Human Immunodeficiency Virus Type 1 gp120 and Tat Induce Mitochondrial Fragmentation and Incomplete Mitophagy in Human Neurons.

HIV enters the central nervous system (CNS) during the early stages of infection and can cause neurological dysfunction, including neurodegeneration and neurocognitive impairment. The specific autophagy responsible for removal of damaged mitochondria (mitophagy) and mitochondrial dynamics constitute neuronal mitochondrial quality control mechanisms and are impaired in neurodegenerative disorders and numerous other diseases. The release of HIV proteins gp120 and Tat from infected cells is thought to play an important role in HIV-associated neurocognitive disorders (HAND), but the mechanism(s) leading to impairment are poorly understood. Here, we report that exposure of human primary neurons (HPNs) to HIV gp120 and Tat accelerates the balance of mitochondrial dynamics toward fission (fragmented mitochondria) and induces perinuclear aggregation of mitochondria and mitochondrial translocation of dynamin-related protein 1 (DRP1), leading to neuronal mitochondrial fragmentation. HIV gp120 and Tat increased the expression of microtubule-associated protein 1 light chain 3 beta (LC3B) protein and induced selective recruitment of Parkin/SQSTM1 to the damaged mitochondria. Using either a dual fluorescence reporter system expressing monomeric red fluorescent protein and enhanced green fluorescent protein targeted to mitochondria (mito-mRFP-EGFP) or a tandem light chain 3 (LC3) vector (mCherry-EGFP-LC3), both HIV proteins were found to inhibit mitophagic flux in human primary neurons. HIV gp120 and Tat induced mitochondrial damage and altered mitochondrial dynamics by decreasing mitochondrial membrane potential (ΔΨm). These findings indicate that HIV gp120 and Tat initiate the activation and recruitment of mitophagy markers to damaged mitochondria in neurons but impair the delivery of mitochondria to the lysosomal compartment. Altered mitochondrial dynamics associated with HIV infection and incomplete neuronal mitophagy may play a significant role in the development of HAND and accelerated aging associated with HIV infection.