Interestingly, HIV infectious virions and viral proteins have been detected in astrocytes, despite these cells lacking CD4 receptors and CCR5 (32). Astrocytes can internalize HIV through endocytosis and maintain viral latency by suppressing viral replication (33–35). Although HIV cannot replicate, it can interact with astrocytes, leading to the production and release of viral proteins such as Tat, Nef and Rev, contributing to inflammation and nerve damage (36). Inflammation in the nervous system can disrupt the energy metabolism of astrocytes (37). Given that astrocytes provide vital energy support to neurons, any disturbance in their energy metabolism can lead to neuronal energy metabolism disorders (38–40). In addition, inflammation can stimulate the proliferation and differentiation of astrocytes, resulting in the formation of glial scars, which impede axon regeneration and cell migration and directly affect neuronal growth (41, 42). More importantly, as a significant component of BBB, astrocytes may influence the function and structure of the BBB when affected by HIV (43).

Microglia, a component of the innate immune system, are often referred to as the “macrophages” of the CNS (44). Excessive activation of microglia can contribute to the development of various neurological disorders, including Alzheimer's disease (45), Parkinson's disease (46) and HIV-associated neurocognitive disorder (HAND) (47). Microglia more susceptible to HIV infection due to CCR5 is expressed on the cell surface (48). Prolonged microglia activation can increase inflammatory chemokines and cytokines, adversely affecting astrocytes and neurons and increasing neurotoxic substances that induce neuronal apoptosis, ultimately contributing to the development of HAND (49, 50).

Oligodendrocytes, which form the myelin sheath of the axon of the brain, do not touch the axon directly but repeatedly wrap the extension of axons and then gather the myelin sheath of multiple helical structures (51). The formation of the myelin sheath increases the speed and energy efficiency of nerve conduction by facilitating the jump in signal transmission (52), which is essential for cognitive functions (53). The involvement of HIV infection in oligodendrocytes, which specifically express the CXCR4 receptor, remains a topic of debate (54). However, research conducted by Zou et al. indicates that damage to oligodendrocytes is caused by the release of the Tat protein by HIV, resulting in the inhibition of cell growth, developmental retardation, and even cell death (55). In addition to Tat, the gp120 protein has been implicated in oligodendrocyte injury, as it inhibits myelination, induces dysfunction and triggers apoptosis of oligodendrocytes (56, 57).

Neurons are the fundamental functional units of the nervous system and are considered non-regenerative cells (58). The ability of HIV to infect neurons is still a matter of debate. Previous studies have shown that adult neurons express CXCR4, CCR5 and CCR3 on their surface and that CD4 receptors may also be present in certain neurons located in the cerebellum, thalamus, pons and hippocampus (59–61). Nath et al. proposed that proteins such as Tat and gp120 can disrupt the Ca²⁺ homeostasis of neurons and normal neuronal functions, leading to neuronal dysfunction, injury and death (62). Exposure of neurons to Tat and gp120 has been shown to increase the levels of glutamate (Glu) and the expression of N-methyl-D-aspartic acid (NMDA) receptors (63, 64). Furthermore, gp120 can enhance the inhibitory function of neurons by increasing the expression of gamma-aminobutyric acid (GABA) type A receptors (65).

In the early stages of HAND, patients may experience mild difficulties with concentration, motor symptoms, and focal cortical deficits such as apraxia, agnosia, or aphasia (92), although there is no significant observable loss of neurons or other substantial pathological changes detected in HIV patients during this stage (93). In addition, although neuroimaging studies also do not typically reveal significant lesions or structural changes, alterations in certain metabolites have been observed Figure 2 (94). The metabolism of the nervous system is a complex physiological process involving the production of sufficient ATP for energy and the synthesis of neurotransmitters essential for maintaining normal physiological brain functions (95). Upon entering the nervous system, glucose in the blood undergoes a series of enzymatic reactions catalyzed by key enzymes like hexokinase, 1,6-diphosphofructokinase-1 and pyruvate kinase, which can convert glucose into pyruvic acid (Pyr), and subsequently, the tricarboxylic acid cycle generates ATP, providing energy for neuronal functions (96). Neuron-astrocyte interaction is another important mechanism for energy supply in the brain (39, 97). Glucose in astrocytes is converted into glycogen under the influence of glycogen synthase (GYS), which is then gradually broken down into pyruvate (98). Some of these pyruvates are converted into lactate by the enzyme lactate dehydrogenase 5 (LDH5), which is then transported to neurons and converted back into pyruvate by lactate dehydrogenase 1 (LDH1), entering the tricarboxylic acid cycle pathway (99). During this cycle, α-ketoglutaric acid in neurons can react with NH3 to form Glu (100, 101), which can be further converted into gamma-aminobutyric acid (GABA) through the catalytic action of glutamic acid decarboxylase (GAD) (102, 103).

Rottenberg D et al. observed glucose hypermetabolism in the thalamus and basal ganglia, along with hypometabolism in the cortex and subcortical gray matter during the early stages of HIV-associated HAND (104). Zeping Wang et al. found that after receiving ART, glucose metabolism in the frontal cortex of HIV-infected individuals was enhanced, suggesting that the damage to the frontal cortex at this stage is potentially reversible (105). After HIV infection, the level of ATP in the brain is decreased, and the level of ATP in the peripheral blood is increased (106, 107). Tat, an HIV protein, has been implicated in increasing Glu levels and decreasing GABA levels in the brain (108), which may be related to the inhibition of GAD by HIV (109). In the early stages of HIV infection, increased levels of Glu in the brain can contribute to excitatory neurotoxicity, leading to clinical symptoms such as reduced attention (110, 111). As the disease progresses, individuals with HIV and cognitive deficits tend to have lower Glu levels in the parietal gray matter, indicating that decreased Glu levels may contribute to cognitive impairment (112). In addition to HAND, HIV-associated epilepsy is also a significant challenge, with reported incidence rates ranging from 6.1% to 83.75% (113, 114). Although the underlying mechanisms of HIV-related epilepsy are not yet fully understood, it is believed to involve an imbalance of Glu and GABA (108, 115).

As the disease advances, HIV patients often experience worsening motor dysfunction and cognitive impairments, which become increasingly noticeable and drastically hinder their daily activities. Completing complex tasks often takes them longer, and they may sometimes become unable to accomplish them adequately. Specific motor dysfunctions may include slower, less precise movements, clumsiness, an unstable gait, and a loss of balance (86). Simioni et al. discovered that these patients exhibited significant signs of frontal lobe release, cramps and hyper-reflexes, particularly in the legs (86). At this stage, neuroimaging studies have identified white matter signal abnormalities as the most prevalent (116, 117). White matter (WM) consists of the aggregation of nerve fibers in the central nervous system, predominantly composed of axons and oligodendrocytes of neurons, making it a vital component of the neural network (118). The release of Tat protein and gp120 by HIV can result in the injury and apoptosis of oligodendrocytes (55–57). Consequently, the damage and apoptosis of oligodendrocytes impair the formation of effective myelin sheaths, leading to reduced nerve conduction efficiency and cognitive dysfunction in the brain (52, 53). HIV can also have an impact on the axons of neurons, leading to abnormal neural network connections (119). In advanced cases of HAND with severe cognitive dysfunction and motor symptoms, there may be a connection to white matter injury, whereby white matter injury can disrupt the limbic circuit and damage cortico-cortical connections, thereby affecting intelligence and cognitive function (120). The integrity of nerve fiber connections in various regions such as the corpus callosum, cingulate gyrus, anterior limb of the internal capsule, cerebral foot, anterior crown, and frontal-occipital lobe tract is closely related to balance and gait function (121). HIV-induced damage to the brain's white matter can interfere with nerve fiber connections, leading to abnormal gait in patients with HAND (121). Falls have been associated with injuries to the total white matter, periventricular white matter, and deep white matter (122). Blahak et al. suggested that white matter injury can disrupt the prefrontal subcortical motor circuit, resulting in impaired balance and an increased risk of falls (123). In addition to white matter injury, advanced HAND patients may exhibit decreased subcortical volume, caudate nucleus volume, cerebral malacia foci, and brain atrophy (66, 124, 125). HIV can also contribute to other acute central nervous system diseases, such as stroke. Bertrand et al. revealed a higher incidence of stroke in HIV patients compared to the same age group (126). While men generally have a higher risk of cerebrovascular disease, HIV-infected women aged 25–29 years have a relatively higher risk of ischemic stroke (127), possibly due to HIV-related changes in the production of female endogenous sex hormones, including estrogen deficiency (127, 128). In addition, epigenetics may be involved in brain structural damage.

Epigenetic mechanisms play an important role during the infection with retroviruses, including HIV which mediate the integration of the virus into the host genom (129). The change of epigenetic may be related to regional alterations of brain volumes, cortical thickness, cortical surface areas and neuronal microstructure (130). Persistence of latent HIV infection in the CNS was associated with increased levels of chromatin modifiers, which might result in abnormal transcriptomes, leading to inflammation, neurodegeneration, and neurocognitive impairment (131). Paula Desplats et.al detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Moreover, Genome-wide profiling of DNA methylation showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation (132). Long-term HIV-Tat expression led to poorer short-and long-term memory, lower locomotor activity and impaired coordination and balance ability, increased astrocyte activation and compromised neuronal integrity, and decreased global genomic DNA methylation (133). N-terminal acetylation changes induced by viral infection might play a critical role in virus-host interactions in HIV infection (134). The epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions Figure 3.

The prefrontal cortex (PFC) can be divided into two regions based on functional, morphological, and evolutionary differences: the lateral PFC (LPFC) and the medial PFC (MPFC) (162). The ventral portion of medial prefrontal cortex (vMPFC), a portion of the MPFC, plays a crucial role in regulating the CS (163). Upon stimulation, the vMPFC activates the sympathetic nerve, increasing mean arterial pressure (MAP) (164). Notably, it has been reported that lower CD4 levels in HIV patients are associated with greater connectivity between the right vMPFC and right posterior insula and longer QT interval (165).

The insula is involved in various physiological functions, including visceral sensation and visceral movement (166–168). The posterior insula receives and integrates signals related to visceral sensations, which are then projected to the anterior insula (169). After receiving visceral sensory signals from the posterior insular lobe, the anterior insular lobe sends out visceral movement signals, regulating visceral movement, including the CS (170). In HIV-infected individuals, damage to the gray matter of the right insular lobe can result in parasympathetic inhibition and sympathetic excitation, leading to increased heart rate and blood pressure (125, 171, 172). Overstimulation of the posterior insula can contribute to the development of conditions such as atrioventricular block, premature ventricular contractions, prolonged QT interval, and even asystole (173). The insula consists of two different types of neurons simultaneously: 27 percent responsible for sympathetic excitation and 9 percent responsible for sympathetic inhibition (174). Furthermore, the left and right insula have distinct roles in regulating the CS, with the left insula influencing sympathetic activity by regulating peripheral blood and cardiac adrenaline levels, while the right insula exerts the opposite effect by activating the parasympathetic nervous system (171, 172). Due to the insula's complex and multifaceted physiological functions, CS abnormalities resulting from insula damage can be subject to various uncertainties.

The cortical nuclei, including the basolateral nucleus, cortical-like nuclei and central-medial nuclei, are situated in the medial temporal lobe (175). The amygdaloid nucleus, particularly the basolateral nucleus, receives and integrates signals from the cortex, brainstem and thalamus to regulate cardiovascular activity. These signals are then transmitted to the basal ganglia and subsequently reach the central part of the central medial nucleus (CeA). The CeA sends signals to the brainstem, hypothalamus, and other areas to influence blood pressure and heart rate (175–178). Glu secreted by the CeA increases heart rate and blood pressure by activating the sympathetic nervous system, while GABA secreted by the CeA reduces heart rate and blood pressure by activating the parasympathetic nervous system (179–181). In HIV-infected individuals, degeneration or volume loss in the amygdala may impair the transmission of cardiovascular regulatory signals to areas such as the brainstem and hypothalamus, leading to changes in blood pressure and heart rate (182, 183).

The cingulate cortex plays a role in receiving and integrating visceral sensory information, including changes in blood pressure, and it outputs signals that regulate autonomic, neuroendocrine, and cardiovascular responses (184). The posterior cingulate cortex can be further divided into the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) (185). Activation of the ACC has been shown to reduce vagal tone and increase heart rate (186, 187), while inactivation of the ACC enhances the vagal tone and increases heart rate variability (188). HIV may cause impairment of ACC, which could change the heart rate and blood pressure. However, cardiovascular lesions caused by HIV injury to the cingulate gyrus are very complicated due to the presence of both the hypertension and hypotensive regions in the cingulate gyrus (165, 189).

The hypothalamus, acting as a central hub for autonomic nerve outflow and the hypothalamic-pituitary-adrenal (HPA) axis, plays a vital role in regulating cardiovascular functions (190, 191). The hypothalamic paraventricular nucleus (PVN) releases corticotropin-releasing hormone (CRH), which then activates the HPA axis, leading to the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. ACTH, in turn, stimulates the release of glucocorticoids from the adrenal gland, resulting in an increase in blood pressure (192). The activity level of CRH neurons located in the hypothalamic PVN can influence changes in blood pressure (193). Increased activity and/or number of CRH neurons can enhance CRH synthesis, transport and release, ultimately leading to elevated blood pressure (194). CRH neurons in the PVN receive catecholamine signals from brain regions such as the locus coeruleus (LC), nucleus of the solitary tract (NTS) and parabrachial nucleus (195–198), following which CRH neurons are activated, leading to an increased concentration of NA in the PVN, causing hypertension and an elevated heart rate (199, 200). Blood pressure regulation is also influenced by oxytocin (OXY) and arginine vasopressin (AVP), which are released from the supraoptic nucleus (SON), paraventricular nucleus (PVN) and suprachiasmatic nucleus (SCN) of the hypothalamus (201). Pro-oxytocin and pro-vasopressin, synthesized in the SON, PVN, and SCN, are transported, stored in the posterior pituitary, and released into the peripheral circulation to regulate the CS (202). In addition, OXY and AVP signals can project to various brain regions, including the olfactory bulb, orbitofrontal cortex, cingulate gyrus, amygdala, striatum, hippocampus, bed nucleus terminalis, suprachiasmatic nucleus, and autonomic ganglia (203). HIV-gp120 can invade the hypothalamus and directly stimulate the hypothalamic axis to induce cortisol secretion (204). HIV-Vpr and HIV-Tat can enhance glucocorticoid action by increasing the sensitivity of target tissues to glucocorticoids and stimulate the inflammatory cytokine HPA activity, resulting in cortisol secretion (205). In addition, Furthermore, HIV infection may reduce levels of oxytocin, which can disrupt the regulation of blood pressure (72).

The brainstem consists of the midbrain, pons, and medulla oblongata, with the medulla oblongata particularly involved in cardiovascular regulation (206). When blood pressure increases, the nucleus tractus solitarius receives and integrates signals from baroreceptors, and then transmits these signals to neurons in the lateral caudal ventrolateral medulla (CVLM) (207), providing inhibitory signals to neurons in the rostral ventrolateral medulla (RVLM) (207). Subsequently, the inhibitory neural signals from RVLM neurons reduce the output of sympathetic signals from neurons located in the intermediolateral columns of cells in the spinal cord to peripheral organs, ultimately inhibiting cardiovascular activity (207). Furthermore, cardiac parasympathetic fibers originating from the dorsal vagus and hypochondriac nuclei of the medulla oblongata play a role in inhibiting cardiovascular activity. Brailoiu et al. suggested that HIV-Tat can stimulate the vagus nucleus, increasing parasympathetic activity in the heart and resulting in persistent bradycardia (208). Nagamitsu et al. also noted that structural changes in the medulla oblongata might occur in the later stages of HIV infection, which could potentially impact cardiovascular activity (209).

In the early stages of brain damage,the clinical manifestations are characterized by mild difficulties with concentration, motor symptoms and focal cortical deficits (92). As the disease advances, the clinical manifestations are characterized by significant motor dysfunctions, signs of frontal lobe release, cramps and hyper-reflexes, cognitive dysfunction, neuropathic pain, paresthesia, and abnormal gait (86, 120, 121, 249).

Detection of viral load in cerebrospinal fluid (CSF) is an important means to assess whether HIV has invaded the CNS (250). However, viral load levels of HIV in CSF and the count of CD4+ T cells in blood are not necessarily positively correlated with the severity of brain damage (84–87, 251). Some biochemical substances(including glucose, ATP, lactate, Glu, GABA, NA, and catecholamine, et al.) and biomarkers(t-tau, p-tau, β-amiloid42, neopterin, and S100β,et al.) of CSF are utilized to assess metabolic dysfunction and Structural damage of CNS (104, 106–108, 136, 137, 143, 144, 252–255). In addition, integrated brain on a chip and automated organ-on-chips systems,as well as extracellular vesicles, may be employed to evaluate various neurological damage caused by HIV (256–258).

Electroencephalograph (EEG) is commonly utilized for assessing electrophysiological function in the brain. Tinuper et al. found that abnormal EEGs are correlated with CNS involvement and borderline EEGs may be correlated with asymptomatic patients (259). Barco et al.observed a statistically significant correlation between working memory test Trail Making B and delta waves in patients infected with HIV (255). For functional connectivity, connectivity in alpha, beta, theta, and delta band was decreased in the HIV/AIDS patients (255). Compared to the healthy people, the smaller late positive potential and larger P200 amplitudes were observed in HIV/AIDS patients (260).

Magnetic resonance (MRI), a widely used neuroimaging test, is considered to play an important role in the diagnosis of HAND (261). MRI can be employed to observe structural changes in the brain. In addition, some functional MRI (fMRI) tests, including susceptibility weighted imaging (SWI), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), are utilized to verify the metabolic dysfunction and Structural damage of CNS caused by HIV, as well as CNS metabolic disorders (262–264).