Lovastatin Inhibits HIV-1-Induced MHC-I Downregulation by Targeting Nef–AP-1 Complex Formation: A New Strategy to Boost Immune Eradication of HIV-1 Infected Cells
Current combined antiretroviral therapy (cART) mainly targets 3 of the 15 HIV proteins leaving many potential viral vulnerabilities unexploited. To purge the HIV-1 latent reservoir, various strategies including “shock and kill” have been developed. A key question is how to restore impaired immune surveillance. HIV-1 protein Nef has long been known to mediate the downregulation of cell-surface MHC-I and assist HIV-1 to evade the immune system. Through high throughput screening of Food and Drug Administration (FDA) approved drugs, we identified lovastatin, a statin drug, to significantly antagonize Nef to downregulate MHC-I, CD4, and SERINC5, and inhibit the intrinsic infectivity of virions. In addition, lovastatin boosted autologous CTLs to eradicate the infected cells and effectively inhibit the subsequent viral rebound in CD4+ T-lymphocytes isolated from HIV-1-infected individuals receiving suppressive cART. Furthermore, we found that lovastatin inhibits Nef-induced MHC-I downregulation by directly binding with Nef and disrupting the Nef–AP-1 complex. These results demonstrate that lovastatin is a promising agent for counteracting Nef-mediated downregulation of MHC-I, CD4, and SERINC5. Lovastatin could potentially be used in the clinic to enhance anti-HIV-1 immune surveillance.
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REFERENCES
- https://doi.org//10.1146/annurev.med.53.082901.104011
- https://doi.org//10.1038/nm0703-853
- https://doi.org//10.1146/annurev.immunol.21.120601.141053
- https://doi.org//10.1038/nri998
- https://doi.org//10.1016/S1074-7613(02)00307-2
- https://doi.org//10.1016/j.cub.2005.02.058
- https://doi.org//10.1038/nature15400
- https://doi.org//10.1038/nature15399
- https://doi.org//10.1128/JVI.79.1.632-636.2005
- https://doi.org//10.1038/nsmb.2328
- https://doi.org//10.1128/JVI.77.5.3041-3049.2003
- https://doi.org//10.1091/mbc.e11-11-0928
- https://doi.org//10.1038/34929
- https://doi.org//10.1016/0092-8674(94)90360-3
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AUTHORS (19)
CATEGORIES
- Transplantation Immunology
- Tumour Immunology
- Immunology not elsewhere classified
- Immunology
- Veterinary Immunology
- Animal Immunology
- Genetic Immunology
- Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
- Autoimmunity
- Cellular Immunology
- Humoural Immunology and Immunochemistry
- Immunogenetics (incl. Genetic Immunology)
- Innate Immunity