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HIV & the Brain: ARTs, Mitochondria, Stress
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By now its clear aging & HIV is a serious problem that will worsen as presented many times & most recently at CROI 2021 by Kasaie "Mutimorbidity in people with HIV: using ART in the USA Projections to 2030". But a deeper dive & worse than that is already currently about 300,000 PWH in the USA are over 55, 100,000 over 65 & many are suffering physical & mental impairment or disability and are unable to perform normal daily activities, with the MACS cohort reporting 25% of HIV+ MSM over 65 have frailty. Not only are these older frail PWH not necessarily receiving care & services all too often but younger PWH are not being evaluated for pre-frailty so as to allow for interventions that night slow or prevent frailty such as exercise, activity, and counseling. As well, early screening for cognitive deficits can identify when intervention may prevent or slow future decline. There are only a handful of aging/HIV-geriatric clinics that evaluate PWH for these impairments including the Royal Free Hospital Frailty Clinic in London. There is no federal program to support & work with HIV & Ryan White Clinics to integrate HIV-geriatric elements into the HUV care infrastructure. HIV is the only disease for which the federal government provides full funding for a care infrastructure - The Ryan Care Care Act - and in addition to the current health problems of our older PWH generation its estimated by many including the study at CROI above that by 2030 75% of PWH in the USA will be over 50. And 25% will likely be over 65. Clearly we need a HIV care infrastructure that is "patient-oriented", that allows our providers & doctors to spend nor than 15 minutes with elderly disabled PWH. That is one reason why so many of our older most experienced HIV doctors have left their practice to go to work for drug companies, or retired, air have had to sell their practices to a large major hospital who then dictates 15 minute visits due to harsh insurance reimbursement restrictions. WHEN WILL WE CHANGE THIS ? Its time for HHS, ONAP & HRSA to start understanding this problem, to pay attention, to have large transparent open national discussions with PWH stakeholders & NOT only hold closed door discussions with selected individuals. And its time for action - to implement a new HIV care infrastructure that meets the needs of older aging & elderly PWH. Jules Levin
Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726941/
The use of antiretroviral (ARV) drugs with central nervous system (CNS) penetration effectiveness (CPE) may be useful in the treatment of HIV-associated neurocognitive disorder (HAND) as well as targeting a CNS reservoir in strategies to achieve a functional cure for HIV. However, increased cognitive deficits are linked to at least one of these drugs (efavirenz). As mitochondrial dysfunction has been found with a number of ARVs, and as such can affect neuronal function, the objective of this study was to assess the effects of ARV with high CPE for toxicological profiles on presynaptic nerve terminal energy metabolism. This subcellular region is especially vulnerable in that a constant supply of ATP is required for the proper maintenance of neurotransmitter release and uptake supporting proper neuronal function. We evaluated the effects of acute treatment with ten different high CPE ARVs from five different drug classes on rat cortical and striatal nerve terminal bioenergetic function. While cortical nerve terminal bioenergetics were not altered, striatal nerve terminals exposed to efavirenz, nevirapine, abacavir, emtricitabine, zidovudine, darunavir, lopinavir, raltegravir, or maraviroc (but not indinavir) exhibit reduced mitochondrial spare respiratory capacity (SRC). Further examination of efavirenz and maraviroc revealed a concentration-dependent impairment of striatal nerve terminal maximal mitochondrial respiration and SRC as well as a reduction of intraterminal ATP levels. Depletion of ATP at the synapse may underlie its dysfunction and contribute to neuronal dysfunction in treated HIV infection. The protease inhibitors darunavir and lopinavir, but not indinavir, were found to cause a significant loss of maximal mitochondrial respiration and SRC in striatal nerve terminals (Fig. 4c). We found that treatment of striatal nerve terminals with raltegravir impaired maximal mitochondrial respiration and reduced SRC (Fig. 4d). we found that maraviroc reduced maximal mitochondrial respiration and SRC in striatal nerve terminals (Fig. 4e). Further examination of maraviroc revealed a concentration-dependent impairment of striatal nerve terminal maximal mitochondrial respiration and SRC (Fig. 6) as well as a reduction of intraterminal ATP levels (Fig. 7). The NRTI drugs abacavir, emtricitabine, and zidovudine significantly reduced maximal mitochondrial respiration and the associated SRC in striatal nerve terminals (Fig. 4b). The significance of the reductions caused by these NRTI drugs was similar to efavirenz. Previous studies in our laboratory (Purnell and Fox, 2014), and by others have demonstrated several toxic effects of the NNRTI efavirenz on primary neurons and cultured neuroblastoma cell lines (Funes et al, 2015), involving mitochondrial dysfunction. This study demonstrates that striatal (but not cortical) nerve terminals exhibit altered mitochondrial respiratory parameters after exposure to several different ARV drugs, including efavirenz.
HIV infection alters energy metabolism in the brain: contributions to HIV-associated neurocognitive disorders
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742565/
Much attention has been given to direct neurotoxicity associated with the release of viral proteins from infected cells and indirect neurotoxicity mediated by the inflammatory response mounted by both infected and uninfected non-neuronal cells.. In HIV + brains, post-mortem gene expression analyses revealed that HIV-associated neurocognitive impairments are related to gene pathways involved in mitochondrial functioning being significantly down regulated [42]. Distinct alterations in mitochondrial morphology are associated with CNS HIV infection [45]. Mitochondrial size was increased in the frontal cortex of HAND patients suggesting mitochondrial fusion is preferred over fission in these individuals. The brain is particularly sensitive to changes in energy supply. Defects in glucose utilization and mitochondrial dysfunction are hallmarks of nearly all neurodegenerative diseases and are also associated with the cognitive decline that occurs as the brain ages. Chronic neuroinflammation driven by glial activation is commonly implicated as a contributing factor to neurodegeneration and cognitive impairment. Human immunodeficiency virus (HIV) disrupts normal brain homeostasis and leads to a spectrum of HIV-associated neurocognitive disorders (HAND). HIV activates stress responses in the brain and triggers a state of chronic neuroinflammation. Growing evidence suggests that inflammatory processes and bioenergetics are interconnected in the propagation of neuronal dysfunction. Clinical studies of HIV-infected individuals and basic research support the notion that HIV creates an environment in the CNS that interrupts normal metabolic processes at the cellular level and collectively alter whole brain metabolism. In this review, we highlight reports of abnormal brain metabolism from clinical studies and animal models. We also describe diverse CNS cell-specific changes in bioenergetics associated with HIV. Moreover, we propose that attention should be given to adjunctive therapies that combat sources of metabolic dysfunction as a mean to improve and prevent neurocognitive impairments.
Brain on stress: How the social environment gets under the skin ......key to aging: managing stressors of physical & mental health
https://www.natap.org/2012/HIV/101712_01.htm
among HIV-positive men, each additional moderately severe event increased the risk of progressing to AIDS by 50% and of developing an AIDS-related clinical condition by 2.5-fold.17 Moreover, stress has been found to influence the course of virally initiated illnesses to which persons with HIV are especially susceptible."
Stress is a state of the mind, involving both brain and body as well as their interactions; it differs among individuals and reflects not only major life events but also the conflicts and pressures of daily life that alter physiological systems to produce a chronic stress burden that, in turn, is a factor in the expression of disease. This burden reflects the impact of not only life experiences but also genetic variations and individual health behaviors such as diet, physical activity, sleep, and substance abuse; it also reflects stable epigenetic modifications in development that set lifelong patterns of physiological reactivity and behavior through biological embedding of early environments interacting with cumulative change from experiences over the lifespan. Hormones associated with the chronic stress burden protect the body in the short run and promote adaptation (allostasis), but in the long run, the burden of chronic stress causes changes in the brain and body that can lead to disease (allostatic load and overload). Brain circuits are plastic and remodeled by stress to change the balance between anxiety, mood control, memory, and decision making. A powerful top-down therapy (i.e., an activity, usually voluntary, involving activation of integrated nervous system activity as opposed to pharmacological therapy, which has a more limited target) is regular physical activity, which has actions that improve prefrontal and parietal cortex blood flow and enhance executive function (101). Moreover, regular physical activity, consisting of walking 1 h/d for 5 of 7 d/wk, increases hippocampal volume in previously sedentary adults (20)........Social integration and support and finding meaning and purpose in life are known to be protective against allostatic load (105) and dementia.....successful behavioral therapy, which is tailored to individual needs, can produce volumetric changes in both prefrontal cortex in the case of chronic fatigue (119) and amygdala in the case of chronic anxiety.
Neurotoxicity Screening of Antiretroviral Drugs With Human iPSC-Derived Neurons
http://www.natap.org/2016/CROI/croi_148.htm
Impact of antiretroviral treatment containing tenofovir difumarate on the telomere length of aviremic HIV-infected patients / NRTIs, HIV & Telomerase, Aging, Comorbidities
https://www.natap.org/2017/CROI/croi_143.htm
Muscle mitochondrial function and contemporary anti-retroviral therapy
https://www.natap.org/2018/AGE/AGE_21.htm
Excess Mitochondrial DNA Damage in Brain of People With HIV
https://www.natap.org/2016/AGE/AGE_11.htm
HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated
neurocognitive disorders
Jerel Adam Fields a, Elisabeth Serger a, So fia Campos b, Ajit S. Divakaruni e, Changyoun Kim b, Kendall Smith a,
Margarita Trejo b, Anthony Adame b, Brian Spencer b, Edward Rockenstein b, Anne N. Murphy e, Ronald J. Ellis b,
Scott Letendre c, Igor Grant d, Eliezer Masliah a,b,⁎
https://www.natap.org/2017/HIV/1-s2.0-S0969996115300954-main.pdf
HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies
to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondrial fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be
dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracker staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration. Overall, these data, along with the accompanying report, reveal a distinct alteration in mitochondrial morphology associated with HIV infection of the CNS and evidence that gp120 mediates these changes via altered mitochondrial fission/fusion and translocation along microtubules. The increase in mitochondria size is associated with severe HAND, and the alterations in fission/fusion machinery are observed early in neuronal models for HIV protein-mediated neurodegeneration.
Mitochondrial disease: Powerhouse of disease-insulin resistance/diabetes
https://www.natap.org/2006/HIV/041006_05.htm
"....muscle mitochondria could underlie insulin resistance in muscle tissue…"
Lipids can cause insulin resistance by jamming the cellular machinery that helps receive the hormone's signal. But what causes their levels to rise in the cell? There are two main possibilities: a faster rate of lipid breakdown and delivery to muscles from fat tissues; or a defect in the muscle mitochondria themselves. If faulty mitochondria don't burn fats as fast as they should, then that could lead to a build-up of lipids inside the muscle cells.
Mitochondrial toxicity and caspase activation in HIV pregnant women
https://www.natap.org/2017/HIV/062717_02.htm
The HIV pregnancies showed increased adverse perinatal outcome (OR: 4.81 [1.14-20.16]; P < 0.05) and decreased mtDNA content (42.66 ± 5.94%, P < 0.01) compared to controls, even higher in naïve participants. This depletion caused a correlated decrease in mitochondrial protein synthesis (12.82 ± 5.73%, P < 0.01) and function (20.50 ± 10.14%, P < 0.001), not observed in controls. HIV-infected women showed increased obstetric problems and declined genetic and functional mitochondrial parameters during pregnancy, especially those firstly exposed to anti-retrovirals. The apoptotic activation of caspases along pregnancy is emphasized in HIV pregnancies promoted by nucleoside analogues. However, we could not demonstrate direct mitochondrial or apoptotic implication in adverse obstetric outcome probably because of the reduced sample size.
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