**4. Epigenetic changes**

#### **4.1. Methylation levels**

**3. Gait/balance**

8 Advances in HIV and AIDS Control

developing Parkinson's disease [73, 74].

Aging is associated with a cascade of events affecting the function of the Substantia Nigra (SN) neurons, from the dopamine metabolism to the mitochondrial dysfunction and the alteration in protein degradation. The addition of cellular defects linked to aging increases the risks of

With aging, the density of dopamine transporters and dopaminergic neurons decreases, and there is a correlation between the decline of the dopamine system function and the executive function [75]. Several studies show evidence of a link between aging, memory, learning, and dopaminergic change [76–79]. HIV-1 penetrates the brain immediately after the initial infection and is disseminated in various concentrations in different parts of the brain, with a particular affinity for the subcortical regions like the basal ganglia, including the putamen, caudate nucleus, globus pallidus, and Substantia Nigra [80]. HIV-1 RNA is also identified in different regions of the postmortem brain, especially in different nuclei of the basal ganglia [81–83]. Since basal ganglia is the main target of HIV infection in the brain, it is not surprising that the dopaminergic function located in the Substantia Nigra will be altered. Neuropathological assessments of HIV+ patients show that the degeneration of Substantia Nigra is common. Moreover, it could explain the sensitivity of some patients to drug-induced Parkinsonism [84]. HIV-1 and Parkinson's disease both affect nigrostriatal structures with subsequent dopaminergic dysfunction. HIV-1 patients display signs of hypomimia, bradykinesia, poor hand agility, and action or postural tremor exacerbated by age [85]. The aging HIV+ population treated with HAART shows more frequent presentation of HIV-1 Parkinsonism. A significant decrease of dopamine in the Substantia Nigra was subsequently found in the postmortem examination of the HIV+ brains [86]. Alpha-synuclein is one of the major factors in Parkinson's disease pathology, and its expression was found to have increased in the Substantia Nigra of HIV+ postmortem brain [87]. Alpha-synuclein plays a role in the apoptosis of dopamine cells and reinforces the idea that the aging brain of HIV+ individuals may develop PD. Different studies report that the dopamine concentration in the HIV-infected brain can decrease by 50% [80, 86, 88]. The decrease in DA levels in SN was significantly correlated with the decrease in performance in learning, memory, speed of processing information, and verbal fluency.

The presynaptic dopamine transporter (DAT)-mediated dopamine reuptake is crucial for regular dopamine homeostasis and subsequent brain functions like memory, learning, and attention. However, it has been reported that HIV patients with dementia had substantially lower DAT availability in ventral striatum and putamen [89]. The DAT expression and function is also altered by HIV proteins in animals. HIV-1 Tat induces inhibition of the transporter by an allosteric binding to DAT [90]. DAT function and expression is modified in the HIV-1-tg rats [91]. HIV-1 gp120 was similarly described to cause a loss of dopamine-secreting neurons in rats [92–94]. HIV-1 Nef is another viral protein disturbing the dopamine functions, reducing striatal dopamine levels in HIV-1 mice. The animal will consequently develop mania-like

HIV+ subjects present a diminished motor performance at multitasking and a decreased velocity compared to the control group. This may affect the daily life and require more attention to

behaviors and present a reduced content of dopamine and DAT [95].

Epigenetic alterations are one of the hallmarks of aging. As epigenetic changes accumulate upon aging, DNA methylation can be a precise predictor of chronological age [113, 114], since certain CpG sites are highly associated with age [115].

A first large-scale epigenome-wide association study in 2016 analyzed DNA methylation during HIV infection [116] and found a differential DNA methylation associated with the infection. HIV-1, as other viruses, can alter the expression of DNA methyltransferases (DNMTs), like DNMT1 [117, 118] and DNMT3b [119], affecting maintenance and de novo DNA methylation maintenance. The alteration of methylation could be an epigenetic outcome of the integration of HIV-1 DNA into the host genome and could decrease genome stability. These studies were made in blood, and because of the presence of the blood-brain barrier, it was necessary to analyze methylation directly in the brain tissue.

A 2015 study uses blood and brain tissue to find a relationship between HIV status and epigenetic age acceleration [120]. It eliminates different hypothesis explaining age acceleration effects in the brain tissue. It concluded that the telomere length is not involved and finds difficult to explain the age acceleration in the brain by the increase in the amount of senescent or exhausted T-cells like it is working in the blood, because of the blood-brain barrier. The retained hypothesis is an effect of the age acceleration, and independently the T-cells exhaust, confounding the relationship between these two events. In 2016, a comparative DNA methylation profiling on monocytes derived from HIV-infected individuals, with or without impairment, identifies a specific immunoepigenetic signature of cognitive impairment [121]. A total of 1032 loci differentially methylated are associated with cognitive impairment, with loci connected to gene networks in the central nervous system and preferentially located in intergenic regions of the gene and over gene bodies. A more recent analysis was made on DNA from the occipital cortex of 58 HIV+ subjects that were followed for neurocognitive evaluation within 1 year of death [122]. It is the first study to associate HAND status with the epigenetic age of frontal cortex tissue, with an average relative acceleration of 3.5 years. This accelerated epigenetic aging was not the consequence of CD4+ cell count or viral load, the activity of HAART on the CNS, or comorbidities. Interestingly, the entire HAND group presented accelerated aging in the brain tissue, but that was not correlated with HAND gravity or neurocognitive performance. This accelerated aging seems linked to the duration of the infection and suggests that a low level but chronic HIV replication in brain reservoirs maintains pathological processes.

gp120 [137]. HIV-1 Vpr is also able to activate the expression of cytokines, ROS, and inflammatory proteins in uninfected and infected cells. Vpr will elicit a slow but persistent elevation of Ca2+ leading to glutamate signaling impairment in neuronal cells. Moreover, the calcium

Brain Aging in HIV-1 Infection

11

http://dx.doi.org/10.5772/intechopen.77029

The neuroinflammation is present even in the absence of productive infection and may have a different cause, like an undetectable level of virus production, the effects of combination antiretroviral therapy (cART) itself, and/or a chronic and systemic immune action. Together, these factors contribute to HIV-1 neurodegeneration. The stimulated microglia will synthesize neurotoxic molecules, inflammatory mediators like cytokines/chemokines, and provoke glutamate receptor-mediated excitotoxicity, disrupt intracellular calcium concentration and ion channel expression, and mechanisms controlling cAMP levels. Viral latency and residual inflammation are codependent mechanisms promoting each other [140]. The peripheral immune activation and production of peripheral cytokines increase inflammation within the

In the HIV-infected brain, the microglia will produce NF-kappa B, triggering the secretion of the pro-inflammatory cytokine TNFα which stimulates NF-kappa B signaling in neurons of the medial basal hypothalamus in a feed-forward loop. IKKβ/NF-κB inhibits GnRH and activates aging-related hypothalamic GnRH degeneration. The inhibition of IKKβ/NF-κB activation or GnRH treatment can reverse the aging effects of HIV-1 and increase the lifespan [149]. This feedback loop has been linked to the hypothalamic programming of systemic aging [149]. In primary astrocytes, HIV stimulates C3 expression indirectly, via NF-κB-dependent

A senescence-associated secretory phenotype (SASP), a central aspect of cellular senescence, is activated when the certain chemokines/cytokines, especially IL-6, IL-8, and IL-1 α, are secreted. These interleukins play a major role in brain aging [151–153]. HIV-1 infection is quickly followed by the inflammasome activation, allowing the release of IL-6, IL-8, IL-18,

The development of highly active antiretroviral therapy (HAART) has changed the neurodegeneration pattern and prevented the major cognitive impairments of AIDS, increasing

To be effective in the brain, combination antiretroviral therapy (cART) has to cross the blood–brain barrier and be metabolized. However, if these drugs made it possible to alleviate cognitive impairment, they can contribute to it and damage nerve cells. Indeed, long-term cART can generate toxic effects and contribute to HAND. The efavirenz (EFV) metabolites 7-hydroxyefavirenz (7-OH-EFV) and especially 8-hydroxyefavirenz (8-OH-EFV) can provoke damage to dendritic spines. Furthermore, the 8-OH-EFV metabolite can trigger calcium flux in neurons, mainly mediated by L-type voltage-operated calcium channels (VOCCs), and acts as a potent neurotoxin [156]. The mitochondrial respiratory capacity (SRC) is reduced by maraviroc, raltegravir, lopinavir, darunavir, zidovudine, emtricitabine, abacavir, nevirapine,

IFN-γ, IL-1β, IL-2Rα, IL-3, IL-6, TNFα, IL-1Rα, IL-10, IL-1α, and TNFβ [154, 155].

homeostasis is disturbed by Vpr via down-regulation of endogenous PMCA [136].

CNS and have been associated with lower cognitive performance [141–148].

induction of IL-6, which will activate the C3 promoter [150].

**4.5. Influence of cART on neurotoxicity**

survival times.

**4.4. Inflammation links aging to the brain**

#### **4.2. microRNA**

The genome-wide expression analysis of miRNA in aging brains showed a unique expression profile which emphasizes how crucial their role is in the neurodegeneration and the aging process [123].

MiR-34a has been linked to the regulation of several proteins including sirtuin 1 (SIRT1) [124]. SIRT1 is an enzyme implicated in the deacetylation of proteins involved in cell stress, longevity, and glucose metabolism [125]. Mir-34a up-regulation, the reciprocal decline of its target SIRT1, is the biomarker for aging in the brain and a good predictor of deterioration of the brain function. The miR-34a expression is significantly increased in HIV-infected vascular endothelial cells (ECs) [126] as well as in primary neuronal cultures and neuronal cell lines [127]. MiR-146a was also up-regulated in these cells. HIV-1 vpr has the same ability to strongly overexpress miR-34a and miR-146a in neuronal cells and to down-regulate miR-106a [128]. The up-regulation of miR-34a and miR146a [129] and the down-regulation of miR-106a [130] are described to be associated with aging. The increase of miR-34a can cause abnormal mitochondrial dynamics and dysfunctional autophagy [131].

#### **4.3. HIV-1 disrupts the calcium signaling in the brain**

Changes in calcium signaling are major factors leading to aging, as many vital functions of the brain depend on precise calcium homeostasis [132]. Khachaturian presented in 1994 his hypothesis of aging [133] to try to elucidate the neurophysiological mechanisms of Ca2+ signaling that they are associated with aging and neurodegeneration.

HIV-1 disturbs the functional expression and activity of voltage-gated calcium channel (VGCCs) (changes in evoked Ca2+ spikes and L-channel expression) in the mPFC in an agedependent way and implies that ion-channel dysfunction associated with HIV-induced medial PreFrontal Cortex (mPFC) hyper-excitability progresses with age/HIV duration [134].

HIV-infected individuals, especially as they age, are subject to neuronal Ca2+ dysregulation and neurotoxicity elicited by the HIV-1 proteins gp120, Tat, and Vpr [135–137]. Tat protein increases neuronal Ca2+ levels via IP3R and NMDAR and L-type Ca2+ channels, followed by mitochondrial Ca2+ uptake and ROS production, leading to caspase activation and neuronal apoptosis [137–139]. In microglia and astrocytes, Tat and gp120 can interact and trigger the production of cytokines, nitric oxide, and excitotoxins which can intensify the neurotoxic effects of Tat and gp120 [137]. HIV-1 Vpr is also able to activate the expression of cytokines, ROS, and inflammatory proteins in uninfected and infected cells. Vpr will elicit a slow but persistent elevation of Ca2+ leading to glutamate signaling impairment in neuronal cells. Moreover, the calcium homeostasis is disturbed by Vpr via down-regulation of endogenous PMCA [136].

#### **4.4. Inflammation links aging to the brain**

loci connected to gene networks in the central nervous system and preferentially located in intergenic regions of the gene and over gene bodies. A more recent analysis was made on DNA from the occipital cortex of 58 HIV+ subjects that were followed for neurocognitive evaluation within 1 year of death [122]. It is the first study to associate HAND status with the epigenetic age of frontal cortex tissue, with an average relative acceleration of 3.5 years. This accelerated epigenetic aging was not the consequence of CD4+ cell count or viral load, the activity of HAART on the CNS, or comorbidities. Interestingly, the entire HAND group presented accelerated aging in the brain tissue, but that was not correlated with HAND gravity or neurocognitive performance. This accelerated aging seems linked to the duration of the infection and suggests that a low level but chronic HIV replication in brain reservoirs

The genome-wide expression analysis of miRNA in aging brains showed a unique expression profile which emphasizes how crucial their role is in the neurodegeneration and the aging

MiR-34a has been linked to the regulation of several proteins including sirtuin 1 (SIRT1) [124]. SIRT1 is an enzyme implicated in the deacetylation of proteins involved in cell stress, longevity, and glucose metabolism [125]. Mir-34a up-regulation, the reciprocal decline of its target SIRT1, is the biomarker for aging in the brain and a good predictor of deterioration of the brain function. The miR-34a expression is significantly increased in HIV-infected vascular endothelial cells (ECs) [126] as well as in primary neuronal cultures and neuronal cell lines [127]. MiR-146a was also up-regulated in these cells. HIV-1 vpr has the same ability to strongly overexpress miR-34a and miR-146a in neuronal cells and to down-regulate miR-106a [128]. The up-regulation of miR-34a and miR146a [129] and the down-regulation of miR-106a [130] are described to be associated with aging. The increase of miR-34a can cause abnormal

Changes in calcium signaling are major factors leading to aging, as many vital functions of the brain depend on precise calcium homeostasis [132]. Khachaturian presented in 1994 his hypothesis of aging [133] to try to elucidate the neurophysiological mechanisms of Ca2+ sig-

HIV-1 disturbs the functional expression and activity of voltage-gated calcium channel (VGCCs) (changes in evoked Ca2+ spikes and L-channel expression) in the mPFC in an agedependent way and implies that ion-channel dysfunction associated with HIV-induced medial PreFrontal Cortex (mPFC) hyper-excitability progresses with age/HIV duration [134]. HIV-infected individuals, especially as they age, are subject to neuronal Ca2+ dysregulation and neurotoxicity elicited by the HIV-1 proteins gp120, Tat, and Vpr [135–137]. Tat protein increases neuronal Ca2+ levels via IP3R and NMDAR and L-type Ca2+ channels, followed by mitochondrial Ca2+ uptake and ROS production, leading to caspase activation and neuronal apoptosis [137–139]. In microglia and astrocytes, Tat and gp120 can interact and trigger the production of cytokines, nitric oxide, and excitotoxins which can intensify the neurotoxic effects of Tat and

mitochondrial dynamics and dysfunctional autophagy [131].

naling that they are associated with aging and neurodegeneration.

**4.3. HIV-1 disrupts the calcium signaling in the brain**

maintains pathological processes.

**4.2. microRNA**

10 Advances in HIV and AIDS Control

process [123].

The neuroinflammation is present even in the absence of productive infection and may have a different cause, like an undetectable level of virus production, the effects of combination antiretroviral therapy (cART) itself, and/or a chronic and systemic immune action. Together, these factors contribute to HIV-1 neurodegeneration. The stimulated microglia will synthesize neurotoxic molecules, inflammatory mediators like cytokines/chemokines, and provoke glutamate receptor-mediated excitotoxicity, disrupt intracellular calcium concentration and ion channel expression, and mechanisms controlling cAMP levels. Viral latency and residual inflammation are codependent mechanisms promoting each other [140]. The peripheral immune activation and production of peripheral cytokines increase inflammation within the CNS and have been associated with lower cognitive performance [141–148].

In the HIV-infected brain, the microglia will produce NF-kappa B, triggering the secretion of the pro-inflammatory cytokine TNFα which stimulates NF-kappa B signaling in neurons of the medial basal hypothalamus in a feed-forward loop. IKKβ/NF-κB inhibits GnRH and activates aging-related hypothalamic GnRH degeneration. The inhibition of IKKβ/NF-κB activation or GnRH treatment can reverse the aging effects of HIV-1 and increase the lifespan [149]. This feedback loop has been linked to the hypothalamic programming of systemic aging [149]. In primary astrocytes, HIV stimulates C3 expression indirectly, via NF-κB-dependent induction of IL-6, which will activate the C3 promoter [150].

A senescence-associated secretory phenotype (SASP), a central aspect of cellular senescence, is activated when the certain chemokines/cytokines, especially IL-6, IL-8, and IL-1 α, are secreted. These interleukins play a major role in brain aging [151–153]. HIV-1 infection is quickly followed by the inflammasome activation, allowing the release of IL-6, IL-8, IL-18, IFN-γ, IL-1β, IL-2Rα, IL-3, IL-6, TNFα, IL-1Rα, IL-10, IL-1α, and TNFβ [154, 155].

#### **4.5. Influence of cART on neurotoxicity**

The development of highly active antiretroviral therapy (HAART) has changed the neurodegeneration pattern and prevented the major cognitive impairments of AIDS, increasing survival times.

To be effective in the brain, combination antiretroviral therapy (cART) has to cross the blood–brain barrier and be metabolized. However, if these drugs made it possible to alleviate cognitive impairment, they can contribute to it and damage nerve cells. Indeed, long-term cART can generate toxic effects and contribute to HAND. The efavirenz (EFV) metabolites 7-hydroxyefavirenz (7-OH-EFV) and especially 8-hydroxyefavirenz (8-OH-EFV) can provoke damage to dendritic spines. Furthermore, the 8-OH-EFV metabolite can trigger calcium flux in neurons, mainly mediated by L-type voltage-operated calcium channels (VOCCs), and acts as a potent neurotoxin [156]. The mitochondrial respiratory capacity (SRC) is reduced by maraviroc, raltegravir, lopinavir, darunavir, zidovudine, emtricitabine, abacavir, nevirapine, and efavirenz but not by indinavir. Efavirenz and maraviroc provoke a reduction of ATP at the synapse that may contribute to its dysfunction [157, 158]. Additionally, the non-nucleoside reverse transcriptase inhibitor efavirenz can decrease neural stem cell proliferation [159]. Non-nucleoside reverse transcriptase inhibitors (NRTIs) are key players in HAART-induced mitochondrial toxicity due to their capacity to inhibit the DNA polymerase in charge of the synthesis of mitochondrial DNA, Pol-γ [160–162]. Some brains under HAART present neuroinflammation combined with mononuclear phagocyte activation, notably in the hippocampus, and can reach the level seen in AIDS and HIVE pre-HAART [163].

The HIV-1 infection initiates changes in mitochondrial electron transport chain (ETC), mitochondrial trafficking proteins, glycolytic pathways, and proteins implicated in several energy pathways. 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

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13

http://dx.doi.org/10.5772/intechopen.77029

During HAND, mitochondrial fission/fusion mechanism is dysregulated. The mitochondrial fission protein (dynamin 1-like, DNM1L) is decreased in frontal cortex tissues of HAND patients, and the soma of damaged neurons presents elongated and enlarged mitochondria. The GFAP-gp120 mice present the same phenotype, and gp120 also decreases the DNML1 levels. The mitochondrial fusion seems to be the predominant mitochondrial dynamic in the brains of HAND patients [179]. HIV-1 Tat provokes a massive diminution in the mitochondrial membrane potential, a mechanism closely linked to fusion and fission. It is probably the consequence of the quick increase Tat caused on the intracellular Ca2+, whether via the NMDA receptor or L-type calcium channels. The levels of mitochondrial fission protein Drp1 are consequently increased and the mitochondrial morphology is altered by Tat. Unbalanced mitochondrial fission and fusion are responsible for several neurodegenerative disorders [180]. HIV-1 Vpr promotes the formation of permeability transition pores in mitochondria, which disturbs the transmembrane potential and the ATP synthesis. This process permeabilizes the mitochondria and allows the release of cytochrome *c* via a cascade of caspase and leads to apoptosis [181]. Moreover, Vpr decreases rapidly the mitochondrial membrane potential [182], which provokes the formation of the permeability transition pore complex (PTPC) [183], composed by the adenine nucleotide translocator (ANT) on the inner mitochondrial membrane and the voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane. This creation of mitochondrial conductance channels will allow the release of apoptosis-inducing factor cytochrome *c* into the cytoplasm, as described in striatal and cortical neurons of rats [184]. Following HIV-1 Vpr treatment, the intracellular glutathione is reduced, maybe the result of decreased ATP availability when Vpr binds to the ANT on the inner mitochondrial membrane

are usually observed when there is cellular damage leading to ROS production [178].

[185]. HIV-1 Vpr is also described to impair the mitochondria axonal transport [186].

linked pathologies and lengthen the lifespan [188–190].

Defects in autophagy can lead to several neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS) for the most common [187]. Without autophagic cleaning, protein aggregates will accumulate and become toxic to the cells. Aging is slowing down the efficiency of cell autophagy (macroautophagy and chaperone-mediated autophagy) either by diminishing the autophagic flux or by too much cargo accumulation from chronic cell injury [187]. Some interventions intend to increase the autophagy levels like caloric restriction or autophagy-inducing drugs can attenuate age-

The activation of autophagy is beneficial for the virus during the initial phase of HIV-1 infection in many cell types [191]. However, the autophagy inhibition is necessary for virus replication in later phases of infection, stimulating the biogenesis of exosomes enclosing viral products [192]. In HIV-1 dementia, the neurodegeneration seems to be associated with the

**4.8. Autophagy**

#### **4.6. Anti-oxidant defense**

Oxidative phosphorylation is a highly efficient way of generating energy to produce adenosine triphosphate (ATP). Oxygen is a key player in this metabolic pathway in mitochondria to break down the glucose. Reactive oxygen species (ROS), hydroxyl radical (OH<sup>−</sup> ), hydrogen peroxide (H<sup>2</sup> O2 ), and superoxide (O<sup>2</sup> − ) are usually produced at low levels. If the balance between antioxidants and pro-oxidant is disturbed, oxidative damage can occur, followed by mitochondrial dysfunction and accumulation of cytotoxins leading to cell death. The brain is rich in fatty acids, which make neurons highly sensitive to oxidative alteration and peroxidation [164], in particular because it has fewer antioxidants than other tissue and higher iron levels. Under oxidation, the membrane lipids can undergo lipid peroxidation producing malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). The endogenous brain defense against oxidative stress is composed of glutathione peroxidase (GPx1), superoxide dismutases (SOD), catalase, and glutathione (γ-l-glutamyl-l-cysteinylglycine, GSH) [165].

In HAND, oxidative stress increased levels of oxidized proteins and lipid peroxidation products, at the same time than a deficit in GSH and GPx1 [166–169]. The lipid peroxidation induced by HIV-1 affects the specific region of the brain [170] and is correlated with the gravity of HAND [171]. Several viral proteins are involved in this mechanism. Tat is inducing the reactive oxygen species (ROS) superoxide (O<sup>2</sup> − ) and hydrogen peroxide (H<sup>2</sup> O2 ), increasing at the same time the levels of lipid peroxidation. It is able also to induce nitric oxide synthase (iNOS) to generate nitric oxide (NO), which when combined with superoxide (O<sup>2</sup> − ) will form the peroxynitrite (ONOO) [172]. Gp120 triggers the release of arachidonic acid in glial cells [173], from the lipoxygenase and cyclooxygenase pathways [173]. Gp41 can provoke neuronal cell death by a mechanism involving NO formation, iNOS, and a deficit in glutathione, which will subsequently disrupt the mitochondrial function [174, 175]. Vpr induces the production of ROS after a reduction in the total GSH/GSSG ratio and an increase in the level of oxidized glutathione (GSSG) [176].

#### **4.7. Mitochondria**

In the mitochondrial theory of aging (or free-radical theory of aging), the reactive oxygen species, which are the products of respiration, damage the membranes, mitochondrial DNA (mtDNA), and proteins, causing an accumulation of cellular and molecular injuries subsequently responsible for aging. It creates a "vicious cycle" when the mtDNA damage increases ROS production, which will damage even more the mtDNA [177].

The HIV-1 infection initiates changes in mitochondrial electron transport chain (ETC), mitochondrial trafficking proteins, glycolytic pathways, and proteins implicated in several energy pathways. 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].

During HAND, mitochondrial fission/fusion mechanism is dysregulated. The mitochondrial fission protein (dynamin 1-like, DNM1L) is decreased in frontal cortex tissues of HAND patients, and the soma of damaged neurons presents elongated and enlarged mitochondria. The GFAP-gp120 mice present the same phenotype, and gp120 also decreases the DNML1 levels. The mitochondrial fusion seems to be the predominant mitochondrial dynamic in the brains of HAND patients [179]. HIV-1 Tat provokes a massive diminution in the mitochondrial membrane potential, a mechanism closely linked to fusion and fission. It is probably the consequence of the quick increase Tat caused on the intracellular Ca2+, whether via the NMDA receptor or L-type calcium channels. The levels of mitochondrial fission protein Drp1 are consequently increased and the mitochondrial morphology is altered by Tat. Unbalanced mitochondrial fission and fusion are responsible for several neurodegenerative disorders [180]. HIV-1 Vpr promotes the formation of permeability transition pores in mitochondria, which disturbs the transmembrane potential and the ATP synthesis. This process permeabilizes the mitochondria and allows the release of cytochrome *c* via a cascade of caspase and leads to apoptosis [181]. Moreover, Vpr decreases rapidly the mitochondrial membrane potential [182], which provokes the formation of the permeability transition pore complex (PTPC) [183], composed by the adenine nucleotide translocator (ANT) on the inner mitochondrial membrane and the voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane. This creation of mitochondrial conductance channels will allow the release of apoptosis-inducing factor cytochrome *c* into the cytoplasm, as described in striatal and cortical neurons of rats [184]. Following HIV-1 Vpr treatment, the intracellular glutathione is reduced, maybe the result of decreased ATP availability when Vpr binds to the ANT on the inner mitochondrial membrane [185]. HIV-1 Vpr is also described to impair the mitochondria axonal transport [186].

#### **4.8. Autophagy**

and efavirenz but not by indinavir. Efavirenz and maraviroc provoke a reduction of ATP at the synapse that may contribute to its dysfunction [157, 158]. Additionally, the non-nucleoside reverse transcriptase inhibitor efavirenz can decrease neural stem cell proliferation [159]. Non-nucleoside reverse transcriptase inhibitors (NRTIs) are key players in HAART-induced mitochondrial toxicity due to their capacity to inhibit the DNA polymerase in charge of the synthesis of mitochondrial DNA, Pol-γ [160–162]. Some brains under HAART present neuroinflammation combined with mononuclear phagocyte activation, notably in the hippocam-

Oxidative phosphorylation is a highly efficient way of generating energy to produce adenosine triphosphate (ATP). Oxygen is a key player in this metabolic pathway in mitochondria

between antioxidants and pro-oxidant is disturbed, oxidative damage can occur, followed by mitochondrial dysfunction and accumulation of cytotoxins leading to cell death. The brain is rich in fatty acids, which make neurons highly sensitive to oxidative alteration and peroxidation [164], in particular because it has fewer antioxidants than other tissue and higher iron levels. Under oxidation, the membrane lipids can undergo lipid peroxidation producing malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). The endogenous brain defense against oxidative stress is composed of glutathione peroxidase (GPx1), superoxide dismutases

In HAND, oxidative stress increased levels of oxidized proteins and lipid peroxidation products, at the same time than a deficit in GSH and GPx1 [166–169]. The lipid peroxidation induced by HIV-1 affects the specific region of the brain [170] and is correlated with the gravity of HAND [171]. Several viral proteins are involved in this mechanism. Tat is inducing the

−

the same time the levels of lipid peroxidation. It is able also to induce nitric oxide synthase

the peroxynitrite (ONOO) [172]. Gp120 triggers the release of arachidonic acid in glial cells [173], from the lipoxygenase and cyclooxygenase pathways [173]. Gp41 can provoke neuronal cell death by a mechanism involving NO formation, iNOS, and a deficit in glutathione, which will subsequently disrupt the mitochondrial function [174, 175]. Vpr induces the production of ROS after a reduction in the total GSH/GSSG ratio and an increase in the level of oxidized

In the mitochondrial theory of aging (or free-radical theory of aging), the reactive oxygen species, which are the products of respiration, damage the membranes, mitochondrial DNA (mtDNA), and proteins, causing an accumulation of cellular and molecular injuries subsequently responsible for aging. It creates a "vicious cycle" when the mtDNA damage increases

ROS production, which will damage even more the mtDNA [177].

(iNOS) to generate nitric oxide (NO), which when combined with superoxide (O<sup>2</sup>

), hydro-

) are usually produced at low levels. If the balance

) and hydrogen peroxide (H<sup>2</sup>

O2

), increasing at

) will form

−

to break down the glucose. Reactive oxygen species (ROS), hydroxyl radical (OH<sup>−</sup>

−

(SOD), catalase, and glutathione (γ-l-glutamyl-l-cysteinylglycine, GSH) [165].

pus, and can reach the level seen in AIDS and HIVE pre-HAART [163].

), and superoxide (O<sup>2</sup>

**4.6. Anti-oxidant defense**

12 Advances in HIV and AIDS Control

O2

reactive oxygen species (ROS) superoxide (O<sup>2</sup>

glutathione (GSSG) [176].

**4.7. Mitochondria**

gen peroxide (H<sup>2</sup>

Defects in autophagy can lead to several neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS) for the most common [187]. Without autophagic cleaning, protein aggregates will accumulate and become toxic to the cells. Aging is slowing down the efficiency of cell autophagy (macroautophagy and chaperone-mediated autophagy) either by diminishing the autophagic flux or by too much cargo accumulation from chronic cell injury [187]. Some interventions intend to increase the autophagy levels like caloric restriction or autophagy-inducing drugs can attenuate agelinked pathologies and lengthen the lifespan [188–190].

The activation of autophagy is beneficial for the virus during the initial phase of HIV-1 infection in many cell types [191]. However, the autophagy inhibition is necessary for virus replication in later phases of infection, stimulating the biogenesis of exosomes enclosing viral products [192]. In HIV-1 dementia, the neurodegeneration seems to be associated with the inhibition of neuronal autophagy, a decrease in autophagy-inducing protein, and an increase in sequestosome-1/p62 [193]. Autophagy genes like *SQSTM1*, *ATG5*, and *LAMP1* appear to be differentially regulated at the transcriptional, translational, and post-translational levels by HIV-1 in the brain at a different stage of the disease [194]. Basal autophagy is inhibited by the HIV-1 infection in CD4+, monocyte/macrophage lineage [195], as well as in neurons and astrocytes and leads to neuro-glial toxicity [196].

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Neurovirology. 2016;**22**:201-212

based morphometry. NeuroImage. 2007;**34**:44-60

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Nef binds BECN1 and inhibits the proteolytic stages of autophagy in HIV-infected macrophages [197, 198]. In astrocytes, Nef is also blocking the fusion of autophagosome to lysosome to escape the viral degradation, increasing LC3II and p62/SQSTM1 levels. It is interesting to note that LC3 and Gag interact and that basal autophagy promotes optimal Gag processing and yields of HIV in macrophages [195]. Gag processing is increased when autophagy is induced, manipulating the autophagy process to maximize the viral replication in infected macrophages. The Gag protein is the main target of autophagy, but HIV-1 has taken advantage of Gag targeting for its replication, especially in macrophages. HIV-1 Tat is targeted for degradation via an ubiquitin-independent pathway, as an anti-HIV effect, interacting with p62/SQSTM1 in CD4+ T lymphocytes. However, Tat can counteract this degradation by decreasing the quantity of the autophagy markers LC3II andp62/SQSTM1 coupled with the membrane in neurons [199]. Moreover, Tat can bind to the lysosomal-associated membrane protein 2A (LAMP2A) to regulate the fusion of autophagosomes with lysosomes. Through this interaction with LAMP2, Tat may allow abnormal autophagolysosome formation, leading to neurodegeneration [199]. Gp120 on the opposite is inducing autophagy in neuronal cells [200], probably as a protective mechanism from the toxic effects of gp120 [201].
