Most recent HIV cure efforts have focused on strategies to induce virus from HIV-infected cells during antiretroviral therapy (ART), thus leaving the cellular reservoir vulnerable to the host immune system, while ART prevents new cells from being infected. Unfortunately, such efforts have not demonstrated much activity. On the other hand, it has been documented for almost two decades that routine clinical vaccines can induce viral production from infected cells, even during ART, and that these levels of induction are much higher than those seen by recently described interventions (e.g. histone deacetylase inhibitors [HDACi], IL-7, disulfram). Therefore, based on newly generated preliminary data, we propose a randomized clinical trial to determine how two commonly used vaccines (against Influenza and Pneumococcus) can stimulate the immune system and induce HIV transcription in the setting of ART. Specifically, we propose a randomized cross-over controlled trial where 56 participants will receive one injection every three months (Influenza, Pneumococcal, and Placebo) in random order with multiple specimen collections after each injection. The primary objective of this study will be to determine if participants have a higher absolute increase in levels of cell-associated HIV RNA transcription after receiving active vaccines when compared placebo injection. Secondary objectives will be to determine if these vaccines also: (i) induce HIV transcription selectively or non-selectively (as evaluated by panmixis tests between sequences obtained from cellular HIV DNA and RNA populations), (ii) influence total HIV DNA levels, (iii) influence fraction of replication competent proviral levels (s evaluated by quantitative viral outgrowth assays), (iv) stimulate generalized and lymphocyte immune activation, and (v) stimulate vaccine- and HIV- specific immune responses. To best delineate these possible effects, we will also measure other sources of incidental immune stimulation, like shedding of herpesviruses, microbial translocation and incident illnesses.

Public Health Relevance

In a randomized placebo controlled clinical trial, this project will evaluate two routine vaccines (Influenza and Pneumococcus) in HIV-infected individuals receiving HIV therapy to determine if these vaccines can induce HIV RNA production in infected blood cells. If these clinically proven vaccines can unmask the HIV reservoir in this way, then this type of safe immune stimulation may be important in the design of future HIV cure strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI118422-02
Application #
9212094
Study Section
Special Emphasis Panel (ZAI1-PCR-A (S2))
Program Officer
Smiley, Stephen T
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$766,465
Indirect Cost
$251,217
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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