Our long-term goal is to evaluate the effect of pegylated interferon (peg-IFN) ? as an anti-HIV reservoir immunotherapy that could potentiate eradication strategies against HIV. The short-term goal of this proposal is to conduct a randomized clinical trial (RCT) to determine whether a 20-week treatment course with peg-IFN-?2b 1ug/kg/week, with or without a 4-week ART interruption, will reduce HIV-1 proviral DNA levels in circulating PBMC and gut mucosa-associated lymphoid tissue (MALT) in ART- treated long-term viral suppressed subjects with immune reconstitution. In our recently completed clinical trial (NCT00594880), we demonstrated that treatment with peg-IFN-?2a started on ART resulted in 12 week viral suppression during ART interruption (peg-IFN-?2a monotherapy) in 50% of the subjects, concurrently with activation of intrinsic anti-HIV genes, higher NK responses, and a significant reduction in integrated proviral HIV DNA (a measure of latent reservoir). In order to reproduce our findings, determine the requirement for viral reactivation to trigger anti-HIV responses, and gather insights into mechanism of action, we propose to conduct a randomized clinical trial (RCT) to test our primary hypothesis that 20 weeks of treatment with peg-IFN-?2b (with or without HIV reactivation following ART interruption) will activate intrinsic and immune-mediated anti-HIV responses resulting in a reduction of integrated HIV DNA in chronically HIV-infected, immune-reconstituted individuals when compared to a control group of individuals undergoing comparable ART treatment in the absence of peg-IFN-?2b. We propose to test this hypothesis by addressing the following specific aims:
Specific Aim 1 : to assess the effectiveness of a 20-week course of peg-IFN-?2b to reduce measures of HIV reservoir by conducting an RCT to a) compare the change in integrated proviral HIV DNA/peripheral blood CD4+ T cell in ART suppressed subjects receiving peg-IFN-?2b treatment to an expected change of zero in the control group (primary endpoint);b) assess the requirement for viral replication (via short-term ART interruption) to activate immune mechanisms leading to the reduction of integrated HIV DNA;c) compare total and integrated HIV DNA levels in MALT-associated CD4+ T lymphocytes from rectal mucosal biopsies;d) compare levels of integrated DNA to other measures of viral reservoir (Q-VOA, ddPCR).
Specific Aim 2 : to characterize the anti-HIV intrinsic (host gene expression), innate and CD8 T-cell responses underlying changes in integrated HIV DNA following peg-IFN-?2b immunotherapy, as well as their correlation with secondary viral measures (ddPCR or Q-VOA).

Public Health Relevance

The identification and characterization of innovative strategies to reduce integrated HIV-1 DNA by harnessing host-mediated mechanisms are paramount to achieving eradication of HIV-1 without continued ART. This project pursues a strategy already observed to induce reductions in integrated HIV DNA by now reconfirming this activity while: a) determining impact on tissue levels, and b) obtaining added insights as to how it works.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI110434-01
Application #
8671884
Study Section
Special Emphasis Panel (ZAI1-BP-A (S4))
Program Officer
Morton, Tia M
Project Start
2014-01-03
Project End
2017-12-31
Budget Start
2014-01-03
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$1,543,905
Indirect Cost
$612,384
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104