Bidirectional Relationship between HIV/HBV Infection and Comorbid Depression and/or Anxiety: A Systematic Review on Shared Biological Mechanisms

Background: Mental disorders that are comorbid with chronic infectious diseases may worsen clinical outcomes and patients’ quality of life. We hypothesized that depression and/or anxiety syndromes or symptoms comorbid with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) infection might stem from shared biological mechanisms. Methods: We conducted a systematic review applying the PRISMA statement by searching into the PubMed, APA PsycInfo, and Scopus databases. We examined the literature on HIV/HBV infection comorbid with depression and/or anxiety in adults ≥18 years. Results: Thirty-one studies on HIV and three on HBV were analyzed. The Tat protein contributed to HIV-associated mood disorders due to the protein’s ability to cause neurodegeneration and induce hypothalamic–pituitary–adrenal (HPA) axis dysregulation in response to natural stressors. The decreased brain-derived neurotrophic factor (BDNF) levels also emerged as a mechanism involved in HIV neuropathogenesis and the associated mood symptoms. Neuroinflammation was implicated in depression and/or anxiety onset in patients with HIV/HBV infections. Microglial activation and release of cytokines, in particular, appeared as potential pathogenetic mechanisms. Furthermore, an altered balance between quinolinic acid and kynurenic acid production emerged in HIV patients with comorbid depression, indicating a glutamatergic dysfunction. Inflammatory cytokine production and the downregulation of cellular immune responses contributed to persisting inflammation, delayed healing, and functional decline in patients with chronic hepatitis B (CHB) infection. A shift in type 1–type 2 cytokine balance might be implicated in HBV-related immune pathogenesis, and depression and anxiety might be considered immunomodulatory factors. Cytokines also caused HPA axis hyperactivity, frequently observed in HIV/HBV patients with comorbid depression/anxiety. Conclusions: The present systematic review showed, for the first time, that HIV/HBV and depression and/or anxiety might have several biological mechanisms as common denominators. The longitudinal course of the highlighted biological mechanisms should be explored to establish the causative interrelationship among the involved mechanisms. In addition, future research should investigate the possibility that a patient’s clinical outcome might improve using pharmacological treatments acting on the biological mechanisms we described as common denominators of chronic inflammatory infective diseases and depression/anxiety.


Introduction
Human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) are significant global health burdens.According to the World Health Organization (WHO) [1], by the end of 2021, 38.4 million people worldwide lived with HIV, with 1.5 million new infection cases and 650,000 deaths.People living with HIV (PLWH) are forced to deal with an increased risk of mental symptoms/disorders, mainly anxiety and depression, possibly associated with perceived stigma and consequent social withdrawal, insomnia, and guilt feelings [2][3][4].HIV patients face an alarming prevalent depression compared to the general population, with 30-50% presenting comorbid depressive symptoms [5].The risk of depression in PLWH is estimated to be twice that of the general population [6], and suicide ideation is considerably high, consistent with the depression rates [3,4,7].
Hepatitis B infection is the most widespread infection in the WHO Western Pacific Region (116 million people are chronically infected), in the African Region (81 million), and in the Eastern Mediterranean Region (60 million).Hepatitis B virus (HBV) infection contracted in adulthood leads to chronic hepatitis in less than 5% of cases, whereas in infancy and early childhood it is in 95% of cases.In 2019, hepatitis B caused 820,000 deaths, primarily due to cirrhosis and hepatocellular carcinoma (WHO, 2017).Nikbakht Dastjerdi et al. showed that chronic hepatitis B (CHB) patients might suffer from depression (36.6%) and anxiety (40%) and experience a high psychopathological burden [8].Furthermore, in CHB patients and HBsAg-positive inactive carriers, comorbid anxiety symptoms appear to be more severe than in the general population, differently from comorbid depressive symptoms, which are more serious solely in the case of HBsAg-positive inactive carriers [9].
Depression and anxiety increase the risk of contracting infectious diseases and reactivating latent infections.Tsai et al. revealed that patients with HBV infection affected by comorbid depression/anxiety had a 1.189-fold increased risk of hepatitis B flares compared to the control cohort throughout a 16-year follow-up, with a higher incidence in the first year [10].Major depression impacts the clinical outcomes and quality of life (QoL) of people with HIV or HBV and might impede treatment adherence.Comorbid depression might contribute to the progression of HIV infection toward increased morbidity and mortality [11][12][13][14].In addition, psychosocial and lifestyle factors might increase the burden associated with depression in PLWH [15][16][17].
In the general population, depression and/or anxiety severity are associated with acute and chronic systemic inflammation markers, which might promote a susceptibility to depression [18][19][20][21][22][23][24][25][26].Psychological distress and the associated negative emotions, such as anxiety, may also impact the B-and T-cell-mediated immune system and increase the risk of contracting infectious diseases and/or reactivating latent viral infections [27,28].Lowgrade inflammation and cytokines hypersecretion in the peripheral blood are consistently associated with HIV infection and related comorbidities [29].Therefore, a central issue is establishing whether peripheral markers reflect pathological mechanisms in the central nervous system (CNS) or neuroinflammation results from primary peripheral inflammatory mechanisms.
A few authors hypothesized that deficits in serotonergic or dopaminergic pathways might disclose a depression risk [30,31].Growing evidence supports that HIV-associated depression might relate to the modulatory effects of immune responses leading to cytokinemediated inflammatory processes and to the activation of predominant stress pathways, such as the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), which stimulate immune cells both in the periphery and in the CNS [32].The "cytokine hypothesis of depression" suggested that inflammatory cytokines might act as neuromodulators and mediate behavioral, neuroendocrine, and neurochemical features of depressive disorders [33][34][35][36].Moreover, several studies concluded that nonsteroidal anti-inflammatory drugs (NSAIDs) had both anti-inflammatory and antidepressant effects by inhibiting proinflammatory cytokines [37].Contrarily, other studies proved that NSAIDs administered to patients with comorbid inflammatory diseases and depression might cause severe adverse effects.Furthermore, the cotreatment of NSAIDs with SSRIs was proved to attenuate the effects of antidepressant drugs [38][39][40][41].
Chronic inflammation and depression emerged to be associated also with increased corticotropin-releasing hormone (CRH) and glucocorticoid receptor resistance [42].Both processes, in turn, contribute to increased inflammatory cytokines and persistent inflammation [21].
Further evidence suggests that depression etiology might be related to neuroinflammation through a set of immune responses in the CNS, characterized by microglial activation and inflammatory cytokines release [43,44].
Depression and inflammation appeared to be associated, and HIV infection in the brain elicited a neuroinflammatory response, possibly contributing to causing frequent comorbid depression and HIV infection in PLWH [29].
Our review shows evidence that the hypothesized frequent comorbidity between depression, anxiety symptoms or syndromes, and HIV and HBV, is ascribable to a shared pathophysiology.We conducted a systematic review of the clinical-and population-based literature relevant to HIV and HBV infections comorbid with depression and/or anxiety in adults ≥18 years and hypothesized that they shared underlying biological mechanisms.

Materials and Methods
We complied with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 statement [45], as applicable, and examined studies including patients ≥18 years diagnosed with HIV/HBV-comorbid syndromes or symptoms of depression and/or anxiety.The study was not registered.
We aimed to answer the following research questions: 1.
Which biological mechanisms might explain the comorbidity between the chronic infectious disorder (HIV or HBV) and mood disorders/symptoms in patients whose primary diagnosis was HIV or HBV infection?2.
What are the gaps in the literature regarding this topic?3.
What suggestions can we provide for future studies?
We searched the PubMed, APA PsycInfo, and Scopus databases for relevant trials on animals and humans, with English as a language filter.The date limits were set from inception to June 2023 OR "Amino Acids, Peptides, and Proteins"[MeSH Terms]) AND ("loattrfull text"[Filter] AND "english"[Language])) AND ((fft [Filter]) AND (english[Filter])).In addition, we handsearched the reference lists of the included articles to detect any further relevant studies.

Eligibility Criteria
As mental disorders, we selected depression and anxiety (disease and/or symptoms), assessed through standardized psychopathological rating scales, regardless of clear-cut anxiety or depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria.We extracted all the original studies on comorbidity between HIV or HBV infection and/or depression/anxiety that reported the severity of such conditions through outcome measures (i.e., clinical evaluation and/or blood samples testing for HIV/HBV infections, depression and/or anxiety psychopathological assessment scales).We included the following: (a) randomized controlled trials (RCTs) and longitudinal, crosssectional, case-control, and cohort studies in patients ≥ 18 years, of either gender, with a clinical or laboratory diagnosis of HIV or HBV infection concurrent with depression and/or anxiety, assessed with a psychopathological rating scale; (b) studies on patients treated with approved antiretroviral therapy (ART) for HIV infection or drugs used in HBV-infected patients; (c) studies including patients cotreated with antidepressants and followed up for at least 12 weeks, the usual interval for resolving long-lasting mood symptoms; and (d) basic research studies on the biological mechanisms of animals infected with artificially induced corresponding human HIV or HBV, analyzing, using appropriate tests, the resulting depression-and anxiety-like behaviors.Finally, we excluded studies that were not in English, did not include subjects with proven HIV or HBV infection, did not explore the biological mechanisms shared by HIV/HBV infection and psychiatric disorders such as anxiety and/or depression, concerned pregnant women, or subjects with other medical conditions that were confounding factor for our analysis.Furthermore, we excluded reviews, letters, and editorials.

Selection of Studies
The titles and abstracts of articles were initially screened for inclusion and the relevant data extracted and presented in a tabular format.Finally, data on study characteristics, outcome measures, and type of therapeutical intervention, when applicable, were classified.The search strategy and selection process were displayed as a flow diagram and text, while the selected studies' description as text and tables.The main results regarding each research question were summarized, and the study limitations, literature gaps, and areas needing further investigation were highlighted.
During the selection process, some interventions may have influenced the results.In particular, the use of only three search engines and the use of very specific keywords, on the one hand, may have reduced the number of off-topic results, while, on the other hand, may have resulted in the exclusion of relevant studies.

Quality of the Studies and Risk of the Bias Assessment
Two authors (S.C. and A.C.) independently assessed the quality of the non-randomized studies of interventions (NRSIs) and the risk of bias, through the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) [46].The tool comprises three main domains for bias evaluation-pre-intervention, during the intervention, and postintervention-assessing and classifying the risk of bias for each domain and subdomain as low, moderate, high, or no information (Supplementary Tables S1 and S2).The two authors resolved disagreements by discussing or involving a third author (M.F.).The authors considered an NRSI as follows: (a) as low risk (if at a low risk of bias for all the domains); (b) as moderate risk (if at a moderate risk for at least one domain); (c) as high risk (if at a high risk of bias for at least one domain but not at a critical risk of bias in any domain); and (d) as critical risk (if at critical risk in at least one domain).Also, "no information" was displayed for an NRSI when no exact evaluation of a high or critical risk of bias was achievable and/or information about key domains was missing.

Results
We initially extracted 806 articles, from which we selected 40 articles potentially relevant for full-text screening and excluded 6 that did not address biological mechanisms relevant to our research questions.Supplementary Figure S1 presents the flow chart of the selected studies and describes the reasons for the exclusion.
Among the remaining 34 studies, 31 presented results on shared biological mechanisms associated with HIV infection and depression and/or anxiety, and 3 focused on patients with HBV infection.Specifically, three preclinical studies on animal models reported shared biological mechanisms of HIV infection with depression-like or anxiety-like behaviors; six genetic studies analyzed genotype distribution and allele frequency in patients with comorbid HIV infection and depression or anxiety, and twenty-two non-randomized clinical reports evaluated common biological mechanisms in patients with comorbid HIV infection and depressive disorders (Table 1).The remaining three studies reported shared biological mechanisms involved in HBV-infected patients with comorbid anxiety or depression (Table 2).Cross-sectional study of147 African American F, <45 years old, subgrouped as follows: Glucocorticoid receptor expression (GR, gene: Nr3c1) and its negative regulator FKBP5 via quantitative RT-PCR from peripheral blood mononuclear cells (PBMCs) in baseline and dexamethasone-stimulated conditions.
Depressive symptoms and HIV serostatus independently associated with elevated baseline expression of FKBP5 and Nr3c1 and with reduced LPS-induced release of IL-6 and TNF-α.Plasma levels of tryptophan, kynurenine, kynurenic acid, and quinolinic acid.
Higher quinolinic-to-kynurenic acid ratio (QKA) and higher concentrations of QA in the HIV+ patients with depression than in the HIV+ patients without depression.The overall risk of bias was moderate for most of the included NRSIs in HIV patients-16 studies with moderate and 12 with high risk (Supplementary Table S1).Instead, the overall risk of bias for the NRSIs in HBV patients appeared high for two of the included studies and moderate for the other one (Supplementary Table S2).

Preclinical Studies
The preclinical studies focused on the effects of the transactivator of transcription (Tat) regulatory protein associated with HIV-1 infection that might contribute to HIV-associated mood disorders.In one of the studies, the Tat protein activated brain cytokine signaling and led to the increased expression of indoleamine 2,3-dioxygenase (IDO) in male mice, thus causing a depressive-like behavior [47] (Table 1).On the other hand, Tat protein and morphine might differently induce depressive-like behaviors associated with increased neuroinflammation, synaptic losses, and immune fatigue within the prefrontal cortex of male mice [49].Furthermore, the enhanced expression of the Tat 1-86 protein also caused dose-and time-dependent anxiety-like effects in the (GT-tg) bigenic mice of study [48] (Table 1).

Genetic Studies
A correlation between depression severity and FK506-binding protein 5 (FKBP5) gene expression (a negative regulator of the glucocorticoid receptor gene) in individuals homozygous for GG of the FKBP5 single nucleotide polymorphism (SNP) rs3800373 was emphasized [51].Deficits in glucocorticoid signaling (decreased nuclear translocation of the glucocorticoid receptors and a lower transcription of FKBP5), instead, were synergistically associated in women with comorbid HIV and depressive symptoms [59] (Table 1).In addition, the authors highlighted an association between depressive symptoms and HIV serostatus in baseline and dexamethasone-stimulated conditions in patients with elevated baseline expression of FKBP5 and nuclear receptor subfamily 3 group C member 1 gene (Nr3c1).Furthermore, BDNF receptors were reported to be involved in the depression pathophysiology of patients with HIV infection.A particular SNP in the neurotrophic tyrosine kinase receptor type 2 (NTRK2 gene, encoding the receptor complex formed by TrkB) might contribute to comorbid HIV infection and major depressive disorder (MDD) in individuals with different ethnic backgrounds [54,67].
In HIV-infected patients, the comorbidity between neuroinflammation and psychopathological symptoms might be mediated by imbalances in the kynurenic pathway (KP).Two key KP enzymes are the kynurenine-aminotransferase II (KATII), which yields antioxidative kynurenine acid (KYN A) in astrocytes, and the kynurenine-3-monooxygenase (KMO), which produces neurotoxic metabolites in microglia.Polymorphisms of KYN pathway-related genes, such as the C-allele variant of KATII-rs1480544, appeared to be associated with psychopathological distress in HIV-positive patients, who consequently showed more severe depressive and anxiety symptoms and greater neuroinflammation [57].Borghetti et al. found that HIV-positive CA genotype carriers of the allele variant of the SLC22A2 808 gene (C to A polymorphism), encoding the organic cation transporter 2 (OCT2), were at higher risk of manifesting anxiety and hostility [60].OCT2 is a lowaffinity carrier for various physiological compounds, including catecholamines, serotonin, and choline neurotransmitters, besides xenobiotics, as heavy metals, antiviral drugs, and beta-lactam antibiotics in mammals.Also, OCT2 takes part in the postsynaptic reuptake of the extraneuronal neurotransmitters, especially catecholamines, which escape from the high-affinity transporters.Moreover, OCT2 is essential in modulating the response to stress by inhibiting the corticosterone release driven by the HPA system, thus reducing stress and depression-like behaviors.

Studies Investigating Chronic Inflammatory Mechanisms
Chronic, low-level CNS inflammation is a primary mechanism contributing to HIV neuropathogenesis.HIV enters the brain 4-8 days after peripheral infection and the infected cells produce chemokines, cytokines, neurotoxic mediators, and viral proteins that contribute to chronic inflammation and ongoing neuronal damage.Concerning such an issue, Praus et al. described a positive correlation between elevated levels of anxiety or depression and cerebrospinal fluid (CSF) cells and proteins [50].Saloner et al. suggested that depression pathophysiology in HIV-positive patients was associated with low central dopaminergic activity and neuroinflammation [64].On the other hand, Woods et al. concluded that the neurotoxic effects of the HIV protein gp120 are responsible for reducing the availability of BDNF in PLWH [68].
Neopterin, a catabolic product of the purine nucleotide guanosine triphosphate (GTP), synthesized by human macrophages upon stimulation with the cytokine interferon-gamma (IFN-γ), is indicative of a pro-inflammatory immune status.The measurement of neopterin concentrations in body fluids provides information about the activation of cellular immune responses in humans under the control of T helper type 1 (TH1) cells.A high neopterin production is associated with the increased synthesis of reactive oxygen products, which indirectly allows the assessment of the oxidative stress' extent elicited by the immune system.An increased neopterin production may also correlate with MDD and subclinical depressive symptoms in acutely infected HIV patients.Warriner et al. reported that neopterin plasma levels might act as systemic immune markers useful in identifying treatment-resistant HIV-positive patients at greater risk of developing chronic depression [52] (Table 1).On the other hand, Saloner et al. highlighted that plasma levels of neopterin were associated with lifetime MDD but not with ongoing depressive symptoms in such patients [71].The authors concluded that the association might be related to the amino acid metabolism and neurotransmitter synthesis disruptions occurring in the inflammatory process.Otherwise, Anderson et al. hypothesized a contribution of peripheral macrophage activation in comorbid depression pathogenesis in PLWH [28].The authors reported that sCD163, a biomarker of macrophage activation, was higher in the plasma of HIV-positive patients and significantly associated with severe depressive symptoms compared to HIV-negative patients (Table 1).
Furthermore, HIV-positive patients might also present high degrees of psychological distress.In this regard, Fumaz et al. reported that high plasma levels of IL-6 were closely associated with psychological stress and anxiety/depression symptoms [53].In addition, Petersen et al. highlighted a correlation between IL-6 and depression exclusively in men, suggesting that the depression-inflammation link differed based on sex [74].Bekhbat et al., instead, noticed that depressive symptoms were independently associated with the reduced lipopolysaccharide (LPS)-induced release of IL-6 and TNF-α, in addition to the elevated expression of FKBP5 and Nr3c1 genes [59].
The C-reactive protein (CRP) has long been identified as an inflammatory marker associated with HIV.A linear relationship between serum CRP concentration and depressive symptoms severity appeared in HIV-positive patients.In particular, HIV-positive male patients with a high level of inflammation (CRP > 3 mg/L) showed a greater risk for depression [55].In a sample of HIV-positive Tanzanian adults, Memiah et al. found that elevated levels of CRP and sTNFR-II were positively associated with self-reported mental health symptoms [66].Moreover, Lu et al. suggested that immune activation might be involved in depression risk in both HIV-positive and HIV-negative male patients and that several markers might be associated with higher odds of depressive symptoms (Table 1) [61].
Overall, a recent study hypothesized that the association between HIV status and depressive symptoms might partly be attributable to central and peripheral inflammatory biomarkers [75].Specifically, these biomarkers are the monokine induced by interferon (MIG) and the TNF-α in the plasma and the macrophage inflammatory protein-1 alpha (MIP1-α) and the IL-6 in the CSF, all of which proved to be potential mediators of such an association.Rubin et al. suggested that both hormonal and inflammatory mechanisms might be implicated in cognitive impairments in patients with HIV presenting MDD or remitted MDD (rMDD) [63].In particular, in HIV female patients, basal cortisol concentrations were higher in rMDD versus no-MDD groups, while basal inflammatory cytokines were higher in rMDD versus no-MDD male and female patients with HIV (Table 1).Based on their findings, Derry et al. suggested potential links among depression, inflammation, and health in elderly HIV-positive patients who showed higher serum levels of cytokines and more depressive symptoms, along with a worse physical function, when compared to HIV-positive patients with fewer depressive symptoms and lower cytokine plasma levels [70].Differently, Zuñiga et al. reported that, in HIV-positive patients, the most relevant depression biomarker was the increased plasma levels of TNF-α [65].Furthermore, Musinguzi et al. noticed that IL-6 and TNF-α, rather than CRP, were significantly and positively associated with MDD [58].According to Saylor et al., serum IL-6 appeared to be highly associated with advanced immunosuppression, depression, and HIV-associated neurocognitive disorder in a cohort of HIV-positive patients [62].Instead, Yang et al. suggested a role for endogenous cannabinoid signaling in the modulation of depression in HIV-positive patients [72].A down-regulation of cannabinoid receptor 1 (CBR1), associated with an increased expression of nucleobindin 1 (NUCB1) protein in the temporal cortical neurons, might be responsible for the comorbid mood disorder in the above-mentioned study.
Finally, Taylor et al. suggested that gut microbiome changes and gut mucosal barrier dysfunctions might expose PLWH to proinflammatory microbial products, which might act in neuroinflammation, and increase the risk of MDD [76].

Studies Investigating Monoamine Metabolites and Hormones
Depressive symptoms have been associated with augmented IFN responses and increased tryptophan catabolism in HIV patients.Such findings suggested that minor alterations in the metabolism of monoamines and mitochondrial energetics might contribute to the activation of mechanisms that favor MDD's onset.Such mechanisms, in turn, are possibly influenced by inflammation during HIV infection [56].Drivsholm et al. reported that an altered balance between quinolinic acid (QA) and KYN A production was associated with depression in HIV patients [69].Tryptophan (Trp) is metabolized into KYN through IDO-1, whose activity is enhanced in HIV patients.KYN, in turn, is metabolized via kynurenine aminotransferase (KAT) and KMO, resulting in either KYN A or 3-hydroxykynurenine and QA.Indeed, reduced KYN and KYN A and an increased QA and QA/KYN A ratio are also the most consistently reported findings in patients suffering from depression without infection.In addition, KYN A might act as an antagonist and QA as an agonist of N-methyl-D-aspartate (NMDA) receptors.Altered concentrations of KYN metabolites may lead to glutamatergic dysfunction and, consequently, depression.Such findings suggested that the increased activity of KMO contributed to depression pathogenesis.Accordingly, Drivsholm et al. hypothesized that alterations in the KYN pathway might partly mediate a close relationship between macrophage-driven inflammation and depression in HIV infection [69].Finally, Shortell et al. report a correlation between neuropeptide oxytocin and depressive symptoms in PLWH (Table 1) [73].

Studies on HBV Infection
Increasing evidence sustains that chronic psychophysical stress might suppress protective immune responses and/or exacerbate pathological immune responses by altering the type 1-type 2 cytokine balance, inducing low-grade chronic inflammation, and suppressing the numbers, trafficking, and function of immunoprotective cells [80].
Generally, type 1 cytokines (IL-2, IFN-γ, IL-12, and TNF-ß) favor the development of a strong cellular immune response, whereas type 2 cytokines (IL-4, IL-5, IL-6, IL-10, and IL-13) a strong humoral immune response.A few type 1 and type 2 cytokines are crossregulatory.For example, IFN-γ and IL-12 might decrease type 2 cytokine levels, whereas IL-4 and IL-10 might decrease type 1 cytokine levels [81].Indeed, in patients with CHB, He et al. detailed a marked increase in the plasma levels of IL-10 associated with a decrease in the IFN-γ plasma levels, due to a shift in the type 1-type 2 cytokine balance toward a type-2 response [77].The authors concluded that, in patients with HBV infection, chronic stress and associated anxiety might contribute to the shift, which possibly played a role in the HBVrelated immune pathogenesis (Table 2).The study of Bahramabadi et al. highlighted that chronic inflammation might be related to the downregulation of transforming growth factor (TGF)-β in patients with CHB [78].Moreover, the results confirmed the high prevalence of depression and its role in the downregulation of TGF-β in CHB patients.Accordingly, depression might lead to reduced TGF-β plasma levels and, subsequently, to inflammation in CHB patients through the decreased serum levels of IL-6 and TGF-β.Finally, Safari-Arababadi et al. evaluated the relationship between depression and anxiety with the expression of some inflammatory transcription factors, which are the receptor-interacting protein 1 (RIP1) and the IFN-β promoter stimulator-1 (IPS-1) in the peripheral blood mononuclear cells of CHB patients, known as the critical molecules against HBV [79].The authors hypothesized that depression might be associated with an altered expression of IPS-1 sex-dependently and that only IPS-1 significantly decreased in the male CHB patients with depression compared to the patients without depression (Table 2).

Discussion
The present systematic review aimed to analyze the possible pathophysiological mechanisms underlying comorbid HIV/HBV infections and mental syndromes or symptoms of depression and anxiety to identify the potential literature gaps.For the first time, we recognized several biological mechanisms as common denominators of the hypothesized reciprocal/bidirectional relationship between HIV/HBV and depression/anxiety.However, it remains unclear whether such mechanisms are the expression of peripheral inflammatory processes, with the subsequent involvement of microglia activation, decreased neurogenesis, and increased apoptosis, or rather primary CNS processes extending to peripheral organs.Most studies lack the longitudinal course and the causal relationship with the comorbid processes.
The literature primarily focused on comorbid mental disorders in HIV patients, rather than HBV infection.A few reviews have reported on inflammatory mechanisms as a possible link between depression/anxiety and chronic infectious diseases [82][83][84].In particular, HIV might predispose infected individuals to depression via interrelated mechanisms, and neuroinflammation might contribute to the highly prevalent mood disorders in PLWH.Further reviews, moreover, revealed that, in HIV patients with concurrent psychopathological symptoms, ART possibly attenuated virus-associated neuroinflammatory activities and acted on the shared biological mechanisms of the comorbid conditions [85].
The literature analysis highlighted that HIV-1 replication in the CNS initiated after invading monocytes and CD4+ T cells and that the virus spread to microglial cells and astrocytes within the brain parenchyma [86].In addition, infected macrophages entered the brain in low abundance during early HIV-1 infection and activated microglial cells to initiate producing and releasing cytokines [32].Furthermore, overactivated microglial cells were involved in exacerbating neuronal injury through the synthesis and secretion of proinflammatory and cytotoxic factors [87].Also, the literature shows that several HIV proteins might interact with neurons, microglia, and astrocytes, further contributing to neuroinflammation.HIV proteins, including Tat gp120, Vpr, and Nef, might directly induce neuronal damage [88][89][90][91], while activated microglia might contribute to neurodegeneration by releasing cytokines and toxins, which damage neurons and astrocytes [92,93].
Preclinical studies suggest that the activation of the Tat regulatory protein might be involved in the underlying mechanisms of depression-and anxiety-like behaviors in mice models of HIV infection [47][48][49] and lead to dendritic pruning, decreased spine density, and synapse loss [94].Tat mRNA and proteins were also found in the CNS of patients with HIVassociated neurocognitive disorders [95].Furthermore, the extent of cognitive decline might correlate with dendritic damage and synapse loss rather than with neuronal death [96].The functional Tat protein promotes cytokine production and infiltration, oxidative stress, and neurotoxicity [32].Also, the Tat protein might contribute to dysregulating the HPA system in response to natural stressors, thus producing significantly high corticosterone levels and potentiating psychomotor and anxiety-like behaviors [97].
BDNF, a neurotrophic factor whose receptors are crucial in depression pathophysiology, appeared to be implicated in mood symptoms observed in HIV disease.Indeed, positive PLWH showed significantly lower BDNF plasma levels when compared with negative PLWH [68] due to the reduced processing of proBDNF into mature BDNF [54].In addition, genetic factors, such as rs6265 polymorphism in the BDNF gene, might contribute to lower BDNF levels in HIV-1-positive individuals.Furthermore, Avdoshina et al. reported that a particular SNP in the NTRK2 gene might contribute to HIV infection and major depressive disorder (MDD) comorbidity in individuals with different ethnic backgrounds [54].
One primary mechanism contributing to HIV neuropathogenesis is the chronic inflammation in the CNS, with HIV-infected microglia responding vigorously to proinflammatory signals and producing excessive cytokines [86].Elevated proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β, appeared in the plasma and lymph nodes from the early stage of HIV-1 infection [82,98].Indeed, several studies reported immune activation and increased plasma cytokines (IL-1 and IL-6) in the blood of HIV patients with depressive symptoms [29].
In light of the above considerations, chronic inflammation might contribute to depression pathogenesis also in PLWH.
The central action of inflammatory cytokines might also explain the HPA axis hyperactivity that is frequent in depressive disorders, which interferes with the inhibition of the negative feedback of circulating corticosteroids on the HPA axis.Furthermore, cytokines might reduce the 5-HT levels and lower tryptophan availability by activating the tryptophan-metabolizing enzyme IDO 2,3.The major effects of inflammatory cytokines might explain most symptoms in depressed patients, though it remains unclear whether cytokines are causative of depression or represent an epiphenomenon.
Under physiological conditions, cytokines, especially TNF-α and IL-1, provide essential trophic support to neurons, as they enhance neurogenesis, promote long-term potentiation, and maintain normal cognitive functions [32].On the other hand, an excessive and/or prolonged activation of cytokine networks might cause diminished neurotrophic support, decreased neurogenesis, increased glutamatergic activation, oxidative stress, induction of apoptosis in relevant cell types (e.g., astrocytes and oligodendrocytes), and dysregulation of glial/neuronal interactions [32,85].A few studies also identified imbalances in TNF-α, IL-1, and IL-6 as being implicated in mood and cognitive impairments [32,63].
The persistent CNS' cytokine response might, therefore, seem essential in chronic immune activation in the CNS during HIV infection.Moreover, the levels of cytokines correlate with the progression of HIV infection and provide a basis for neurocognitive alterations [83].Growing evidence has also confirmed the association between chronic inflammation and depression, manifested with increased C-reactive protein levels and proinflammatory cytokines, such as IL-1 β, IL-6, and TNF-α [18].In particular, TNF-α levels appeared elevated in the serum and CSF of HIV patients [29].Nevertheless, HIV infection itself might increase TNF-α levels, which, in turn, might impact viral replication [99].Moreover, TNF-α proved crucial in activating the cytokine cascade in several inflammatory diseases and regulating the biological function of macrophages [100].Also, IL-1β appeared decisive in the neuroinflammatory process associated with HIV-1 infection and was induced in human monocytes with subsequent inflammasome activation [101].More precisely, IL-1β was induced in mononuclear phagocytes with the HIV envelope protein gp120 and, in turn, might induce HIV replication in the infected cells [85].In addition, IL-1β appeared elevated in the plasma of HIV-infected patients, had neurotoxic effects on astrocytes and endothelial cells, and increased free radical and metalloproteinase production, which might cause neuronal death [29,102].
On the other hand, depression is associated with high levels of IL-1β, possibly responsible for activating a common pathway leading to depression and cognitive decline [83].
Based on our analysis, IL-6 might also present as a general biomarker of inflammation in HIV subjects, being implicated as a driver of ongoing CNS inflammation in virologically suppressed ART-treated patients.In addition, IL-6 might activate inflammatory cytokine expression in astrocytes and proved to be associated with depressive symptoms [52,53,62].
Chemokines were also responsible for neurological damage and inflammation, possibly contributing to depression onset [32].Moreover, chemokines might act as ligands for HIV co-receptors and mediators of inflammatory responses, contributing to HIV neuropathogenesis by recruiting HIV-infected immune cells to the brain, thus facilitating viral entry into the cells [22,32].
We identified other mechanisms as potential common denominators between HIV infection and mood disorders.For example, reduced monoamines proved to be associated with depressive symptoms, including loss of motivation and energy, which decreased hedonic drive [32].HIV was demonstrated to interfere with monoaminergic function via several mechanisms and act similarly with a few drugs of abuse.Indeed, HIV proteins might bind to the dopamine transporter (DAT) to block the neurotransmitter reuptake, thereby elevating dopamine levels and successively impairing the function of DAT.The accumulated synaptic dopamine levels, by binding to dopamine receptors, might activate adjacent microglia, possibly resulting in increased HIV replication and increased production of inflammatory mediators such as TNF-α and chemokines.In turn, increased HIV replication might lead to increased brain viral load and shedding of HIV proteins, gp120, and Tat.Such proteins, as well as TNF-α, might induce the cell death of adjacent dopaminergic neurons via apoptosis.The autoxidation and metabolism of accumulated synaptic dopamine might lead to the generation of reactive oxygen species (hydrogen peroxide), quinones, and semiquinones, which might also induce the apoptosis of neurons.Increased cell death of dopaminergic neurons might finally lead to a dopamine deficit, which potentially exacerbates the severity and/or accelerates the progression of HIV-associated mood and neurocognitive disorders [32].
Cytokinergic and monoaminergic mechanisms might also synergize when reducing serotonin levels during HIV infection.For example, TNF-α, IL-1β, and IL-6, as well as Tat and gp120, might activate the KYN pathway by stimulating glial IDO.Such an enzyme redirects the available dietary tryptophan to produce KYN, which, in astrocytes, is converted into KYN A and then transformed by activated microglia into 3-hydroxykynurenine (3HK) and QA.In addition, 3HK and QA might act as NMDA receptor agonists and directly contribute to excitotoxicity and Ca2+-mediated cell death.Differently, KYN A might act as an NMDA receptor antagonist, thus inhibiting glutamate release and providing a neuroprotective activity [32,85].Such imbalanced metabolic processes in hyperactivated microglia might cause QA overproduction and consequent glutamate release.The metabolic processes, in turn, might lead to oxidative stress, mitochondrial dysfunction, and death of neurons, astrocytes, and oligodendrocytes [32].Thus, QA might represent a highly excitotoxic marker of HIV-associated neurological diseases whose levels might reflect the extent of immune activation in blood and CNS [32].
Altered glutamatergic functions appeared to also be involved in depression pathogenesis [69].Thus, altered concentrations of the KYN metabolites (3HK and QA) might lead to glutamatergic dysfunction and, consequently, to depression.A few studies analyzed the association between changes in the KYN pathway of tryptophan metabolism and HIV infection, though the modified KYN metabolism appeared to be associated with depression also in non-infected patients [103].Drivsholm et al. reported higher levels of QA and QA/KYN A ratio in PLWH with depression when compared to PLWH without depression, suggesting that increased KMO activity might participate in depression pathogenesis [69].In CNS, KMO was mainly expressed in the macrophages of the microglia, which is why Drivsholm et al. hypothesized that a relationship between macrophage-driven inflamma-tion and depression in HIV infection might be partly mediated by the altered KYN pathway of tryptophan metabolism [69].
Our review also examined chronic HBV infection (CHB), a further example of the bidirectional association between inflammation and mood disorders.
The pathogenesis of CHB infection proved to be immune-mediated [84].Innate and adaptive immune cells are crucial in controlling HBV infection, despite also appearing responsible for the inflammatory process.During the initial phase of HBV infection, innate immunity is activated and causes the production of antiviral cytokines.Such a process is followed by the activation and intrahepatic recruitment of the adaptive immune system, resulting in the elimination of the virus.In CHB infection, further alterations occur in innate and adaptive immunity, including increased regulatory cells, overexpression of coinhibitory receptors, and release of inflammatory mediators.The joint mechanisms prevail over the antiviral response, thus causing persistent viral infection and subsequent immune alterations associated with progression to fibrosis, cirrhosis, and hepatocellular carcinoma.In this regard, cytokines act as both inflammatory and anti-inflammatory molecules possibly contributing to the acute or chronic evolution of inflammatory conditions, whose persistence might trigger damaging and destructive immune responses leading to chronic medical conditions [104].
On the other hand, the continuous remodeling of the immune system throughout people's life appeared to rely on the constant interaction between the cytokines' network and a few factors (epigenetic, environmental, and lifestyle) [105].He et al. observed in CHB patients markedly increased plasma levels of IL-10, a type 2 cytokine crucial to the pathogenesis of many fibrotic diseases, and decreased plasma levels of IFN-G, a type 1 cytokine favoring the development of a strong cellular immune response [77].The authors concluded that stress might be responsible for shifting the type 1-type 2 cytokine balance toward a type-2 response.Such a shift might implicate a role of psychological distress in HBV-related immune pathogenesis.A mechanism by which immune response against HBV is suppressed was reported to stem from the releasing of TGF-β, an antiinflammatory cytokine produced during tissue remodeling and significantly increased in CHB patients compared to healthy controls [106].TGF-β, associated with IL-6, participated in developing Th17, the primary cell type involved in inducing inflammation.Bahramabadi et al. suggested that chronic inflammation in CHB patients might relate to downregulated TGF-β and noticed that a highly prevalent depression might contribute to a decreased TGF-β [78].Reciprocally, depression might lead to reduced TGF-β plasma levels and, subsequently, induce inflammation in CHB patients through decreased serum levels of IL-6 and TGF-β.
As reported in a few studies, IL-6, IL-8, and TNF-α are primary innate immune cytokines that induce inflammation and immune response against viruses [107].Bahramabadi et al. reported that CHB patients might suffer from depression (33.4%) and anxiety (76.7%) and, compared with healthy controls, showed increased serum levels of IL-8, associated with decreased IL-6 and TGF-β levels [78].Accordingly, they concluded that chronic inflammation in CHB patients might relate to downregulated TGF-β, through which depression might also induce inflammation.Therefore, depression and anxiety might be considered immunomodulatory factors.Also, Safari-Arababadi et al. confirmed a link between the host and the virus in depression and anxiety manifestation, which might alter immune-related molecule expression [79].The authors showed that IPS-1 significantly decreased in male CHB patients with mild, moderate, or severe depression compared to patients without depression.However, the manifestation of some inflammatory transcription factors, such as IPS-1 and RIP1, did not change with severe depression and anxiety.Therefore, depression might be associated with the downregulation of IPS-1 in CHB patients depending on their gender.The results indicated depression as a potential factor participating in immune system alterations in male subjects.Furthermore, the hormonal differences between males and females and the effects of sex hormones on immune cell functions might lead to the . The search terms (MeSH headings) included (("Depression"[MeSH Terms] OR "Depressive Disorder"[MeSH Terms] OR "Affective Symptoms"[MeSH Terms] OR "Anxiety Disorders"[MeSH Terms] OR "Anxiety"[MeSH Terms]) AND ("HIV Infections"[MeSH Terms] OR "Hepatitis B"[MeSH Terms]) AND ("Biological Factors"[MeSH Terms] OR "Inflammation"[MeSH Terms] OR "Immune System Phenomena"[MeSH Terms]

Table 1 .
Preclinical and clinical studies investigating shared biological mechanisms in patients with HIV and depression/anxiety symptoms/syndromes.

Table 2 .
Clinical studies on shared biological mechanisms in patients with CHB and depression/anxiety symptoms/syndromes.