Neutralizing Abs suppress HIV infection by accelerating viral clearance from blood circulation in addition to neutralization. The elimination mechanism is largely unknown. We determined that human liver sinusoidal endothelial cells (LSEC) express FcγRIIb as the lone Fcγ receptor, and using humanized FcγRIIb mouse, we found that Ab-opsonized HIV pseudoviruses were cleared considerably faster from circulation than HIV by LSEC FcγRIIb. Compared with humanized FcγRIIb-expressing mice, HIV clearance was significantly slower in FcγRIIb knockout mice. Interestingly, a pentamix of neutralizing Abs cleared HIV faster compared with hyperimmune anti-HIV Ig (HIVIG), although the HIV Ab/Ag ratio was higher in immune complexes made of HIVIG and HIV than pentamix and HIV. The effector mechanism of LSEC FcγRIIb was identified to be endocytosis. Once endocytosed, both Ab-opsonized HIV pseudoviruses and HIV localized to lysosomes. This suggests that clearance of HIV, endocytosis, and lysosomal trafficking within LSEC occur sequentially and that the clearance rate may influence downstream events. Most importantly, we have identified LSEC FcγRIIb-mediated endocytosis to be the Fc effector mechanism to eliminate cell-free HIV by Abs, which could inform development of HIV vaccine and Ab therapy.
Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (M.tb), a serious problem worldwide with over one third of the global population being infected; resulting in 1.3 million deaths. TB treatment includes a combination of 3 or more anti-TB drugs over a prolonged period of time. In the last few decades, multi drug resistant (MDR-TB) and extensively drug resistant TB (XDR-TB) strains have emerged due to the mismanaged use of anti-TB drugs. In this study, we discovered that M.tb infection increases the expression of macrophage drug efflux pump P-Glycoprotein (MDR-1) to extrude various chemical substances including the anti-TB drugs to benefit the M.tb survival. M.tb infection in macrophages suppresses the heat shock factor-1 (HSF1), a transcriptional regulator of MDR-1 through the up regulation of miR-431. Notably, the non pathogenic mycobacterium M. smegmatis or BCG did not increase the MDR-1 expression in human macrophages. Additionally, the inhibition of M.tb phoPR secretion system by pharmacological inhibitor reverses the M.tb mediated up regulation of MDR-1 in macrophages. Finally, inhibition of MDR-1 in macrophages enhances the anti TB drug mediated killing of M.tb. In conclusion, we report a novel finding that M.tb up regulates the MDR-1 in macrophages which limits the exposure of M.tb to sub-lethal concentrations of drugs that promotes M.tb survival and emergence of resistant variants.
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