Inhibition of NF-kB-dependent HIV-1 replication by the marine natural product bengamide A.
Information sheet for Tietjen et al., a study published in Antiviral Research, April 2018
Volunteer donation of blood, generously provided by anonymous volunteers, helped us to better understand the role of bengamide A in blocking the transcription of HIV proviruses. These results were published in Antiviral Research in April 2018.
1) What was the goal of our study?
Our study reports the screening of a small library of pure compounds from marine natural products to discover 6 of them that may be new HIV inhibitors. One of these, bengamide A, inhibits HIV in cell lines and primary lymphocytes (cells that populate the fighting immune system) at concentrations similar to licensed antiretroviral (ART) drugs. Bengamide A acts by blocking a process called cellular “NF-κB signalling”, which is required for transcription (copying) of HIV proviruses following integration into host genomic DNA.
2) How is this study related to a cure for HIV?
Therapies to cure HIV will likely exploit mechanisms of action that are different from those of existing HIV drugs. While our study does not directly investigate whether bengamide A can contribute to an HIV cure, it supports the hypothesis that blocking NF-κB signalling may help to stabilize HIV proviruses in a latent or quiet state for an extended period of time. Such approaches may be useful toward the long-term goal of drug-free HIV remission, or a “functional” HIV cure by keeping HIV from copying itself in cells where it can linger even when ART is effective.
3) Why are participant samples important to this research?
Drug discovery screens are frequently performed with laboratory grown cell lines, which are easier to work with in experiments but only partially reflect the native cellular environment in real people in which HIV replicates. Many compounds that potently inhibit HIV in cell lines can have little or no activity in primary lymphocytes. Our study shows that the activity of bengamide A on HIV replication in lymphocytes donated by study participants is comparable to that in cell lines. This validation would not have been possible without the generous participation of blood donors.
4) What was learned? What next?
Going forward, we want to investigate whether bengamide A can silence HIV proviruses and keep them in a latent state without transcribing or copying. We also want to elucidate the molecular mechanisms of action of the other 5 natural product "hits" identified in this screen. These studies can help improve our understanding of HIV pathogenesis and latency and potentially inform future HIV drug development.
