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.

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

“…The network representation of Akt/PI3K pathways, previously linked to Th17 lineage polarization (58-60) and reported to be upregulated in human lamina propria T cells (73), pointed to the upregulation of mTOR, a metabolic sensor involved in the regulation of numerous cellular functions via the formation of two different signaling complexes, mTORC1 and mTORC2 (74)(75)(76)(77). Considering the documented role of mTOR-mediated processes in the positive regulation of HIV replication (62,78), we proceeded to the validation of mTOR expression at protein and mRNA levels as well as functional validations in cells from the blood and/or colons of HIV-infected individuals receiving ART and uninfected study participants.…”

“…Evidence exists in the literature that mTOR regulates HIV replication via multiple mechanisms (78,79). One possible mechanism is via the regulation of CCR5 expression (62). However, CCR5 expression on ATRA-treated T cells was not affected by mTOR inhibitors.…”

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 + T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

“…As for the deep reservoir that cannot be activated by current methods, highly effective LRAs are urgently needed to reduce its size to the greatest extent possible. Thereafter, strategies such as the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system, RNA interference, and small-molecule approaches might be utilized to permanently extirpate these deeply silenced viruses (65)(66)(67)(68)(69)(70)(71). In any case, the CAR-T cell method could be used to enhance and maintain immune surveillance (7).…”

In Vitro Interactions between Target of Rapamycin Kinase Inhibitor and Antifungal Agents against Aspergillus Species

“…It has been demonstrated that orally administered INK128 has high absorption and bioavailability in mice, with doses of 3 mg/kg yielding a maximal concentration (C max ) of 0.599 g/ml in plasma (5). In addition, daily administration of INK128 at doses of up to 5 mg/kg over a 2-week period showed no obvious toxicity in mice (17), suggesting that effective antifungal levels of INK128, as observed in our study, could be achieved. However, further studies are needed to investigate the potential for concomitant use of these agents in humans.…”