**4.2 HIV-induced neuroinflammation and neurotoxicity**

With improvements in treatments for HIV (human immunodeficiency virus), lifespan has increased significantly affected persons. However, neuroinflammation and/or toxicity remain major concerns in this disease. The critical relevance of neuroinflammation to the etiology of MS, a disease for which DMF/MMF therapy is already approved, is undeniable [68]. Further, patients with MS are at considerably higher risk for neurotoxicity than are patients without the demyelinating disease [69]. Given these commonalities between MS and HIV-induced neurologic disease, preclinical testing of DMF/MMF in the latter is of interest. Using an *in vitro* model of HIV-mediated neurotoxicity, Cross et al. 2011 [70] showed that HIV infection dysregulates macrophage antioxidant response and reduces the expression of heme oxygenase-1 (HO-1). Importantly, DMF and MMF (5–30 μM) dose-dependently suppressed HIV replication, improved antioxidant response and reduced neurotoxin release, effects that the authors proposed to be mediated via a two-way action of DMF: (1) inhibition of NF-kB nuclear translocation and consequent suppression of HIV replication, and (2) decreased neurotoxin release stemming from HO-1 induction. Further, they also found that DMF reduces CCL2 (C-C Motif Chemokine Ligand 2)-induced monocyte chemotaxis, suggesting that DMF additionally decreased the recruitment of activated monocytes to the CNS (central nervous system) in response to inflammatory mediators. Based on the above, the authors concluded that dysregulation of the antioxidant response during HIV infection drives macrophage-mediated neurotoxicity and DMF could serve as an adjunctive neuroprotectant. In a separate study, Ambrosius et al. [71] evaluated the effect of MMF on microglia activation and subsequent neurotoxicity. MMF treatment (10–30 μM) significantly reduced HIV-mediated neurotoxicity in microglia cells (**Figure 3**). A similar but prior study by a different group showed MMF to be capable of inducing a phenotypic shift from pro-inflammatory to anti-inflammatory macrophages [72] however, Ambrosius et al. did not observe such effects. These differences could be model-dependent or related to methodological differences in the two studies and therefore require further investigation since the authors did not comprehensively evaluate the possible mechanism of action in these short reports. Notwithstanding, however, the opposing effects of DMF/MMF on microglial responses, particularly those of an inflammatory nature, appear to be solidly supported by several other studies [30] which in turn, collectively support additional effort to advance DMF/ MMF therapy for potential use in HIV-associated neuroinflammation and toxicity.
