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.IMPORTANCE Despite viral suppression by antiretrovirals,
HIV proteins continue to be detected in infected cells and neurologic complications remain common in infected people. Although HIV is unable to infect neurons,
viral proteins, including gp120 and Tat, can enter neurons and can cause neuronal degeneration and neurocognitive impairment. Neuronal health is dependent on the functional integrity of mitochondria, and damaged mitochondria are subjected to mitochondrial control mechanisms. Multiple lines of evidence suggest that specific elimination of damaged mitochondria through mitophagy and mitochondrial dynamics play an important role in
CNS diseases. Here, we show that in human primary neurons, gp120 and Tat favor the balance of mitochondrial dynamics toward enhanced fragmentation through the activation of mitochondrial translocation of DRP1 to the damaged mitochondria. However, mitophagy fails to go to completion, leading to neuronal damage. These findings support a role for altered mitophagy in HIV-associated
neurological disorders and provide novel targets for potential intervention.