based Screen

Although current antiretroviral therapies (ART) are successful in controlling HIV-1 infection, a stable viral reservoir reactivates when ART is discontinued. Consequently, there is a major research effort to develop approaches to disrupt the latent viral reservoir and enhance the immune systems ability to clear HIV-1. A number of small molecules, termed latency reversal agents (LRAs), have been identified which can reactivate latent HIV-1 in cell lines and patients cells ex vivo. However, clinical trials have suggested that combinations of LRAs will be required to efficiently reactivate HIV-1 in vivo, especially LRAs that act synergistically by functioning through distinct pathways. To identify novel LRAs, we used an image-based assay to screen a natural compound library for the ability to induce a low level of aggregation of resting primary CD4+ T cells from healthy donors. We identified celastrol as a novel LRA. Celastrol functions synergistically with other classes of LRA to reactivate latent HIV-1 in a Jurkat cell line, suggesting a novel mechanism in its LRA activity. Additionally, celastrol does not appear to activate resting CD4+ T cells at levels at which it can reactivate latent HIV-1. Celastrol appears to represent a novel class of LRAs and it therefore can serve as a lead compound for LRA development.

microbiology↗