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The Wistar Institute

3601 Spruce Street

Room 480

Philadelphia, PA 19104

 

Office: 215-898-3934

Research

Statement of Interest

The Montaner laboratory is investigating mechanisms of disease in HIV-1 infection and novel approaches to augment immune function by combining virological and immune-based research on patient-derived material as well as by using laboratory models of virus infection. The work is focused on 1) regulation of innate immunity, 2) identifying new mechanisms of immunodeficiency and discovering new approaches to reverse them, 3) exploring new therapy management practices, and 4) understanding the relationship between immune antiviral responses and control of HIV-1 infection.

Recent Scientific Advances

 Pilot: use of Peg-Interferon-a2b to reduce latent HIV reservoirs

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.

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NK/DC cross-talk in HCV clearance and antiviral response

The mechanisms of HCV eradication following IFN/ribavirin therapy in HCV/HIV-1 co-infection or HCV mono-infection remain unclear. The goal of this work is to determine the role of innate immunity effectors in therapy response in HCV and HCV/HIV-1 co-infected subjects by investigating Natural Killer (NK) cell and Dendritic Cell (DC) functionality in relation to level of adaptive T cell responses and therapy-induced HCV suppression. We will test the hypothesis that the sustained functional response of innate effector cells (i.e. Natural Killer cell and Dendritic cell function) to IFN/ribavirin therapy is a determinant of both innate and level of adaptive (HCV-specific) responses and ultimately early and sustained HCV virologic suppression. As a corollary, we hypothesize that innate phenotypes and cell-mediated responses associated with HCV control would be selectively enriched in subjects with documented SVS (independent of HIV-1 infection) as compared to healthy or HIV-1-infected donors without HCV infection.

Full text description:

http://projectreporter.nih.gov/project_info_description.cfm?aid=8131142&icde=0

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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.

Full text description:

http://projectreporter.nih.gov/project_info_description.cfm?aid=8115636&icde=0

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NK cell activation and function in HIV-1 exposed uninfected drug users

Multiply-exposed uninfected IV opioid drug users (EU-IVDU) remaining HIV sero-negative are one of very few clinical cohorts where live HIV exposure can be studied in conjunction with epidemiological teams that are studying risk of infection in these subjects. The described seronegative state of subjects known to be at risk of infection via shared needle behavior with persons of unknown status has heightened interest in identifying the mechanism(s) of immune control that may provide resistance to infection in association with HIV exposure and drug use. NK cell activation, increased constitutive degranulation and increased lytic activity, have been proposed in EU-IVDU as a critical feature associated with protection, yet it remains unknown what specific NK membrane protein profiles and functional responses best defines or identifies an NK or DC cell activation program in EU-IVDU. The effects of drug use on NK or PDC activation programs, even in the absence of repeated HIV exposure, are also unknown. We propose to analyze three groups identified by lack of HIV infection (serongative) with different histories of IV opioid drug use.

Full text description:

http://projectreporter.nih.gov/project_info_description.cfm?aid=8044828&icde=0

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Innate Immunity & HIV Infection - Macrophages

Macrophages constitute an important cellular component of the immune responses against viruses. They serve as antigen presenting cells and also secrete inflammatory mediators to activate innate and adaptive immune cells. Although macrophages from HIV-1 infected patients have not been described to be depleted with disease progression as is the case with CD4 T cells, they exhibit immunological dysfunctions. Following HIV-1 infection, effector functions of macrophages such as phagocytosis, chemotaxis, intracellular killing, inflammatory responses and antigen presentation are impaired. Furthermore, macrophages serve as reservoirs of HIV in chronically infected patients and contribute to approximately one percent of the plasma viral load. Our current work on this area addresses investigation of HIV-specific gene regulation effects on macrophages by analyzing patient-derived monocyte-derived macrophages (MDM) and in vitro infected MDMs.

Full text descriptions:

http://projectreporter.nih.gov/project_info_description.cfm?aid=2330462&icde=0

http://projectreporter.nih.gov/project_info_description.cfm?aid=2650113&icde=0

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Interferon-α-2A Immunotherapy for HIV-1 infection

 

Our long-range goal is to determine if pegylated Interferon-α-2A (Peg-IFN-α2A) can sustain HIV-1 suppression in the absence of Anti-Retroviral Therapy (ART) in infected individuals. We conducted a clinical study to compare two different doses of Roche Pegasys(r) Peg-IFN-α2A, 90 and 180 μg per week, for their ability to maintain viral control when initiated at the time of ART interruption in HIV-infected suppressed patients (VL<50 copies /ml) for 24 weeks or more, as determined by observing >0.5 log difference in viral set-points (delta viral load) obtained at two sequential 12 weeks ART discontinuations, with Peg-IFN-α2A administered only during the second discontinuation. Primary analysis was an "intent to treat" analysis and was address the hypothesis that two different doses of Peg-IFN-α2A (90 and 180 μg/week) would be similarly effective at inhibiting viral replication as defined by <0.5 log difference between the delta viral loads of each experimental arm. Secondary aims evaluated: (1) safety, tolerability and dose-dependent, treatment-associated toxicity, of 50 weekly administrations of Peg-IFN-α2A at 180 or 90 μg/week (in association with ART for the initial 2 weeks, followed by 48 weeks of Peg-IFN-α2A, alone); (2) the potential for Peg-IFNa2A-mediated (direct and immune-mediated) antiviral activity to extend viral control over a period of 48 weeks after ART interruption; (3) innate immunity outcomes correlated to Peg-IFN-α2A dose and antiviral activity, by monitoring NK and DC subset changes and the ability to maintain/enhance innate immune functions (DC secretory responses, NK antiviral cytotoxic responses); (4) adaptive immunity outcomes correlated to Peg-IFN-α2A dose and antiviral activity by monitoring T-cell subsets changes and the ability to maintain cell-mediated proliferative and cytokine responses against recall antigens (HIV-1 gag p55).

Full text description:

http://projectreporter.nih.gov/project_info_description.cfm?aid=7006340&icde=0

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TB-related Immune Reconstitution Syndrome

Co-infection with Mycobacterium tuberculosis (MTB) and HIV-1 is a common occurrence in sub-Saharan African Countries. In a significant portion of dual-infected patients initiation of anti-retroviral treatment (ART) results in early onset of clinical and laboratory alterations related to re-acutization of MTB infection, collectively known as Immune Restoration Inflammatory Syndrome (IRIS), the pathogenesis and immune correlates of which are largely unknown at present. We analyzed a cohort of HIV-infected individuals developing MTB-related IRIS after ART initiation, by measuring adaptive and innate immune functions. Specifically, we tested the hypotheses that: A) innate immune function, as measured by accessory cell activation (antigen presentation and responsiveness to Toll-like receptors (TLR) 2 7/8 and 9 stimulation) and natural killer cell responses (cytotoxic and cytokine secretion) is directly associated with IRIS and is significantly increased in IRIS patients as compared to non-IRIS HIV-infected controls undergoing ART for comparable periods of time: and B) baseline frequency, activation and function of innate immune effectors may predict a future IRIS outcome in MTB/HIV-1 dual-infected subjects.

Full text description:

http://projectreporter.nih.gov/project_info_description.cfm?aid=7167619&icde=0

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Pediatric immune correlates of early anti-HIV therapy

Our studies assessing the effect of HIV infection on innate immune effectors in children indicate that depletion of dendritic cell subsets is associated with progressive infection. We have collaborated with the CHER study group, which recently demonstrated that early ART initiation has a positive effect on mortality and morbidity in perinatally infected children (Link), to assess the immunological correlates of early vs. delayed ART initiation. Our results support the hypothesis that perinatal HIV infection results in a different immune scenario as compared to adults, particularly in regards to the maintenance of naive T cell subsets. this may have important consequences in determining the extent of immune reconstitution on ART in neonates.

Full text description:

http://projectreporter.nih.gov/project_info_description.cfm?aid=6843339&icde=0

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Consequences of Intermittent Highly Active Antiretroviral Therapy (HAART)

The Montaner laboratory is investigating whether intermittent HAART can help maintain the benefits of continued therapy while decreasing drug exposure. Although inadequate adherence to HAART may increase the probability of resistant viral mutations, clinical evidence already indicates that complete removal of HAART does not enhance emergence of resistance to an antiretroviral regimen so that reinitiating the same regimen results in a prompt virologic response. Current research in the laboratory is focused on determining if a series of sequential exposures to viral replication in otherwise chronically suppressed patients under HAART, as a consequence of structured treatment interruptions, can affect the efficacy of therapy, levels of CD4 count and viral load levels upon interruption periods.

We are also studying the effect of sequential ART interruption on CD4 count, morbidity and maintenance of Ig titers to neo-antigens.

Full text descriptions:

http://projectreporter.nih.gov/project_info_description.cfm?aid=6213576&icde=0

http://projectreporter.nih.gov/project_info_description.cfm?aid=6696665&icde=0

Collaborations

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.

Full text descriptions:

http://projectreporter.nih.gov/project_info_description.cfm?aid=6170246&icde=0

http://projectreporter.nih.gov/project_info_description.cfm?aid=6554195&icde=0

http://projectreporter.nih.gov/project_info_description.cfm?aid=7498743&icde=0

http://projectreporter.nih.gov/project_info_description.cfm?aid=7737817&icde=0

http://projectreporter.nih.gov/project_info_description.cfm?aid=7841490&icde=0

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Immune Correlates of Bacterial/Viral Co-infections

The long-range goal of our interest in this area is to determine the factors that predict the manner in which pathogenesis develops during poly-microbial infections. We are addressing the manner in which the developing immune response to a primary infection affects a coincident secondary inflammatory process (co-infection immune response). The short-term goal of this project will be to determine the manner in which BCG-associated inflammation and its modulation of antigen presenting cells affects a new immune response to a vaccine antigen delivered as and inactivated organism vaccine. Taken together, this work seeks to identify innovative targets for increased susceptibility to bacterial/viral co-infections by addressing understudied areas of innate immunity and chronic inflammation as central factors to decreased adaptive responses and protective immunity.

Full text description:

http://projectreporter.nih.gov/project_info_description.cfm?aid=6606309&icde=0

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HIV-1 Patient Partnership Program

In collaboration with Philadelphia FIGHT (a community-based HIV-1 clinical research organization), The Children's Hospital of Philadelphia, and with the support of Martha Stengel Miller and The Philadelphia Foundation, the Montaner laboratory has entered the fifth year of the HIV-1 Patient Partnership Program with over 600 participating adult and pediatric patients in the program. The objectives of this program are to establish a collaborative link between this research and HIV-1 patients in Pennsylvania, provide clinical material for basic research, and sponsor the Jonathan Lax Memorial Lecture. Furthermore, the laboratory makes its research accountable to the patient community by hosting research seminars for them and other interested individuals on outcomes of patient-supported research. Participating patients represent a cross-section of the HIV-1 epidemic in Philadelphia (4000+ patients). Research with clinical material obtained from this program is focused on mechanisms of AIDS immunopathology.

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