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    • A final model is presented to

    2018-10-23

    A final model is presented to suggest that the altered microbial composition of the -infected bile duct may promote tumor development. Specifically, the authors propose that infection and colonization of bile ducts with fosters a carcinogenic microenvironment through bacterial metabolic activity, suggesting that increased accumulation of bile acids and ammonia could enhance Homoharringtonine or genomic instability, similar to what has been reported in colitis-associated colorectal cancer (). Together, the results implicate parasite and host interactions in the dysregulation of local physiology that contributes to carcinogenesis as alters the bile duct environment and promotes the proliferation of a new bacterial player (). Although the findings from these patient-based studies are intriguing, many questions regarding the relative contribution and mechanisms by which local microbiome shifts may influence the development or progression of CCA in the context of infection remain to be addressed. We highlight the need for future studies to employ careful sampling design and to analyze microbial data with prudence. In the context of comparing CCA-associated bile ducts to healthy tissues and the potential mechanistic link that underlies infection, dysbiosis, and promotion of a carcinogenic microenvironment, the findings by Chng et al. must be interpreted with caution, as must all associational studies. In particular, the enrichment of specific microbes within human tumors should not be considered causative for tumorigenesis, progression or severity (). Nonetheless, the value of patient-based epidemiological studies is the provision of testable hypotheses for basic science experiments to determine the contribution, if any, of noted associations. The manuscript by Chng et al. should entice further investigation of how infection can affect microbial communities, the microbial metabolome, and the local immune microenvironment in CCA development and progression. Conflicts of Interest
    HIV DNA integration is essential for the persistence of HIV infection and, to date, represents an insurmountable obstacle to an HIV cure. By contrast, drugs that block the NS5B polymerase enzyme of HCV for only 12weeks can frequently cure HCV infection because no integration step is involved in the HCV replication cycle. Although inhibitors of each of HIV reverse transcriptase, protease, and integrase have been successfully used to treat HIV infection, none of these are able to reverse the persistence of integrated DNA copies of the viral genome. Hence, viral loads typically rebound rapidly after treatment interruption due to activation and expression of the viral genome from latently infected cells within the viral reservoir (). Early initiation of antiretroviral therapy remains the only way to limit the size of the HIV reservoir and, thus far, several interventions, including treatment intensification with the integrase strand transfer inhibitor (INSTI) raltegravir, have failed to achieve diminution of the reservoir. Strategies that have been developed to eradicate HIV include a “Shock and Kill” approach, whereby latently infected cells are activated and then killed by antiretroviral drugs (ARVs), stimulation by Toll-like receptors, and the use of neutralizing or cytotoxic T lymphocyte-specific antibodies (). Alternative approaches propose to push the virus into latency by using Tat inhibitors that limit HIV post-latency reactivation (). Other HIV inhibitors have been developed that target the interaction between the viral integrase and the cellular transcription factor lens epithelium-derived growth factor (LEDGF) (). The rationale is that LEDGF can increase the efficiency of HIV integration while also being necessary for HIV to integrate preferentially within transcriptionally active genomic regions (). In cells depleted of LEDGF, HIV integration sites were enriched in GC-rich genomic regions and were less frequent in actively transcribed regions than when LEDGF was present (). Of course, integration within transcriptionally active regions has potent implications for the establishment of latency, as the cellular transcriptional state influences both HIV transcription driven by its promoter located in the long terminal region (LTR) and reactivation from latency. Inhibitors that target the interaction between integrase and LEDGF are variously termed non-catalytic integrase inhibitors (NCINIs), allosteric inhibitors (ALLINIs), or LEDGF inhibitors (LEDGINs). The molecular mechanisms by which LEDGINs inhibit HIV replication are not completely understood and some LEDGINs can inhibit HIV post-integration events more efficiently than integrase activity itself.