A major challenge in HIV research is to restore immune function in HIV-infected individuals. HIV infection causes CD4 T cell depletion, leading to immunodeficiency and death. HAART induces restoration of CD4 T cell counts to normal levels in a majority of individuals who achieve durable virologic suppression. However, the magnitude of CD4 T cell recovery and is variable and a significant subset of individuals who achieve virologic suppression on HAART have poor CD4 T cell recovery. Unique challenges in drug abusing populations include the difficulty of achieving consistent adherence to HAART in individuals who are actively abusing drugs or have demographic characteristics that adversely influence health care access. Furthermore, drug abuse and HCV co-infection may influence responses to HAART. The overall goal of this proposal is to understand mechanisms that lead to recovery of immune function in HIV-infected individuals who achieve durable virologic suppression following HAART initiation. The working hypothesis is that individuals who achieve durable virologic suppression and good CD4 T cell recovery following HAART initiation have a coordinated pattern of epigenetic modification in CD4 T cells that is altered and leads to CD4 T cell dysfunction in individuals who have poor CD4 T cell recovery. We will use systems biology approaches to identify early epigenetic signatures that predict restoration of CD4 T cells in HIV-infected individuals from the MACS and ALIVE cohorts following initiation of successful HAART. Epigenetic mapping data will be integrated with clinical data, gene expression profiling, and mechanistic studies to better understand relationships between early epigenetic signatures, disease markers, and underlying mechanisms. The studies will lead to a better understanding of mechanisms that determine CD4 T cell restoration in IV drug abusers and other at-risk populations infected with HIV and may identify new therapeutic strategies to improve restoration of CD4 T cells in these populations.

Public Health Relevance

A major challenge in HIV research is to restore immune function in HIV-infected individuals. HIV infection causes depletion of CD4 T cells, leading to immunodeficiency and death. Highly active anti-retroviral therapy (HAART) induces restoration of CD4 T cell counts to normal levels in a majority of individuals who achieve suppression of HIV to undetectable levels. However, the magnitude of CD4 T cell recovery and is variable and many individuals on successful HAART have poor CD4 T cell recovery. Unique challenges in drug abusing populations include the difficulty of achieving consistent adherence to HAART in individuals who are actively abusing drugs or have demographic characteristics that adversely influence health care access. Furthermore, drug abuse may influence responses to HAART. The overall goal of this proposal is to understand mechanisms that lead to recovery of immune function in HIV-infected individuals who achieve durable virologic suppression following HAART initiation using systems biology to define the epigenetic profile of CD4 T cells on a genome-wide scale and integrate results with clinical outcomes, gene expression profiling, and mechanistic studies. The studies will lead to a better understanding of mechanisms that determine CD4 T cell restoration in IV drug abusers and other at-risk populations infected with HIV and may identify new therapeutic strategies to improve restoration of immune function in these populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1DA028994-06
Application #
8712438
Study Section
Special Emphasis Panel (ZDA1-NXR-B (12))
Program Officer
Satterlee, John S
Project Start
2009-09-30
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$840,263
Indirect Cost
$360,113
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Mukerji, Shibani S; Locascio, Joseph J; Misra, Vikas et al. (2016) Lipid Profiles and APOE4 Allele Impact Midlife Cognitive Decline in HIV-Infected Men on Antiretroviral Therapy. Clin Infect Dis 63:1130-9
Cassol, Edana; Misra, Vikas; Morgello, Susan et al. (2015) Altered Monoamine and Acylcarnitine Metabolites in HIV-Positive and HIV-Negative Subjects With Depression. J Acquir Immune Defic Syndr 69:18-28
Cassol, Edana; Misra, Vikas; Dutta, Anupriya et al. (2014) Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment. AIDS 28:1579-91
Cassol, Edana; Misra, Vikas; Holman, Alexander et al. (2013) Plasma metabolomics identifies lipid abnormalities linked to markers of inflammation, microbial translocation, and hepatic function in HIV patients receiving protease inhibitors. BMC Infect Dis 13:203
Gabuzda, Dana; Yankner, Bruce A (2013) Physiology: Inflammation links ageing to the brain. Nature 497:197-8
Cassol, Edana; Misra, Vikas; Morgello, Susan et al. (2013) Applications and limitations of inflammatory biomarkers for studies on neurocognitive impairment in HIV infection. J Neuroimmune Pharmacol 8:1087-97
Kamat, Anupa; Misra, Vikas; Cassol, Edana et al. (2012) A plasma biomarker signature of immune activation in HIV patients on antiretroviral therapy. PLoS One 7:e30881
Holman, Alexander G; Gabuzda, Dana (2012) A machine learning approach for identifying amino acid signatures in the HIV env gene predictive of dementia. PLoS One 7:e49538
Mukerji, Joya; Olivieri, Kevin C; Misra, Vikas et al. (2012) Proteomic analysis of HIV-1 Nef cellular binding partners reveals a role for exocyst complex proteins in mediating enhancement of intercellular nanotube formation. Retrovirology 9:33
Kamat, Anupa; Lyons, Jennifer L; Misra, Vikas et al. (2012) Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection. J Acquir Immune Defic Syndr 60:234-43

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