title: Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice.
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 recently 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 < 50 nM), in the absence of toxicity. INK128 inhibited R5 HIV entry by reducing CCR5 levels. INK128 also inhibited both basal and induced transcription of HIV genes, consistent with inhibition of mTORC2, whose activity is critical for phosphorylation of PKC isoforms and, in turn, induction of NF-κB. INK128 enhanced the antiviral potency of the CCR5 antagonist maraviroc, and had favorable antiviral interactions with HIV inhibitors of reverse transcriptase, integrase and protease. In humanized mice, INK128 decreased plasma HIV RNA by >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.
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; aheredia@ihv.umaryland.edu rgallo@ihv.umaryland.edu.
authors.forename: Alonso
authors.initials: A
authors.lastname: Heredia
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Nhut
authors.initials: N
authors.lastname: Le
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Gartenhaus
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Edward
authors.initials: E
authors.lastname: Sausville
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Sandra
authors.initials: S
authors.lastname: Medina-Moreno
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Juan C
authors.initials: JC
authors.lastname: Zapata
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Charles
authors.initials: C
authors.lastname: Davis
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; aheredia@ihv.umaryland.edu rgallo@ihv.umaryland.edu.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gallo
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Robert R
authors.initials: RR
authors.lastname: Redfield
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000495:Allosteric Site; D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use; D001583:Benzoxazoles / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D020134:Catalytic Domain; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008214:Lymphocytes / Q000166:cytology / Q000821:virology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D000255:Adenosine Triphosphate; D019380:Anti-HIV Agents; D001583:Benzoxazoles; D007376:Interleukin-2; D016328:NF-kappa B; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C572449:sapanisertib; D000225:Adenine
keywords: CCR5; HIV resistance; HIV transcription; humanized mice; mTOR inhibitors