Skip Navigation Links

Project Information

Previous Project 16838 of 27,422 Next

INHIBITION OF HEAT SHOCK PROTEIN 90 FOR SUSTAINED REMISSION OF HIV FROM PERSISTENT TISSUE RESERVOIRS

Agency:
NIAID

HHS/NIH/National Institute of Allergy and Infectious Diseases (NIAID)

Project Number:
1R56AI147895-01A1
Contact PI / Project Leader:
STODDART, CHERYL
Awardee Organization:
UNIVERSITY OF CALIFORNIA SAN FRANCISCO

Description

Abstract Text:
PROJECT SUMMARY Persistent HIV-infected resting CD4+ T cells can remain undetected in tissue and organ reservoirs despite decades of successful antiretroviral therapy (ART). The lack of gene activity in resting CD4+ T cells enables the integrated replication-competent provirus to persist indefinitely. HIV replication in activated CD4+ T cells is cytopathic, and infected cells are cleared by the immune system. However, a small percentage of HIV-infected activated CD4+ T cells revert to the resting G0 phenotype and remain undetected in tissue reservoirs. These HIV- infected resting cells can be readily activated, and rebound viremia in patients with interrupted ART invariably originates from persistent HIV-infected tissue reservoirs. An ongoing project in my laboratory is focused on the essential role of heat shock protein 90 (Hsp90) in HIV replication. We have shown that mild heat shock (39.5°C) accelerates HIV transcription in chronically infected T-cell lines and increases HIV replication up to 30-fold in primary human cells. Accelerated HIV transcription coincides with increased cellular Hsp90 activity at 39.5°C. Hsp90 is responsible for activating cellular transcription factors, and the Hsp90 inhibitor 17-AAG significantly reduces gene expression by the NF-kB, NFAT, and STAT5 host transcription factors. Further, 39.5°C reactivates HIV replication in ART-suppressed aviremic HIV-infected patient samples and in human resting CD4+ T cells isolated from fully suppressed humanized mice. Further, we show that a more potent next-generation Hsp90 inhibitor has even greater anti-HIV activity with a highly favorable therapeutic ranking and that clinical HIV subtypes display increased viral transcription at 39.5°C in primary human T cells and macrophages. Most importantly, Hsp90 inhibition prevents HIV rebound in fully suppressed humanized mice, and we identified persistent HIV-infected human cells in the mouse spleen. Two different Hsp90 inhibitors blocked HIV transcription in this persistent tissue reservoir and sustained HIV remission up to 11 weeks after drug cessation. Further, we now have evidence that persistent HIV infection in spleen, brain, and lung reservoirs is established soon after inoculation, which produces infectious virus despite highly potent ART. HIV-infected human T cells and macrophages are also found in the mouse liver, bone marrow, and reproductive tract. We hypothesize that increased Hsp90 activity at 39.5°C activates host transcription factors that are essential for HIV transcription. This hypothesis will be addressed in the following Specific Aims: 1) Determine the gene expression profile of heat-shock activated HIV-infected human resting CD4+ T cells, 2) Identify specific Hsp90 protein complexes that regulate HIV persistence in resting CD4+ T cells, and 3) Characterize persistent HIV reservoirs in vivo and investigate the source of rebound viremia. We anticipate these studies will lead to a better understanding of how Hsp90 regulates HIV transcription, and our in vivo results will provide insight into the nature of rebound viremia from persistent tissue reservoirs.
Project Terms:
Address; Aftercare; Animal Model; Anti-Retroviral Agents; antiretroviral therapy; Autopsy; base; Blood; Bone Marrow; Brain; CD4 Positive T Lymphocytes; Cell division; Cell Line; Cells; Chronic; Clinical; collaboratory; Complex; Disease remission; DNA Sequence; Double Stranded DNA Virus; experience; follow-up; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Grant; Half-Life; Heat-Shock Proteins 90; Heat-Shock Response; Highly Active Antiretroviral Therapy; Histone Deacetylase Inhibitor; HIV; HIV Infections; HSP 90 inhibition; Human; Human Resources; humanized mouse; Immune system; in vivo; Infection; Infection prevention; inhibitor/antagonist; innovation; insight; Integration Host Factors; Interphase Cell; Interruption; Investigation; Laboratories; Lead; Length; Liver; Location; Lung; lymph nodes; macrophage; Molecular; Molecular Chaperones; mouse model; Mus; Nature; next generation; NF-kappa B; Organ; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Positive Transcriptional Elongation Factor B; preservation; prevent; protein complex; Proviruses; Public Health; Reporting; reproductive tract; Research; Resources; Rest; RNA; Role; Sampling; screening; seroconversion; skills; Source; Spleen; Stat5 protein; Therapeutic; Tissues; T-Lymphocyte; transcription factor; Viral; Viral reservoir; Viremia; Virus; Withholding Treatment

Details

Contact PI / Project Leader Information:
Name:  STODDART, CHERYL
Other PI Information:
Not Applicable
Awardee Organization:
Name:  UNIVERSITY OF CALIFORNIA SAN FRANCISCO
City:  SAN FRANCISCO    
Country:  UNITED STATES
Congressional District:
State Code:  CA
District:  12
Other Information:
Fiscal Year: 2020
Award Notice Date: 10-Jul-2020
DUNS Number: 094878337
Project Start Date: 10-Jul-2020
Budget Start Date: 10-Jul-2020
CFDA Code: 855
Project End Date: 30-Jun-2021
Budget End Date: 30-Jun-2021
Agency: ?

Agency: The entity responsible for the administering of a research grant, project, or contract. This may represent a federal department, agency, or sub-agency (institute or center). Details on agencies in Federal RePORTER can be found in the FAQ page.

HHS/NIH/National Institute of Allergy and Infectious Diseases (NIAID)
Project Funding Information for 2020:
Year Agency

Agency: The entity responsible for the administering of a research grant, project, or contract. This may represent a federal department, agency, or sub-agency (institute or center). Details on agencies in Federal RePORTER can be found in the FAQ page.

FY Total Cost
2020 NIAID

HHS/NIH/National Institute of Allergy and Infectious Diseases (NIAID)

$723,454

Results

i

It is important to recognize, and consider in any interpretation of Federal RePORTER data, that the publication and patent information cannot be associated with any particular year of a research project. The lag between research being conducted and the availability of its results in a publication or patent award varies substantially. For that reason, it's difficult, if not impossible, to associate a publication or patent with any specific year of the project. Likewise, it is not possible to associate a publication or patent with any particular supplement to a research project or a particular subproject of a multi-project grant.

ABOUT FEDERAL REPORTER RESULTS

Publications: i

Click on the column header to sort the results

PubMed = PubMed PubMed Central = PubMed Central Google Scholar = Google Scholar

Patents: i

Click on the column header to sort the results

Similar Projects

Download Adobe Acrobat Reader:Adobe Acrobat VERSION: 3.41.0 Release Notes
Back to Top