Morgan James Chapman

Introduction: Human immunodeficiency virus (HIV) and tuberculosis (TB) are each among the 10 most common causes of mortality in low income countries despite improvements in therapies, with few of these therapies capable of treating HIV-TB coinfections¹. In coinfections, HIV and Mycobacterium tuberculosis (Mtb) synergize leading to enhanced CD4+ T cell depletion, more severe Mtb respiratory infections, and deteriorating patient conditions associated with cytokine storm^{2, 3}. With many standard-of-care antimicrobials leading to neurotoxicity or failing due to resistance, creative solutions are needed to effectively treat these coinfections⁴. Gallium, an FDA approved imaging contrast agent, is a potent antimicrobial capable of competing for iron needed in a plethora of bacterial enzymes⁵. Nanoparticles are synthetic vesicles less than 300 nm in size capable of delivering a payload to a specific location, and when loaded with gallium, they may provide the creative solution needed to treat these coinfections.  Methods: Using nanoencapsulation and extrusion, Choi et al. produced nanoparticles loaded with gallium protoporphyrin, a gallium/heme-mimetic complex⁶. To assess biodistribution, GFP-labeled GaNPs were injected intramuscularly and tracked via sampling of homogenized mouse tissue⁷. Using reverse transcriptase and bacterial CFU plating, Choi et al were able to quantify the viral replication and bacterial growth respectively within the alveolar macrophage⁶. Lastly, to evaluate the immunologic effects of the loaded nanoparticles, Choi et al used western blots, ELISAs, and fluorescent microscopy to observe changes in cytokine regulators, cytokines, and phagosome maturation⁶. Results: Preincubation of alveolar macrophages with GaNP led to reduced replication of both Mtb and HIV, whereas post-exposure incubation exclusively led to reduced replication of Mtb⁶. On intramuscular injection, a significant subset of GaNPs located to the alveolar macrophage where in addition to their direct antimicrobial effects, were capable of promoting phagosome maturation and reducing cytokines associated with poor outcomes in human patients^{6, 7}. Conclusion: Gallium nanoparticles offer a unique mode of therapy for these coinfections by targeting multiple etiological steps; the cytokine storm, phagosome disruption, and microbial replication. Combining the inherent antimicrobial activity of gallium with the targeted delivery of the nanoparticles results in higher delivery to the site of infection, reduced risk of resistance development, fewer off-target effects, and less total gallium needed to effectively treat coinfections. These traits combined with its immunomodulatory effects support GaNP’s efficacy and safety as a long-term prophylactic and treatment for HIV-TB coinfections.

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7. Choi S-R, Britigan BE, Switzer B, Hoke T, Moran D, Narayanasamy P. In Vitro Efficacy of Free and Nanoparticle Formulations of Gallium(III) meso-Tetraphenylporphyrine against Mycobacterium avium and Mycobacterium abscessus and Gallium Biodistribution in Mice. Molecular Pharmaceutics. 2018;15(3):1215-1225. doi:10.1021/acs.molpharmaceut.7b01036