Considerable progress has been made over the last decade towards understanding host factors that contribute to differential susceptibility to HIV-1 transmission and AIDS progression. Genetic background has been shown to be an important determinant of both HIV-1 infection and AIDS progression. However, little work has been directed to understanding the role(s) of polymorphisms in innate immunity genes in HIV transmission or AIDS progression. Toll-like receptor 4 (TLR4), which mediates responses to Gram-negative bacteria (e.g. lipopolysaccharide or endotoxin) in mouse and humans, has also been implicated as a determinant of HIV infection and viral replication in vitro. Recently, two functional polymorphisms in human TLR4 have been reported: 896 A to G (Asp299Gly) and 1190 A to G (Thr399Ile). Both loss of function mutations have been demonstrated to have functional relevance to human response to endotoxin. To evaluate the potential role of TLR4 in HIV-1 transmission and AIDS progression we established a research collaboration with the multicenter AIDS cohort study (MACS), which is funded by NIAID. We designed the study to test the following hypotheses in homosexual men recruited to MACS: 1) the Asp299Gly and Thr399Ile polymorphisms in TLR4 confers enhanced risk to HIV-1 transmission, and 2) the TLR4 polymorphisms are associated with slowed progression to AIDS in HIV-infected individuals. ? ? A second project has been designed to investigate the mechanisms of susceptibility to respiratory syncytial virus (RSV) infection and disease progression. RSV is the leading viral respiratory cause of hospitalization in infants and young children in the United States and in the world. The reason why some previously healthy infants develop LRI (bronchiolitis and pneumonia) while others remain asymptomatic or only develop upper respiratory tract symptoms after RSV infection is not well understood. Evidence exists that the degree of previous injury of the lung parenchyma in small infants could play a role in disease severity, as children with chronic lung disease are at high risk of RSV LRI. However, the majority of hospitalizations occur in previously healthy infants. Another potentially important factor that can cause lung injury during RSV LRI is innate immunity. The pulmonary infiltration during RSV LRI is composed overwhelmingly by neutrophils and macrophages and damage to the small airways (10-300 microns) affected by the virus could easily cause debris accumulation in the lumen, inflammation and edema of the small airways, and compromise ventilation. Further, most infants with RSV-associated wheezing do not respond to b2-bronchodilators, but may benefit from inhaled a-agonists that decrease edema/inflammation. Additionally, high levels of CXC chemokines (particularly MIP-1a, MCP-1 and IL-8) have been associated with increased RSV disease severity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES100557-05
Application #
7329130
Study Section
(EGG)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2006
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Cho, Hye-Youn; Imani, Farhad; Miller-DeGraff, Laura et al. (2009) Antiviral activity of Nrf2 in a murine model of respiratory syncytial virus disease. Am J Respir Crit Care Med 179:138-50
Cho, Hye-Youn; Kleeberger, Steven R (2009) Nrf2 protects against airway disorders. Toxicol Appl Pharmacol :
Melendi, Guillermina A; Zavala, Fidel; Buchholz, Ursula J et al. (2007) Mapping and characterization of the primary and anamnestic H-2(d)-restricted cytotoxic T-lymphocyte response in mice against human metapneumovirus. J Virol 81:11461-7
Melendi, Guillermina A; Hoffman, Scott J; Karron, Ruth A et al. (2007) C5 modulates airway hyperreactivity and pulmonary eosinophilia during enhanced respiratory syncytial virus disease by decreasing C3a receptor expression. J Virol 81:991-9
Melendi, Guillermina A; Laham, Federico R; Monsalvo, A Clara et al. (2007) Cytokine profiles in the respiratory tract during primary infection with human metapneumovirus, respiratory syncytial virus, or influenza virus in infants. Pediatrics 120:e410-5
Bukreyev, Alexander; Serra, Maria Elina; Laham, Federico R et al. (2006) The cysteine-rich region and secreted form of the attachment G glycoprotein of respiratory syncytial virus enhance the cytotoxic T-lymphocyte response despite lacking major histocompatibility complex class I-restricted epitopes. J Virol 80:5854-61
Klein, M Ines; Coviello, Silvina; Bauer, Gabriela et al. (2006) The impact of infection with human metapneumovirus and other respiratory viruses in young infants and children at high risk for severe pulmonary disease. J Infect Dis 193:1544-51
Polack, Fernando P; Irusta, Pablo M; Hoffman, Scott J et al. (2005) The cysteine-rich region of respiratory syncytial virus attachment protein inhibits innate immunity elicited by the virus and endotoxin. Proc Natl Acad Sci U S A 102:8996-9001
Polack, Fernando P; Teng, Michael N; Collins, Peter L et al. (2002) A role for immune complexes in enhanced respiratory syncytial virus disease. J Exp Med 196:859-65
Thach, D C; Kleeberger, S R; Tucker, P C et al. (2001) Genetic control of neuroadapted sindbis virus replication in female mice maps to chromosome 2 and associates with paralysis and mortality. J Virol 75:8674-80