Currently, more than 33 million individuals are infected with human immunodeficiency virus (HIV) worldwide. HIV infection results in masive dysfunction of the immune system, particularly in mucosal tissues, which ultimately results in progression to Acquired Immunodeficiency Syndrome and death. During HIV infection, the integrity of the gastrointestinal (GI) tract is compromised, which allows microbial products to translocate from the lumen of the GI tract into circulation, which contributes to immune activation. Immune activation is the strongest predictor of disease progression during HIV infection, and is characterized by dysregulation of virtually every arm of the immune system. While many aspects of mucosal immune dysfunction after HIV infection have been described, the precise events which precipitate these events, and the mechanisms that underlie these dysfunctions are still unclear. In order to develop more effective therapeutic approaches aimed at restoring healthy mucosal immune function during HIV infection, a more complete understanding of mucosal immunity during HIV infection is needed. Thus, here we propose to evaluate both the kinetics and mechanisms by which the mucosal immune system is altered during acute Simian Immunodeficiency Virus (SIV) infection in rhesus macaques. We hypothesize that loss of essential homeostatic mucosal immune cells is the result of increased proinflammatory cells due to SIV replication in mucosal tissues. We will address this using two approaches- in the first aim, we will evaluate the kinetics by which damage to the GI tract and mucosal immune dysfunction occur during acute SIV infection. We hypothesize that increased inflammation after SIV infections results in loss of homeostatic immune cells, which in turn leads to damage to structural barrier of the GI tract. We will address this by evaluating the frequency and function of multiple mucosal immune cells ex vivo, and evaluating the damage to the tight epithelial barrier of the GI tract, microbial translocation and immune activation in vivo at multipe time points during acute SIV infection. This will allow a better understanding of temporal associations between dysfunctions in mucosal immunity after SIV infection to provide insight into cause and effect of each event. In the second aim, we will expand upon Aim I by determining the mechanisms underlying the mucosal dysfunctions that occur after SIV infection. We hypothesize that increased inflammation in mucosal tissues is the result of proliferation and/or increased homing of proinflammatory cells, and that this results in loss of cells that contribute to mucosal homeostasis due to loss in functionality and/or death. To address this, we will evaluate markers of proliferation, early activation, apoptosis, exhaustion, and homing of these cell subsets. Furthermore, we will use in vitro studies to assess whether we can alter the functions of mucosal immune cells based on our hypothesis that increased proinflammatory molecules after SIV infection abrogates homeostatic immune function in mucosal tissues. Taken together, these proposed studies will provide an in-depth assessment into how and why mucosal immune function is altered after SIV infection, and provide insight into developing novel therapeutic strategies for treatment of HIV infection. Public Health Relevance Statement (provided by the applicant): During HIV infection, there is massive dysfunction of the mucosal immune system that is associated with progression to AIDS, and the proposed studies are to determine the kinetics and mechanisms of this dysfunction after SIV infection. These studies will be essential to understand better how damage occurs in mucosal tissues during SIV infection in order to develop more effective therapeutic approaches aimed at treating HIV and AIDS.

Public Health Relevance

(provided by the applicant): During HIV infection, there is massive dysfunction of the mucosal immune system that is associated with progression to AIDS, and the proposed studies are to determine the kinetics and mechanisms of this dysfunction after SIV infection. These studies will be essential to understand better how damage occurs in mucosal tissues during SIV infection in order to develop more effective therapeutic approaches aimed at treating HIV and AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI098440-02
Application #
8611897
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Sharma, Opendra K
Project Start
2013-02-04
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$108,000
Indirect Cost
$8,000
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195