Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

Heredia, Alonso; Latinovic, Olga; Gallo, Robert C.; Melikyan, Gregory B.; Reitz, Marv; Le, Nhut; Redfield, Robert

doi:10.1073/pnas.0810843106

Cited by 59 publications

(75 citation statements)

References 47 publications

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“…The fastest entry rates were noted for PBMC. Although surface expression of CCR5 on TZM-bl and U87-CD4-CCR5 cells is substantially greater than that that found on resting peripheral blood lymphocytes, interleukin-2 (IL-2)-stimulated PBMC, such as those used in the assays reported here, express levels of CCR5 comparable to or greater than the levels observed for CCR5-expressing U87 cells (13,39,44,62).…”

Section: Discussionmentioning

confidence: 77%

HIV-1 Clinical Isolates Resistant to CCR5 Antagonists Exhibit Delayed Entry Kinetics That Are Corrected in the Presence of Drug

Putcharoen

Lee

Henrich

et al. 2012

J Virol

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HIV CCR5 antagonists select for env gene mutations that enable virus entry via drug-bound coreceptor. To investigate the mechanisms responsible for viral adaptation to drug-bound coreceptor-mediated entry, we studied viral isolates from three participants who developed CCR5 antagonist resistance during treatment with vicriviroc (VCV), an investigational small-molecule CCR5 antagonist. VCV-sensitive and -resistant viruses were isolated from one HIV subtype C-and two subtype B-infected participants; VCV-resistant isolates had mutations in the V3 loop of gp120 and were cross-resistant to TAK-779, an investigational antagonist, and maraviroc (MVC). All three resistant isolates contained a 306P mutation but had variable mutations elsewhere in the V3 stem. We used a virus-cell ␤-lactamase (BlaM) fusion assay to determine the entry kinetics of recombinant viruses that incorporated full-length VCV-sensitive and -resistant envelopes. VCV-resistant isolates exhibited delayed entry rates in the absence of drug, relative to pretherapy VCV-sensitive isolates. The addition of drug corrected these delays. These findings were generalizable across target cell types with a range of CD4 and CCR5 surface densities and were observed when either populationderived or clonal envelopes were used to construct recombinant viruses. V3 loop mutations alone were sufficient to restore virus entry in the presence of drug, and the accumulation of V3 mutations during VCV therapy led to progressively higher rates of viral entry. We propose that the restoration of pre-CCR5 antagonist therapy HIV entry kinetics drives the selection of V3 loop mutations and may represent a common mechanism that underlies the emergence of CCR5 antagonist resistance. Human immunodeficiency virus entry is a competition at the target cell membrane between viral inactivation and successful binding to CD4 and a coreceptor, either CCR5 or CXCR4 (16,30,32,33,37,38). Engagement of receptor and coreceptor by gp120 and the subsequent rearrangement of gp41, the HIV fusion glycopeptides, leads to fusion (18,21,29,57,60,63). Smallmolecule antagonists that bind CCR5 and inhibit gp120-CCR5 binding through an allosteric mechanism have been developed (9,23,51,53,56,61). Maraviroc (MVC) is an FDA-approved CCR5 antagonist, and vicriviroc (VCV) is an investigational compound whose development has been halted (10, 47).HIV can escape CCR5 antagonism through the outgrowth of preexisting CXCR4-using populations or by the selection of resistance mutations (2, 52, 58). Mutations in the third hypervariable loop (V3 loop) of HIV-1 gp120 most commonly cause CCR5 antagonist resistance, but no canonical sites or amino acid substitutions have been identified; resistance mutations from one isolate generally do not confer resistance when transferred into unrelated env backbones (12, 17, 24, 26, 27, 34-36, 49, 54). This varied nature of HIV CCR5 antagonist genotypic resistance contrasts with resistance patterns established in other antiretroviral drug classes, for which canonical mutations (M184V in r...

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Section: Discussionmentioning

confidence: 77%

HIV-1 Clinical Isolates Resistant to CCR5 Antagonists Exhibit Delayed Entry Kinetics That Are Corrected in the Presence of Drug

Putcharoen

Lee

Henrich

et al. 2012

J Virol

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“…9). Previous work has shown that rapamycin, which targets mTORC1 but not mTORC2 (10), interferes with the HIV steps of CCR5-mediated entry and with basal (but not induced) transcription of the HIV LTR (11)(12)(13)(14). These activities of rapamycin effectively inhibit replication of CCR5 (R5)-tropic HIV, but not CXCR4 (X4)-tropic HIV, in primary lymphocytes (11,13,15).…”

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confidence: 99%

“…Because mTORC1 controls CCR5 expression and basal HIV transcription (11)(12)(13), and because mTORC2 controls phosphorylation of PKC (9,(20)(21)(22), required for NF-κB induction of HIV transcription (23,24), we hypothesized that TOR-KIs could inhibit both R5 and X4 HIV. We have evaluated the anti-HIV potential of TOR-KIs using INK128 (25)(26)(27), currently in clinical trials of cancer.…”

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confidence: 99%

Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice

Heredia

Gartenhaus

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.

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“…A similar trend has been observed for TAK779 as well, which may be due to the fact that HEK 293T cells express substantially higher amounts of CCR5, as compared with U87 cells and PBMCs (see Table 1). Indeed, previous reports highlighted that increasing the CCR5 expression level at the cell surface decreases the antiviral potency of small molecule CCR5 inhibitors (51,52). High amounts of CCR5 in HEK 293T cells might suggest that these cells contain more receptors than G-proteins, as compared with the other cell types.…”

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confidence: 99%

New Insights into the Mechanisms whereby Low Molecular Weight CCR5 Ligands Inhibit HIV-1 Infection

García-Pérez

Rueda

Staropoli

et al. 2011

Journal of Biological Chemistry

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Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

Cited by 59 publications

References 47 publications

HIV-1 Clinical Isolates Resistant to CCR5 Antagonists Exhibit Delayed Entry Kinetics That Are Corrected in the Presence of Drug

HIV-1 Clinical Isolates Resistant to CCR5 Antagonists Exhibit Delayed Entry Kinetics That Are Corrected in the Presence of Drug

Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice

New Insights into the Mechanisms whereby Low Molecular Weight CCR5 Ligands Inhibit HIV-1 Infection

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