Our goal is to develop new strategies of therapy that are better tolerated and more sustainable for patient populations than the life-long use of antiretroviral therapy.
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.
Current Research Activities and Interests
Innate Immunity & HIV-1 Infection: Dendritic cells & 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, we are 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-? 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).
Tomescu Costin, Chehimi Jihed, Maino Vernon C, Montaner Luis J: Retention of viability, cytotoxicity, and response to IL-2, IL-15, or IFN-alpha by human NK cells after CD107a degranulation. Journal of leukocyte biology 85(5): 871-6, May 2009.
Giri Malavika S, Nebozyhn Michael, Raymond Andrea, Gekonge Bethsebah, Hancock Aidan, Creer Shenoa, Nicols Calen, Yousef Malik, Foulkes Andrea S, Mounzer Karam, Shull Jane, Silvestri Guido, Kostman Jay, Collman Ronald G, Showe Louise, Montaner Luis J: Circulating monocytes in HIV-1-infected viremic subjects exhibit an antiapoptosis gene signature and virus- and host-mediated apoptosis resistance. Journal of immunology (Baltimore, Md. : 1950) 182(7): 4459-70, Apr 2009.
Papasavvas Emmanouil, Foulkes Andrea, Li Xiaohong, Kostman Jay R, Mounzer Karam C, Montaner Luis J: Evidence of a decrease in CD4 recovery once back on antiretroviral therapy after sequential > or =6 weeks antiretroviral therapy interruptions. Journal of acquired immune deficiency syndromes (1999) 50(3): 334-5, Mar 2009.
Firnhaber Cynthia, Zungu Khumbuzile, Levin Simon, Michelow Pam, Montaner Luis J, McPhail Patrick, Williamson Anna-Lise, Allan Bruce R, Van der Horst Charlie, Rinas Allen, Sanne Ian: Diverse and high prevalence of human papillomavirus associated with a significant high rate of cervical dysplasia in human immunodeficiency virus-infected women in Johannesburg, South Africa. Acta cytologica 53(1): 10-7, Jan-Feb 2009.
Papasavvas Emmanouil, Pistilli Maxwell, Reynolds Griffin, Bucki Robert, Azzoni Livio, Chehimi Jihed, Janmey Paul A, DiNubile Mark J, Ondercin Joe, Kostman Jay R, Mounzer Karam C, Montaner Luis J: Delayed loss of control of plasma lipopolysaccharide levels after therapy interruption in chronically HIV-1-infected patients. AIDS (London, England) 23(3): 369-75, Jan 2009.
Papasavvas Emmanouil, Moore Elizabeth C, Sun Junwei, Azzoni Livio, Pistilli Maxwell, Mounzer Karam, Shull Jane, Kostman Jay R, Montaner Luis J: HIV type 1 viremia on ART is positively associated with polyclonal T cell proliferation in subjects with T cell IFN-gamma secretion levels comparable to those of uninfected subjects. AIDS research and human retroviruses 24(9): 1203-8, Sep 2008.
Papasavvas Emmanouil, Azzoni Livio, Pistilli Maxwell, Hancock Aidan, Reynolds Griffin, Gallo Cecile, Ondercin Joe, Kostman Jay R, Mounzer Karam, Shull Jane, Montaner Luis J: Increased soluble vascular cell adhesion molecule-1 plasma levels and soluble intercellular adhesion molecule-1 during antiretroviral therapy interruption and retention of elevated soluble vascular cellular adhesion molecule-1 levels following resumption of antiretroviral therapy. AIDS (London, England) 22(10): 1153-61, Jun 2008.
Chattergoon Michael A, Muthumani Karuppiah, Tamura Yutaka, Ramanathan Mathura, Shames Jason P, Saulino Vera, Robinson Tara M, Montaner Luis J, Weiner David B: DR5 activation of caspase-8 induces DC maturation and immune enhancement in vivo. Molecular therapy : the journal of the American Society of Gene Therapy 16(2): 419-26, Feb 2008.
Wysocka Maria, Newton Sarah, Benoit Bernice M, Introcaso Camille, Hancock Aidan S, Chehimi Jihed, Richardson Stephen K, Gelfand Joel M, Montaner Luis J, Rook Alain H: Synthetic imidazoquinolines potently and broadly activate the cellular immune response of patients with cutaneous T-cell lymphoma: synergy with interferon-gamma enhances production of interleukin-12. Clinical lymphoma & myeloma 7(8): 524-34, Sep 2007.
Chehimi Jihed, Azzoni Livio, Farabaugh Matthew, Creer Shenoa A, Tomescu Costin, Hancock Aidan, Mackiewicz Agnes, D'Alessandro Lara, Ghanekar Smita, Foulkes Andrea S, Mounzer Karam, Kostman Jay, Montaner Luis J: Baseline viral load and immune activation determine the extent of reconstitution of innate immune effectors in HIV-1-infected subjects undergoing antiretroviral treatment. Journal of immunology (Baltimore, Md. : 1950) 179(4): 2642-50, Aug 2007.
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Last updated: 02/19/2013
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