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    • TW37 cost HIV viral protein R Vpr is a multifunctional virio

    2018-11-13

    HIV-1 viral protein R (Vpr) is a multifunctional virion-associated accessory protein (). Vpr functions both early after entry into TW37 cost and also following integration of the proviral genome (). Vpr is a component of the preintegration complex, and following nuclear import Vpr likely plays a major role in regulating the expression of immediate-early HIV-1 genes from the now integrated proviral genome. This mechanism is utilized prior to the transition to Tat-driven gene expression. Vpr is critical in the viral replication cycle in non-dividing cells, such as monocytes (), whereas it has been shown to be dispensable in T-lymphocytes (). In the manuscript by Chiang et al. within this issue of , a new host factor is described as playing a role in HIV-1 susceptibility (). This host factor, MRJ-L, is the large splice isoform of DNAJB6 (a homolog of heat shock protein 40) and the authors state that it has been shown to interact with Vpr, however this data, to date has not been published and therefore this point is in need of further detailed exploration. The authors, studying cohorts of “men who had sex with men” (MSM), found that macrophage expression of MRJ-L varied among healthy subjects but was significantly and substantially higher in HIV-1-infected subjects. The macrophage MRJ-L expression level predicted the risk of HIV-1 infection with similar power as whether or not subjects engaged in unprotected sexual contact. To demonstrate a cause-and-effect relationship between MRJ-L expression and HIV-1 susceptibility, monocytes from healthy subjects were isolated and then differentiated and infected ex vivo. Interestingly, this experiment revealed that macrophages with high MRJ-L expression were more susceptible to HIV-1 infection than those with low MRJ-L expression. Furthermore, RNAi knockdown of MRJ-L in high-expressing cells decreased susceptibility to infection, while lentiviral over-expression of MRJ-L in low-expressing cells increased their susceptibility to infection. These results clearly implicate high expression of MRJ-L with macrophage susceptibility to HIV infection. The authors were able to identify a plausible mechanism, showing that MRJ-L colocalizes with Vpr and is required for localizing Vpr to the nucleus. Although the localization experiments were performed in HeLa cells, because of the importance of Vpr in macrophages, the extension can be made that MRJ-L plays a major role in the nuclear transport of this important viral protein (and possibly the whole pre-integration complex) in other cell types. The stochastic expression of MRJ-L in uninfected subjects raises the possibility that genetic factors controlling this variability are also responsible for variability in susceptibility to infection. Numerous studies have demonstrated the role of host proteins in HIV-1 susceptibility, and the strong evidence provided by Chiang et al. that MRJ-L levels impact susceptibility to infection makes it an attractive therapeutic target. However, caution needs to be taken with regard to developing a therapy to reduce MRJ-L expression. Studies have shown a link between decreased levels of MRJ-L and malignancies such as breast cancer, with MRJ-L being shown to regulate several key players in tumor formation and metastasis, and demonstrating its ability to functionally retard tumor growth (). More complete studies are needed to determine the role of MRJ-L in macrophages, as well as more directed therapeutic targeting to specific cells to avoid potentially devastating off-target consequences. Conflicts of Interest
    Many liquid tumors (lymphomas and leukemias) have characteristic genomic alterations that are critical to their disease development and progression. For example, greater than 90% of the chronic myelogenous leukemias (CML) are caused by the t(9;22)(q34;q11) or BCR/ABL translocation, whereas more than 75% of mantle cell lymphomas have the t(11,14)(q13, 32) translocation (). Because these genomic alterations are frequently drivers of the oncogenesis process, targeted therapies that inhibit the resultant aberrant signaling pathways have achieved remarkable clinical success. Imatinib, which inhibits the ABL tyrosine kinase, is considered one of the first molecularly targeted therapies for cancer (). A recent study suggested that patients with CML that are long-term responders to imatinib have similar survival as the general population (). Today, many targeted therapies are in clinical use or are under clinical development for the treatment of lymphomas and leukemias ().