BEAT-HIV Study – Currently enrolling
We are currently enrolling participants in the largest HIV Cure-related clinical trial conducted in the United States to date. The purpose of this study is to determine if treatment with pegylated interferon alpha 2b (peg-IFN-α2b) will reduce the amount of integrated HIV DNA in peripheral blood cells and tissues of individuals with chronic HIV infection receiving antiretroviral treatment (ART). A reduction and/or clearance of the latent viral reservoir, i.e. virus that remains dormant in HIV-infected subjects receiving suppressive treatment, is considered essential for HIV eradication. By measuring the changes in integrated proviral HIV DNA, which is considered a surrogate measure of the latent reservoir, the investigators will establish if peg-IFN-α2b treatment should be considered as a component of future viral eradication strategies.
In our recently completed clinical trial (NCT00594880), we demonstrated that treatment with peg-IFN-α2a started on ART resulted in 12 week viral suppression during ART interruption (peg-IFN-α2a 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).
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Pilot: Use of Peg-Interferon-α2b to reduce latent HIV reservoirs – Enrollment closed
The long-term goal of this research is to evaluate the effect of Peg-IFN-α-2b as an immunotherapy to potentiate eradication strategies against HIV. The short-term goals of this proposal are a) to determine whether Peg-IFN-α-2b can reduce HIV-1 proviral DNA levels in circulating PBMC and GALT in HIV-1-infected individuals who have achieved long-term ART-mediated immune reconstitution, and b) to investigate the role of innate and adaptive immune mechanisms in controlling the size of HIV latent reservoir.
Early innate/IGA anti-HIV/SIV response in exposed uninfected
Our understanding of early anti-viral mechanisms in the cervico-vaginal compartment that may reduce HIV-1 or SIV infectivity in the absence IgG-mediated or CD8 T-cell responses remains incomplete and is the basis for this work. Evidence for resistance to infection in highly HIV-exposed women that remain seronegative (exposed sero-negative, ESN) in presence of anti-HIV responses is also supported by non-human primate (NHP) models where repeated low-dose cervico-vaginal challenges in Rhesus macaques can result in a refractory state that can only be overcome by increased infectious doses or by-pass of the mucosal micro- environment (e.g. intravenous viral challenge). Our preliminary data now shows for the first time that repeated cervico-vaginal exposures to SIV in the NHP can result in an increase in innate effector cell infiltrates including (1) plasmacytoid dendritic cells expressing IFN-a as a potential inductive factor associated with the local increase in tissue APOBEC 3G expression, and (2) CD68 macrophages infiltrates among Fc-receptor bearing cells. We will test the hypothesis that uninfectious viral exposures in the female cervico-vaginal compartment can induce an innate/IgA mechanism mediating a state of reduced mucosal infectivity.
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Innate Immunity & HIV-1 Infection - Dendritic Cells and Natural Killer Cells
Direct or indirect interactions of viral particles with innate and specific adaptive immunity effector cells affects the cross talk between antigen presenting cells (APCs), NK cells and the antigen specific T and B-lymphocytes, and may contribute to regulate HIV disease progression. Specifically, the laboratory is pursuing analysis of the effects of HIV infection in macrophages, dendritic cells and Natural Killer cells.
A relationship between levels of HIV replication and innate cell function is supported by our preliminary data on DC and NK subset changes and viral replication in HIV-infected individuals showing an impairment of NK cell responses, APC endocytic uptake, differential expression of cell surface molecules associated with APC function, increased APC apoptosis, decreased IL-12 secretion, decreased IFN-γ secretion and a loss of plasmacytoid dendritic cells (PDCs) and myeloid dendritic cells (MDCs) in PBMC. Based on these observations and the observed effects of antiretroviral therapy on DC and NK cell subsets, the inverse correlation between viral load and DC subsets in untreated HIV positive subjects and our observations of augmented NK lytic activity by activated DC, we are addressing longitudinal analysis and mechanistic experiments on DC/HIV interactions to test the hypothesis that HAART-mediated viral suppression restores mature NK and DC subsets necessary to activate innate mechanisms of antiviral control through lysis of infected cells.
The long-term goal of this area of focus is to define the contribution of two major components of the innate immune system (accessory and Natural Killer cells) in controlling HIV replication thereby modifying disease progression.
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HIV-1 Patient Partnership Program
With long-standing commitment from Philadelphia FIGHT (a community-based HIV-1 primary care provider) and the University of Pennsylvania along with the support of Henry S. Miller, Jr. and Ken Nimblett, the Herbert Kean, M.D. Family Endowment, and the Robert I. Jacobs Fund of The Philadelphia Foundation, the HIV-1 Patient Partnership Program was established to provide clinical material for basic research and to sponsor the Jonathan Lax Memorial Lecture.
Research with clinical material obtained from this program is focused on mechanisms of AIDS immunopathology. This collaborative link, between our research team and over 5000 HIV-1 patients in the Philadelphia region, has led to the largest HIV Cure clinical trial to date – the BEAT-HIV Study.
The Jonathan Lax Lecture honors the memory of Jonathan Lax, a businessman, inventor, teacher, and one of the best known AIDS activists in Philadelphia’s community-based clinical research network, where he volunteered with many groups to try and speed the drug approval process. He left funds to start a clinic - today called the Jonathan Lax Center - that is now the largest provider of AIDS care, independent of a patient’s ability to pay, in Philadelphia. The Lax Lecture is a public lecture held in June of each year at The Wistar Institute, where leading international HIV scientists interact with local researchers, clinicians, and patient advocates. Previous speakers include NIAID Director Anthony Fauci, Partners In Health Founder and Harvard Professor Paul Farmer, Project Inform Founder Martin Delaney, and 2008 Nobel Laureate Françoise Barré-Sinoussi.
The Montaner laboratory makes its research accountable to the patient community through community advisory board (CAB) review and community representation on Data Safety Monitoring Boards for actively enrolling studies. In addition, we provide community-focused research seminars at Philadelphia’s AIDS Education Month and the annual Lax Lecture, so that community members and other interested individuals are informed about the outcomes of patient-supported research.