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Research Interests Our goal is to develop a better understanding of HIV-1 immunopathogenesis and new immune-based strategies of anti-HIV therapy that are better tolerated and more sustainable for patient populations than the life-long use of antiretroviral therapy.Research DescriptionIntroductionThe 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 InterestsInnate 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).
Cai, Y, Reddy Poli, A.N., Vadrevu, S., Gyampoh, K., Hart, C., Ross, B., Fair, M., Xue, F., Salvino, J.M., Montaner, L.J.: Reversible BCL6 BTB-specific Inhibitor Represses T Cell Activation, Tfh Cells Differentiation and Germinal Center Reaction in vivo Eur J Imm : 2021.
Zhang, C., Lum, K.Y., Taki, A.C., Gasser, R.B., Byrne J.J., Wang, T., Blaskovich, M., Register, E.T., Montaner, L.J., Tietjen, I., Davis, R.A.: Design, synthesis, and screening of a drug discovery library based on an Eremophila-derived serrulatane scaffold Phytochemistry 190 : 112887,2021.
Tomescu, C., Kroll, K, Colon, K., Papasavvas, E., Frank, I., Tebas, P., Mounzer, K., Reeves, R.K., Montaner, L.J.: Identification of the Predominant NK Effector Subsets Mediating ADCC Against HIV-infected Targets Coated with BNAbs or Plasma from PLWH. Eur J Immuol Online ahea of print : 2021.
Papasavvas, E., Azzoni, L., Paggliuzza, A., Abdel-Mohsen, M., Ross, B.N., Fair, M., Howell, B., Hazuda, D., Chomont, N., Li, Q., Mounzer, K., Kostman, J.R., Tebas, P., Montaner L.J.: Safety, Imune, and Antiviral Effects of Pegylate Interferon Alpha 2b administration in antiretriviral therapy-suppresed individuals: Results of pilot clinical trial. AIDS Res Hum Retroviruses Online ahead of print : 2021.
Giron, L.B.*, Palmer, C.S.*, Liu, Q., Yin, X., Papasavvas, E., Sharaf, R., Etemad, B., Damra, M., Goldman, A.R., Tang, H.-Y., Johnston, R., Mounzer, K., Kostman, J.R., Tebas, P., Landay, A., Montaner, L.J., Jacobson, J.M., Li, J.Z., Abdel-Mohsen, M.: Non-invasive plasma glycomic and metabolic biomarkers of post-treatment control of HIV. Nature Communications 12 (1): 3922,2021.
Papasavvas, E., Azzoni, L., Ross, B.N., Fair, M., Howell, B.J., Hazuda, D.J., Mounzer, K., Kostman, J.R., Tebas, P., Montaner, L.J.: Comparable HIV suppression by pegylated-IFN-α2a or pegylated-IFN-α2b during a 4-week analytical treatment interruption. AIDS Online ahead of print : 2021.
Giron, L.B., Papasavvas, E., Yin, X., Goldman, A., Tang, H-Y., Palmer, C., Landay, A., Li, J., Koethe, J., Mounzer, K., Kostman, J., Liu, Q., Montaner, L.J., Abdel-Mohsen, M.: Phospholipid metabolism is associated with time to HIV rebound upon treatment interruption mBio 12 (1): e03444-20,2021.
Papasavvas, E., Azzoni, L, Ross, B.N., Fair, M, Yuan, Z., Gyampoh, K., Sciorillo, A.C., Paggliuzza, A., Lada, S., Wu, Gioxin, G., Goh, S.L., Banck-Teets, C., Holder, D.J., Zuck, P.D., Damra, M., Lynn, K.M., Tebas, P., Mounzer, K., Kostman, J.R., Abdel-Mohsen, M., Richman, D., Chomont, N., Howell, B.J., Montaner, L.J.: Intact HIV reservoir estimated by the intact proviral DNA assay correlates with levels of total and integrated DNA in the blood during suppressive antiretroviral therapy Clin Infect Dis 72 (3): 495-498,2021.
Ziani, W., Shao, J., Wang, X, Russell-Lodrigue, K., Liu, Y.-Z., Montaner, L.J., Veazey, R., Xu, H.: Increased proviral DNA in circulating cells correlates with plasma viral rebound in SIV-infected rhesus macaques after antiretroviral therapy interruption J Virology 95 (6): e02064-20,2021.
Gondim, M.V.P., Sherrill-Mix, S., Bibollet-Ruche, F., Russell, R.M., Trimboli, S., Smith A.G., Li, Y., Liu, W., Avitto, A.N., DeVoto, J., Connell, J., Fenton-May, A.E., Pelligrino, P., Williams, I., Papasavvas, E., Lorenzi, J.C.C., Salantes, D.B., Mampe, F., Monroy, M.A., Cohen, Y.Z., Heath, S., Saag, M.S., Montaner, L.J., Collman, R.G., Siliciano, J., Siliciano, R.F., Plenderleith, L., Sharp, P.M., Caskey, M., Nussenzweig, M.C., Shaw, G.M., Borrow, P., Bar, K.J., Hahn, B.H.: Heightened resistance to type 1 interferons characterizes HIV-1 at transmission and following analytical treatment interruption Science Translational Medicine 13 (576): eabd8179,2021.
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