The goal of combination antiviral therapy (cART) for HIV is to suppress viral replication and restore immune function. This is possible with modern cART however immune reconstitution (IR) is often incomplete and significant immunologic abnormalities persist, even after years of therapy. The underlying mechanisms driving these persistent immune abnormalities are likely related to the fact that systemic immune activation (IA) does not fully normalize in treated patients. Chronic IA has a detrimental effect on the anatomy of lymphoid tissues and is a primary factor in the incomplete IR in treated HIV infection. Chronic IA is associated with expression of multiple inflammatory cytokines, including TGF-? that initiates a process of collagen deposition in the parafollicular T cell zone (TZ) of secondary LN and GALT. This cumulative, gradual process of TZ fibrosis destroys the fibroblastic reticular network (FRCn) which is a mesh of hollow fibers that form the skeletal anatomy of the TZ. T cells absolutely require contact with the FRCn for migration, formation of immune responses, gain access to IL-7 from the FRCn that is required for survival. Loss of the FRCn is associated with impaired T cell survival, especially of the naive and central memory (CM) phenotype. This explains, at least in part, the mechanism of incomplete IR and persistent immunologic abnormalities in the setting of cART. We have performed two pilot studies in a non-human primate model of SIV infection to stop and/or reverse TZ fibrosis using the TGF-? inhibitor pirfenidone. We show in our preliminary data success with this approach which provides the rationale for our proposed pilot study of a TGF-? inhibitor in human HIV infection to determine if there is potential to restore the FRCn and thus improve immune function. We will perform a double-blind placebo controlled study in 50 HIV+ people on cART using the drug losartan, an FDA approved angiotensin receptor inhibitor (ARB) that inhibits TGF-? at the level of phosphorylation of SMAD 2,3 and animal and human studies show it reverses existing fibrosis in lung, liver, and kidney. We will not use pirfenidone because it is not FDA approved in the U.S. and is unavailable from the company that makes it. However, we strongly believe losartan is a more suitable choice in a proof of concept pilot trial. The mechanism of action against collagen formation is the same as pirfenidone and it is safe and well tolerated with a long and established safety record. Importantly, and in distinction to pirfenidone, losartan also inhibits matrix metalloproteases that stimulate collagen production and has anti-inflammatory properties that may IA in a broader context. It inhibits LPS-induced inflammatory signaling, an important component of microbial translocation, and decreases levels of tumor necrosis factor (TNF), IL-6, and soluble adhesion molecules. Our hypothesis is that treatment with the losartan will 1) decrease levels of IA as shown by a decrease in IL-6, TNF, ICAM-1;2) reverse existing fibrosis;3) restore LN architecture, 4) improve peripheral and lymphatic CD4 T cells and their function;and 5) be safe and well tolerated.

Public Health Relevance

This pilot study will test the concept that decreasing immune activation and reversing pathologic damage to anatomic structures in lymph nodes will improve the health of HIV infected people taking anti-retroviral therapy. We will perform a double-blind placebo controlled trial of losartan (which has antifibrotic and anti-inflammatory properties) and perform tissue based studies to determine if fibrosis in lymphoid tissues can be reversed and normal anatomy and function is restored. We will determine if T cell populations become more normal as a result of this intervention, if immune activation is decreased, and if immune function improves. If successful this could point to adjunctive therapies for HIV that may lead to normal immune function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI105872-01
Application #
8509163
Study Section
Special Emphasis Panel (ZAI1-QV-A (J1))
Program Officer
Embry, Alan C
Project Start
2013-02-11
Project End
2018-01-31
Budget Start
2013-02-11
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$1,036,344
Indirect Cost
$268,015
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455