There is substantial evidence that immune activation is the determining factor for disease progression and co-morbidities in HIV infection. Peripheral immune activation, which is triggered by HIV, impacts the function of T cells and monocytes. HIV-induced monocyte proteins have been investigated as markers of an activated state that is tied to neuropathogenesis in the CNS. This is supported by SIV macaque models pointing to immune responses in the periphery being linked to CNS damage. In humans, an activated peripheral monocyte phenotype correlates with lower N-acetylaspartate (NAA), which is linked to neuronal dysfunction. However, there remains considerable debate whether LPS, type 1 interferon (IFN) or other factors are the causative agents. Our research shows that monocytes from HIV-infected subjects have a type 1 IFN gene expression profile. It is our overall hypothesis that in HIV disease type 1 IFN is responsible for chronic immune activation, which is associated with disease progression including cognitive impairment. We will: 1) investigate a number of variables that could produce the IFN-induced monocyte phenotype, 2) define a new IFN- induced monocyte phenotype, CD169, 3) determine the impact of immune activation on chemotaxis and cytokine elaboration and 4) determine if monocyte activation enhances LPS tolerance. Understanding the mechanism for continued activation in chronically HIV-infected individuals is crucial for mitigating CNS damage.

Public Health Relevance

In spite of availability, adherence and effective antiretroviral therapy, there are still individuals who carry an HIV detectable viral load as well as those who are treated with no detectable viral load and have HIV-associated neurological disorders (HAND). We will show that continued peripheral activation by IFN-? is detrimental to HIV-infected individuals. We will investigate several mechanisms to suppress activation including compounds directed against peripheral markers of activation and inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH096673-02
Application #
8513414
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2012-07-18
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$328,320
Indirect Cost
$112,320
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Pulliam, Lynn (2014) Cognitive consequences of a sustained monocyte type 1 IFN response in HIV-1 infection. Curr HIV Res 12:77-84
Pulliam, Lynn; Calosing, Cyrus; Sun, Bing et al. (2014) Monocyte Activation from Interferon-* in HIV Infection Increases Acetylated LDL Uptake and ROS Production. J Interferon Cytokine Res 34:822-8