Treatment agents for inhibiting HIV and cancer in HIV infected patients

Inactive Publication Date: 2016-11-24
UNIV OF MARYLAND
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0013]Methods are provided in certain embodiments with a therapeutically effective amount of mTOR inhibitor that inhibits both R5 and X4 HIV replication. Other methods are provided with a ther

Problems solved by technology

Still, the pace of new infections continues at far too high a level—particularly among certain groups.
The HIV virus has been difficult to treat in view of the emergence of drug-resistant viral strains, the need for sustained adherence to complex treatment regimens, and the toxicity of currently used antivirals agents.
With the exception of some derived from tumors, most primary cell cultures have limited lifespan.
Patients on therapy can fail treatment, among other factors, because of the emergence of drug resistance.
This need for the development of alternative antiretroviral agents is primarily due to drug resistance but also for sustained adherence to complex treatment reg

Method used

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  • Treatment agents for inhibiting HIV and cancer in HIV infected patients
  • Treatment agents for inhibiting HIV and cancer in HIV infected patients
  • Treatment agents for inhibiting HIV and cancer in HIV infected patients

Examples

Experimental program
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example 1

Materials and Methods

Cell Proliferation and Infectivity Assays

[0092]PBLs were isolated from buffy coats of HIV seronegative donors (New York Blood Center). The laboratory-adapted strains HIV BaL and HIV HXB2; primary isolates HIV 92BR020, 92UG031, 93BR029, and 93UG082; and multidrug resistant molecular clone NL4329129-2 were obtained from the NIH AIDS Repository. Primary isolate 2044 was from Paul Clapham (Windeyer Institute), and 1633 and 1638 from the Institute of Human Virology (University of Maryland School of Medicine). Maraviroc, efavirenz, raltegravir, and indinavir were from the NIH AIDS Repository. INK128 was purchased from ApexBio. Proliferation of PBLs was measured by the MTT kit (Roche), following the manufacturer's directions. PBL infectivity assays were performed as described herein.

Cell Fusion Assay

[0093]CD4 cells were isolated from PBL cultures maintained for 7 days in the presence of different concentrations of INK128. Isolation of CD4 cells was done by positive sel...

example 2

INK128 Inhibits R5 and X4 HIV Replication in Primary Cells

[0104]The chemical structure of INK128 is shown in FIG. 1A. The effect of INK128 was evaluated on proliferation of peripheral blood lymphocytes (PBLs) from four different donors. For each donor, PBLs were activated by treatment with anti-CD3 / CD28 antibodies for 3 days, cultured in the presence of IL-2 and various dilutions of INK128 for 5 days, followed by measurement of cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays (FIG. 1B). INK128 did not inhibit cell proliferation at concentrations of up to 100 nM. Therefore, 100 nM was selected as the highest INK128 concentration in subsequent experiments evaluating antiviral activity.

[0105]The antiviral activity of INK128 was investigated in PBLs infected with CCR5 (R5)-tropic and CXCR4 (X4)-tropic HIV reference strains BaL and HXB2, respectively. In experiments with PBLs from three donors, INK128 inhibited replication of both viruses, ...

example 3

INK128 Inhibits Entry of R5, but not X4, HIV in Primary Lymphocytes

[0107]The mechanism of INK128 inhibition of HIV was evaluated. Because INK128 activity was more potent against R5 than against X4 HIV, it was hypothesized that INK128 affects entry of these viruses differently. To test this, cell-cell fusion assays were performed between 293T cells expressing R5 or X4 HIV envelopes (effectors) and INK128-treated primary CD4+ T cells (targets). In this assay, targets are labeled with the fluorescent dye calcein (green) and effectors with CMTMR (red) before co-culture. Fused cells score positive for both dyes. INK128 inhibited fusion of CD4+ T target cells with R5 HIV JRFL Env, but not with X4 HIV HXB2 Env (FIG. 3A). These data, obtained with CD4 targets from two different donors, suggested inhibition at an early step of the R5, but not X4, HIV lifecycle. Downstream steps in HIV infection were evaluated by measuring early products of reverse transcription and integrated provirus using ...

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Abstract

Methods are provided for treating HIV and cancer in a subject in need thereof by administering to the subject therapeutically effective amounts of an mTOR inhibitor. Other methods are provided for treating subjects infected with HIV by administering to the subject therapeutically effective amounts of the mTOR inhibitor INK128, GSK2126458, AZD2014 or Torin-2.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of provisional application 62 / 163,408, entitled “A Single Treatment Agent for Inhibiting HIV and Cancer in HIV Infected Patients,” filed May 19, 2015, the entire contents of which are incorporated herein.BACKGROUND[0002]Human Immunodeficiency Virus (HIV), the virus that causes AIDS, is one of the world's most serious health and development challenges. According to the World Health Organization (WHO) there were approximately 36.9 million people worldwide living with HIV / AIDS in 2014. Of these, 2.6 million were children (<15 years old).[0003]In the United States, the CDC estimates that 1,218,400 persons aged 13 years and older are living with infection, including 156,300 (12.8%) who are unaware of their infection. Over the past decade, the number of people living with HIV has increased, while the annual number of new HIV infections has remained relatively stable. Still, the pace of new infections conti...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61K45/06A61K31/5377A61K31/4745A61K31/501
CPCA61K31/519A61K31/4745A61K45/06A61K31/5377A61K31/501A61K2300/00
Inventor REDFIELD, ROBERT R.HEREDIA, ALONSODAVIS, CHARLES E.GARTENHAUS, RONALD B.SAUSVILLE, EDWARD A.
Owner UNIV OF MARYLAND
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