Luis J. Montaner, D.V.M., D.Phil.

Professor
Immunology Program
215-898-9143, Office

Introduction

Working closely with adult and pediatric HIV/AIDS patient populations in the Philadelphia region, the Montaner laboratory is investigating strategies for strengthening the immune system's response to HIV as well as novel treatment strategies. They are addressing the mechanisms of immune dysfunction associated with disease progression and testing whether reductions in drug treatment could be pursued that would decrease drug-related toxicity without diminishing treatment benefits.

Research Summary

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

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 ispursuing 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-g 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. The short-term goal of our effort is to address the consequences of immune reconstitution on innate immunity following antiretroviral therapy, with particular emphasis on correlates of DC and NK cell functions and the consequences of HIV interactions with DC subsets. While adaptive HIV-specific immune responses continue to be an area of active investigation in AIDS research, the potential contribution of innate immune response, such as the relationship between DC subsets, disease progression and its consequences on other innate functions such as NK function remains largely unexplored in HAART settings. This study represents a hypothesis-driven collaborative effort by The Wistar Institute, the Infectious Disease Division of the University of Pennsylvania Hospital, Philadelphia FIGHT, Schering-Plough, Becton Dickinson, The Women's Interagency Study Cohort and the Multiple AIDS Cohort Study (MACS).

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.

Immunobiology of IL-12 and IL-13 in Health and HIV-1 Infection: Identification of immune mechanisms that potentiate the body's own immune function while decreasing viral replication remains a major goal of AIDS research and therapy. Consistent with this objective, research in the Montaner laboratory is focused on defining the mechanism by which: 1) interleukin (IL)-13 acts to enhance immune responsiveness while inhibiting HIV-1 expression and infectivity, and 2) IL-12 secretion is impaired.

IL-12 is impaired in HIV-1 infection. A decrease in IL-12 secretion in HIV-1 infection has been proposed as a major defect in the ability to control HIV-1 and other opportunistic infections otherwise cleared by cell-mediated responses. Investigation in the Montaner laboratory into potential mechanisms responsible for impaired IL-12 secretion in HIV-1 infection are focused on TNF-a as a candidate suppressive molecule in disease and the role of transcriptional factor regulation in the transcription of the IL-12p40 molecule. Questions presently being investigated include: 1) the molecular mechanisms responsible for IL-12 inhibition in HIV infection, 2) mechanism for TNF-a inhibition of IL-12p40, and 3) role of upstream CACCC regions on the IL-12p40 promoter.

The need to develop new immunotherapeutic approaches is evidenced by the fact that no anti-viral or immune reconstitution approach yet exists that directly addresses the intrinsic functional defect in antigen presentation and T-cell activation in HIV-1 infection. Data indicate that IL-13 can affect antigen presentation function by enhancing antigen-specific CD4 T-cell responses in cells from HIV-1-positive individuals regardless of the patient's CD4 count or antiretroviral therapy. Moreover, studies have shown that IL-13 is 1) deficient in activated T-cells from HIV-1-positive individuals, 2) capable of restoring the deficiency in pinocytosis in macrophages of HIV-1-positive individuals, and 3) acutely induces HLA-DR and CD86 expression in macrophages, 4) restores IL-12 secretion by macrophages of HIV-1-positive individuals, 5) can act in combination with tumor necrosis factor (TNF)-a to inhibit the expression and infectivity of HIV-1 in macrophages, and finally, 6) induces the expansion of T cells that secrete putative inhibitory factors able to protect against de novo HIV-1 infection. The long-term relevance of this research to human health rests in the potential use of IL-13 as adjunct immunotherapy, to increase vaccine efficacy in both healthy and immunocompromised populations, and in its potential future clinical use to inhibit HIV-1 replication in vivo.

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. This proposal represents a collaborative effort by The Wistar Institute and the departments of Dermatology, and the Center for Clinical Epidemiology and Biostatistics from the University of Pennsylvania.

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.

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.