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    • Our study is limited by the

    2018-11-07

    Our study is limited by the small sample size and the lack of data on expressed reservoir markers (e.g. cell-associated HIV RNA), replication competent virus and tissue reservoirs that are relevant to HIV remission (Li et al., 2016). The longitudinal reservoir assessment in 50 Fiebig I/II is a major strength compared to past studies (Groves et al., 2012, Jain et al., 2013, Williams et al., 2014). Finally, the consequences of a small HIV reservoir size from early ART on clinical outcomes are not well understood. The following is the supplementary data related to this article.
    Funding Sources This work was supported by cooperative agreements (W81XWH-07-2-0067, W81XWH-11-2-0174) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, and the U.S. Department of the Army and by an intramural grant from the Thai Red Cross AIDS Research Center. The Government Pharmaceutical Organization (GPO), Thailand, Gilead, Merck and ViiV Healthcare provided support for antiretroviral medications. JA was partially funded by NIAIDR01AI114236.
    Role of the Funders
    Conflict of Interest Statement
    Author Contributions
    Acknowledgements
    Introduction RSV is the primary cause for hospitalization during the first year of life in infants worldwide, and it is the leading cause of lower respiratory tract infection leading to bronchiolitis, pneumonia, and respiratory failure (Lozano et al., 2012). RSV is also a significant cause of respiratory illness in immunocompromised adults and the elderly (Falsey et al., 2005). While the majority of infected subjects present symptoms, the nature and severity of the symptoms vary among individuals (Ciencewicki et al., 2014; Caballero et al., 2015). For some, infection induces cold-like symptoms; others require hospitalization, and a small percentage of cases require intensive care and may result in death. The wide variation in response to RSV infection suggests that susceptibility and disease are influenced by multiple host intrinsic factors (Stark et al., 2002; Miyairi and DeVincenzo, 2008; Gelfand, 2012; Feldman et al., 2015). Previous in vivo mouse studies suggest that RSV infectivity is a multigenic trait, but did not identify the aromatase inhibitors responsible for infection (Prince et al., 1979; Stark et al., 2002; Stark et al., 2010). The innate and acquired immune systems have been implicated in the pathogenesis of RSV infection, including surfactant association proteins, viral response receptors and proteins, and inflammatory cells and their products such as chemokines, cytokines, and soluble inflammatory mediators [e.g. (Mukherjee and Lukacs, 2013; Varga and Braciale, 2013)]. However, roles for each of these components in the pathogenesis of RSV disease are unclear. RSV disease is complex and, while candidate gene single nucleotide polymorphisms (SNPs) have associated with RSV disease severity in infants [e.g. (Miyairi and DeVincenzo, 2008; Daley et al., 2012; Ciencewicki et al., 2014; Caballero et al., 2015)], the mechanisms of differential disease susceptibility remain unclear. To better understand the genetic basis of RSV disease, we performed a genome-wide association (GWA) study of disease following infection in inbred strains of mice to identify candidate quantitative trait loci (QTL) and genes that associate with specific disease phenotypes. We identified 7 significant and 8 suggestive QTLs and candidate susceptibility genes including macrophage receptor with collagenous structure (Marco), an innate immunity scavenger receptor. Targeted deletion of mouse Marco worsened RSV disease phenotypes, consistent with a protective role in disease pathogenesis. We then identified and characterized in vitro a human MARCO promoter SNP that diminished mRNA expression basally and after RSV infection. The SNP is located in an antioxidant response element (ARE) of the MARCO promoter and is a binding site for the transcription factor nuclear factor (erythroid derived)-2 like 2 (NFE2L2), also known as nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2). Deletion of the ARE also reduced MARCO mRNA expression following RSV infection in airway epithelial cells. Moreover, compared to the wild-type C allele, we found that the MARCO promoter rs1318645 SNP G allele associated with increased disease severity in populations of RSV-infected infants. Our modeling of disease after RSV infection in mice thus identified a host susceptibility gene candidate that has implications for better understanding human disease.