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Ceramide, a target for antiretroviral therapy
Catherine M Finnegan1, Satinder S Rawat, Anu Puri
1Laboratories of Experimental and Computational Biology, Molecular Immunoregulation, and Experimental Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Summary
Increasing ceramide levels in cells inhibits HIV-1 infection. The drug N-(4-hydroxyphenyl)retinamide (4-HPR) effectively reduces HIV susceptibility with minimal toxicity, suggesting its therapeutic potential.
Area of Science:
- Lipid metabolism
- Cellular biology
- Virology
Background:
- Ceramides are key lipids regulating cellular responses.
- Sphingolipids play a role in HIV entry into target cells.
- Modulating ceramide levels may alter HIV susceptibility.
Purpose of the Study:
- To investigate the hypothesis that ceramide level modulation affects HIV infection susceptibility.
- To evaluate the anti-HIV potential of agents that increase cellular ceramide.
Main Methods:
- Cellular ceramide levels were modulated using N-(4-hydroxyphenyl)retinamide (4-HPR), sphingomyelinase (Smase), or exogenous long-chain ceramide.
- HIV infectivity assays were performed on TZM-bl cells, CD4+ lymphocytes, and monocytes.
- Cell viability was assessed to determine drug toxicity.
Main Results:
- 4-HPR demonstrated dose-dependent inhibition of HIV-1 infection in TZM-bl cells (IC50 <1 microM).
- Elevated ceramide levels (50-100%) via 4-HPR, Smase, or exogenous ceramide inhibited HIV-1 infection.
- Significant reduction in infectivity was observed in CD4+ lymphocytes and macrophages without toxicity.
Conclusions:
- Enhancing cellular ceramide levels is a viable strategy to inhibit HIV-1 infection.
- 4-HPR shows promise as a non-toxic anti-HIV therapeutic due to its ability to increase ceramide and reduce viral entry.