HIV-1 reduces Abeta-degrading enzymatic activities in primary human mononuclear phagocytes.

ABSTRACT

The advent and wide introduction of antiretroviral therapy has greatly improved the survival and longevity of HIV-infected patients. Unfortunately, despite antiretroviral therapy treatment, these patients are still afflicted with many complications including cognitive dysfunction. There is a growing body of reports indicating accelerated deposition of amyloid plaques, which are composed of amyloid-ß peptide (Aß), in HIV-infected brains, though how HIV viral infection precipitates Aß accumulation is poorly understood. It is suggested that viral infection leads to increased production and impaired degradation of Aß. Mononuclear phagocytes (macrophages and microglia) that are productively infected by HIV in brains play a pivotal role in Aß degradation through the expression and execution of two endopeptidases, neprilysin (NEP) and insulin-degrading enzyme. In this study, we report that NEP has the dominant endopeptidase activity toward Aß in macrophages. Further, we demonstrate that monomeric Aß degradation by primary cultured macrophages and microglia was significantly impaired by HIV infection. This was accompanied with great reduction of NEP endopeptidase activity, which might be due to the diminished transport of NEP to the cell surface and intracellular accumulation at the endoplasmic reticulum and lysosomes. Therefore, these data suggest that malfunction of NEP in infected macrophages may contribute to acceleration of ß amyloidosis in HIV-inflicted brains, and modulation of macrophages may be a potential preventative target of Aß-related cognitive disorders in HIV-affected patients.