naling Pathway and Enhances AIDS Virus Infection. PLoS ONE 7: e31167. doi:10.1371/journal.pone.0031167 Editor: Jialin Charles Zheng, University of Nebraska Medical Center, United States of America Received October 27, 2011; Accepted January 3, 2012; Published February 16, 2012 Copyright: 2012 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. E-mail: [email protected] Introduction Injection drug users are at a significant high risk for aquiring HIV infection and contribute to the spread of the virus. Several early studies indicated that intravenous use of opiates influences the outcome of HIV infection. IDUs frequently involve the abuse of heroin, the most common abused opiate. Heroin injection increased the risk of acquiring HIV and progression to AIDS. However, because of the extreme complexity of opiate addition and/or HIV infection, it has been extremely difficult to compare different clinical and epidemiological findings in studying the impact of opiate abuse on HIV disease progression. In contrast, laboratory in vitro studies have yielded relatively agreeable data, showing that morphine, the active metabolite of heroin, enhances susceptibility of the immune cells to HIV infection. Peterson et al. first reported that morphine enhances HIV replication in human PBMC coculture system. Several studies showed that morphine could activate mu opioid receptors of human immune cells and up-regulate the expression of CCR5 and CXCR4, the key HIV entry coreceptors. Morphine-mediated induction of CCR5 and CXCR4 was associated with increased HIV infection of macrophages. Morphine also enhanced simian immunodeficiency virus infection and replication in both in vivo and in vitro systems. Morphine treatment increased SIV replication in CEM6174 cells. Injection with morphine enhanced SIV replication in Rhesus Macaques. Induction of CCR5 expression in monkey peripheral mononuclear cells by morphine contributes to enhanced SIV replication. However, it has also been reported that morphine treatment slowed SIV disease progression. Although the role of opiates in promoting HIV disease progression is still debatable, overwhelming evidence indicates that heroin and other opiate derived 870281-82-6 substances affect both adaptive and innate immunity. Innate immunity is the first line of the defense mechanism against viral infections. Interferons are key players in host innate immunity, as they possess antiviral activity against a variety of viruses, including HIV. While both type I IFNs and type II IFN have been known for ” decades as the antiviral cytokines, a novel class of cytokines was recently discovered and named as type III IFNs . Although IFN-l exerts its action through a receptor complex distinct “2991807 from that for the type I IFNs, IFN-l shares a number of common biological February 2012 | Volume 7 | Issue 2 | e31167 Morphine Enhances HIV/SIV Infection functions with type I IFNs. Similar to type I IFNs, IFN-l has potent antiviral activity against viral infections, including HIV. Given the critical