HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution

Abstract

With the advent of the combination antiretroviral therapy era (cART), the development of AIDS has been largely limited in the United States. Unfortunately, despite the development of efficacious treatments, HIV-1 associated neurocognitive disorders (HAND) can still develop and as many HIV-1 positive individuals age, the prevalence of HAND is likely to rise because HAND manifests in the brain with very low levels of virus. However, the mechanism producing this viral disorder is still debated. Interestingly, HIV-1 infection exposes neurons to proteins including Tat, Nef, Vpr which can drastically alter mitochondrial properties. Mitochondrial dysfunction has been posited to be a cornerstone of the development of numerous neurodegenerative diseases. Therefore, we investigated mitochondria in an animal model of HAND. Using an HIV-1 transgenic rat model expressing 7 of the 9 HIV-1 viral proteins, mitochondrial functional and proteomic analysis were performed on a subset of mitochondria that are particularly sensitive to cellular changes, the neuronal synaptic mitochondria. Quantitative mass spectroscopic studies followed by statistical analysis revealed extensive proteome alteration in this model paralleling mitochondrial abnormalities identified in HIV-1 animal models and HIV-1 infected humans. Novel mitochondrial protein changes were discovered in the electron transport chain (ETC), the glycolytic pathways, mitochondrial trafficking proteins, and proteins involved in various energy pathways, and these findings correlated well with the function of the mitochondria as assessed by a mitochondrial coupling and flux assay. By targeting these proteins and proteins upstream in the same pathway, we may be able to limit the development of HAND.

Human Immunodeficiency Virus Promotes Mitochondrial Toxicity

“…The effect of Tat upon ATP production has conflicting data (Perry et al 2005; Tiede et al 2011; Villeneuve et al 2016), with indications of both increases and decreases in ATP production, in all instances preceding cell death. Nevertheless, the ability of Tat to cause a drastic inhibition of ATP synthase (Lecoeur et al 2012; Norman et al 2007) points to a disruption of mitochondrial function.…”

HIV in the cART era and the mitochondrial: immune interface in the CNS

“…HIV proteins, such as transactivator of transcription (Tat), glycoprotein (gp) 120, viral protein (VP) R, and negative factor (Nef ) have been linked to immune activation, oxidative stress, altered mitochondrial transport, altered autophagic flux, induction of apoptosis, Ca 2+ signaling, and neurotoxicity (Bansal et al, 2000;Dinkins, Arko-Mensah, & Deretic, 2010;Nath, Conant, Chen, Scott, & Major, 1999;Nath, Padua, & Geiger, 1995;Piller, Jans, Gage, & Jans, 1998;Rozzi, Avdoshina, Fields, & Mocchetti, 2018;Sawaya, Khalili, Mercer, Denisova, & Amini, 1998;Teodorof-Diedrich & Spector, 2018;Thangaraj et al, 2018;Valcour & Shiramizu, 2004). The involvement of HIV proteins in mitochondrial dysfunction in the brain was highlighted in a study that found alterations in the electron transport chain (ETC), glycolytic pathways, mitochondrial trafficking proteins and proteins crucial to various energy pathways in a rat model for HIV-induced neurotoxicity (Villeneuve et al, 2016).…”

“…Later studies found alterations to mitochondrial related markers in the brains of HIV+ patients on cART, although the mechanisms of ART-induced neurotoxicity are not completely understood and also likely depend on genetic and environmental factors. To study the contribution of HIV and HIV proteins to HAND, rodent models were developed that expressed HIV proteins in the brain (Kim et al, 2003;Mucke, Masliah, Rockenstein, & Toggas, 1993;Villeneuve et al, 2016). Others have developed "humanized" mice that allow for HIV-infection to be recapitulated in vivo.…”

Brain Aging in HIV-1 Infection

“…In the presence of HIV-1 proteins, the mitochondria face a higher energy demand, will consume more oxygen, and show a higher capacity to produce ATP. These mechanisms are usually observed when there is cellular damage leading to ROS production [178].…”