P-D8 Targeting of the catalytic site of host mTOR controls HIV in vivo. (January 2016)

• Record Type: Journal Article
• Authors: Heredia, Alonso; Le, Nhut; Gartenhaus, Ronald; Sausville, Edward; Medina-Moreno, Sandra; Zapata, Juan; Davis, Charles; Gallo, Robert; Redfield, Robert
• Is Part Of: Journal of acquired immune deficiency syndromes. Volume 71(2016)Supplement 1
• Publication Date: 2016-01
• Subjects: AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome -- Periodicals; AIDS (Disease); Periodicals; 616.9792005
• DOI: 10.1097/01.qai.0000479633.64677.4d
• Languages: English
• ISSNs: 1525-4135

Abstract

Abstract : HIV necessitates host factors for successful completion of its life cycle. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric inhibitor of mTOR that selectively inhibits mTORC1. Rapamycin interferes with viral entry of CCR5 (R5)-tropic HIV and with basal transcription of the HIV LTR, potently inhibiting replication of R5 HIV but not CXCR4 (X4)-tropic HIV in primary cells. The newly developed ATP-competitive mTOR kinase inhibitors (TOR-KIs) inhibit both mTORC1 and mTORC2. Using INK128 as a prototype TOR-KI, we demonstrate potent inhibition of both R5 and X4 HIV in primary lymphocytes EC50 2 log10 units and partially restored CD4/CD8 cell ratios. Targeting of cellular mTOR with INK128 (and perhaps others TOR-KIs) provides a potential strategy to inhibit HIV, especially in patients with drug resistant HIV strains.