Secondary lung infections remain a frequent and potentially life-threatening complication in individuals with chronic Human Immunodeficiency Virus (HIV). Unfortunately, the contributing factors to the >25-fold increased rate of pneumonia in HIV+ persons are not well defined. The fact that HIV+ persons with relatively preserved CD4-T-cell counts remain at high risk for bacterial pneumonia suggest the possibility that impaired function of other lung immune cells such as alveolar macrophages (AM) may contribute to pneumonia pathogenesis. AM express Toll-like receptors (TLR) that recognize conserved and essential molecular components of bacterial pathogens and activation of TLR initiates a crucial sequence of intracellular signaling cascades that result in effective clearance of invading bacteria. Recognizing the importance of TLR4 in recognition and biological response to bacterial LPS, preliminary data in this application demonstrate significant derangement of TLR4- mediated activation of AM from asymptomatic HIV+ subjects. Importantly, the derangement : a) is specific;b) may represent AM reprogramming to an LPS-tolerant phenotype;c) is in part attributed to HIV-targeting of specific AM regulatory molecules that influence host defense function;and d) is independent of HAART. Taken together, these provocative preliminary data support the central hypothesis that HIV infection of AM results in targeted and specific impairment of macrophage TLR mediated signaling pathways, impairing critical components of first line host defenses in the lungs. Testing the hypothesis will be accomplished through 3 specific aims: 1) To determine the anti-inflammatory signaling pathways selectively activated by HIV that modulate TLR-mediated host defense responses. 2) To determine the relative balance between MyD88-dependent and MyD88-independent signal transduction pathways in host defense function of AM from HIV+ persons in response to TLR4 activation. 3) To identify HIV-derived (Nef, gp120, ssRNA) and host-derived (IL-10) factors that contribute to HIV-mediated immune dysregulation in response to TLR4 activation in AM from HIV+ persons. Our goals are to define the molecular mechanism for HIV-induced impairment of AM TLR-mediated effector cell response, and to identify molecular targets that can enhance or rescue effector cell function (without triggering HIV replication) in AM from HIV+ persons at risk for bacterial pneumonia. These results will be used to develop new preventive and novel adjunctive strategies to treat AIDS-related pneumonia.

Public Health Relevance

HIV+ individuals have up to 25-fold greater risk of getting bacterial pneumonia compared to the general population although the mechanism of increased susceptibility is incompletely understood. Our goal is to define the molecular mechanisms why these patients are susceptible to opportunistic infections and identify targets that can enhance the immune response of these patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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AIDS Immunology and Pathogenesis Study Section (AIP)
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Peavy, Hannah H
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Beth Israel Deaconess Medical Center
United States
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Bernard, Mark A; Zhao, Hui; Yue, Simon C et al. (2014) Novel HIV-1 miRNAs stimulate TNF? release in human macrophages via TLR8 signaling pathway. PLoS One 9:e106006
Bernard, Mark A; Han, Xinbing; Inderbitzin, Sonya et al. (2014) HIV-derived ssRNA binds to TLR8 to induce inflammation-driven macrophage foam cell formation. PLoS One 9:e104039
Birrane, Gabriel; Li, Huchun; Yang, Suping et al. (2013) Cigarette smoke induces nuclear translocation of heme oxygenase 1 (HO-1) in prostate cancer cells: nuclear HO-1 promotes vascular endothelial growth factor secretion. Int J Oncol 42:1919-28
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
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