The lungs remain a frequent target of HIV-related disease, although the mechanism(s) accounting for this increased susceptability are poorly understood. Alveolar macrophages (AM) are the predominant immune cell in the lungs, and serve a central role in mediating an effective """"""""first-line"""""""" host response to infectious challenge. AM are infected with HIV, but evidence for effector cell dysfunction remains controversial. Preliminary data in this application demonstrate that HIV-1 infection impairs mannose receptor-mediated phagocytosis of P. carinii, an important pulmonary pathogen in the HIV+ host. The macrophage mannose receptor is a prototype of a host defense surface protein of innate immunity which mediates recognition of specific carbohydrate moities expressed on the surface of pathogens. In the context of AIDS-related opportunistic infections, such pathogens include P. carinii, M. tuberculosis, MAC and C. neoformans. The Central Hypothesis is that HIV-1 and associated lung specific-factors dysregulate AM innate immune defense function, which in the setting of CD4+ T-lymphocyte depletion, predisposes the host to opportunistic lung infections. The goal of this project is to define the mechanism(s) underlying pulmonary innate immune cell dysregulation using the AM mannose receptor as the prototypic receptor of macrophage innate immunity. To test this hypothesis, experiments will address these Specific Aims: number 1) to characterize the expression and function of the cell membrane associated mannose receptor (mMR) comparing alveolar macrophages (AM) from healthy individuals to asymptomatic HIV-infected persons at high or low clinical risk for opportunistic pulmonary infections, and correlate with HIV-1 RNA and proviral DNA expression in the alveolar airspace; number 2) examine the mechanism of impaired mMR-mediated phagocytosis in AM in HIV-infected individuals by investigating the effects of in vitro HIV-1 infection, and the influence of specific exogenous and AAV vector-transduced structural and regulatory HIV-1 proteins on AM from healthy individuals; number 3) define the mMR-mediated signal transduction pathways comparing AM from healthy to HIV-infected individuals, and examine the influence of HIV-1 infection and HIV-1 gene products on Rho GTPase (Cdc42, Rac and Rho) and NF-kappaB/I-kappaB activity. Defining specific abnormalities in AM innate function will provide a rational basis for developing novel agents to augment local immune function, which could reduce the incidence or severity of pulmonary infections in patients with AIDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063655-02
Application #
6363572
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Colombini-Hatch, Sandra
Project Start
2000-03-02
Project End
2005-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
2
Fiscal Year
2001
Total Cost
$391,500
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Anandaiah, Asha; Sinha, Sanjeev; Bole, Medhavi et al. (2013) Vitamin D rescues impaired Mycobacterium tuberculosis-mediated tumor necrosis factor release in macrophages of HIV-seropositive individuals through an enhanced Toll-like receptor signaling pathway in vitro. Infect Immun 81:2-10
Han, Xinbing; Li, Xin; Yue, Simon C et al. (2012) Epigenetic regulation of tumor necrosis factor ? (TNF?) release in human macrophages by HIV-1 single-stranded RNA (ssRNA) is dependent on TLR8 signaling. J Biol Chem 287:13778-86
Han, Xinbing; Tachado, Souvenir D; Koziel, Henry et al. (2012) Leu128(3.43) (l128) and Val247(6.40) (V247) of CXCR1 are critical amino acid residues for g protein coupling and receptor activation. PLoS One 7:e42765
Anandaiah, Asha; Dheda, Keertan; Keane, Joseph et al. (2011) Novel developments in the epidemic of human immunodeficiency virus and tuberculosis coinfection. Am J Respir Crit Care Med 183:987-97
Li, Xin; Han, Xinbing; Llano, Juliana et al. (2011) Mammalian target of rapamycin inhibition in macrophages of asymptomatic HIV+ persons reverses the decrease in TLR-4-mediated TNF-ýý release through prolongation of MAPK pathway activation. J Immunol 187:6052-8
Tachado, Souvenir D; Li, Xin; Bole, Medhavi et al. (2010) MyD88-dependent TLR4 signaling is selectively impaired in alveolar macrophages from asymptomatic HIV+ persons. Blood 115:3606-15
Patel, Naimish R; Swan, Katharine; Li, Xin et al. (2009) Impaired M. tuberculosis-mediated apoptosis in alveolar macrophages from HIV+ persons: potential role of IL-10 and BCL-3. J Leukoc Biol 86:53-60
Tachado, Souvenir D; Li, Xin; Swan, Katharine et al. (2008) Constitutive activation of phosphatidylinositol 3-kinase signaling pathway down-regulates TLR4-mediated tumor necrosis factor-alpha release in alveolar macrophages from asymptomatic HIV-positive persons in vitro. J Biol Chem 283:33191-8
Koziel, Henry (2008) Rho GTPases in alveolar macrophage phagocytosis. Methods Enzymol 439:303-13
Tachado, Souvenir D; Zhang, Jianmin; Zhu, Jinping et al. (2007) Pneumocystis-mediated IL-8 release by macrophages requires coexpression of mannose receptors and TLR2. J Leukoc Biol 81:205-11

Showing the most recent 10 out of 16 publications