Human Immunodeficiency Virus Promotes Mitochondrial Toxicity

Abstract

Combined antiretroviral therapies (cART) have had remarkable success in reducing morbidity and mortality among patients infected with human immunodeficiency virus (HIV). However, mild forms of HIV-associated neurocognitive disorders (HAND), characterized by loss of synapses, remain. cART may maintain an undetectable HIV RNA load but does not eliminate the expression of viral proteins such as trans-activator of transcription (Tat) and the envelope glycoprotein gp120 in the brain. These two viral proteins are known to promote synaptic simplifications by several mechanisms, including alteration of mitochondrial function and dynamics. In this review, we aim to outline the many targets and pathways used by viral proteins to alter mitochondria dynamics, which contribute to HIV-induced neurotoxicity. A better understanding of these pathways is crucial for the development of adjunct therapies for HAND.

Keywords: Ca2+; HAND; Mitochondria; Neurotoxicity; Tat; gp120.

Figure 1

Neuronal mitochondria in HAND display disrupted cristae. Cortical sections from HIV+ subjects with no cognitive alterations and HAND subjects were analyzed by transmission electron microscopy (TEM) as previously described (Avdoshina et al. 2016a) to visualize mitochondria. Please note that mitochondria (arrows) in HAND exhibit loss of well-defined cristae (bar = 1 μm). Magnification 25,000X.

Figure 2

Viral protein gp120 alters mitochondrial morphology. Mitochondrial morphology was visualized by TEM in cortical sections from wild type (WT) and gp120 transgenic (gp120-tg) mice. Note that mitochondria (arrows) in gp120-tg mice display broken cristae. Often, mitochondria in gp120-tg animals are abnormally elongated (bar =1 μm).

Figure 3

Tat rapidly increases [Ca²⁺]_i in a NMDA receptor independent manner. Cultured rat cortical neurons (DIV7) prepared as described previously (Avdoshina et al. 2016b) were exposed for up to 200 sec to recombinant Tat (100nM) or NMDA (100 μM) alone or in combination with the NMDA receptor antagonist MK801 (60μM). A and B: Representative Fluo-4 fluorescence images of cortical neurons captured before (baseline) and after application of Tat or NMDA in the presence of absence of MK801. C and D: Mean Fluo-4 fluorescence of A and B, respectively (n >20 cells). Note that addition of Tat resulted in a significant increase in [Ca²⁺]_i, which was not prevented when the NMDA receptor antagonist MK801 was added concurrently. Neurons were responsive to NMDA, which caused a rapid and robust rise in [Ca²⁺]_i, prevented by the concurrent administration of MK801 (B and D).