Molecular Role of HIV-1 Human Receptors (CCL5–CCR5 Axis) in neuroAIDS: A Systematic Review

Chronic HIV-1 infection can cause neurological illness, also known as HIV-associated neurocognitive disorders (HAND). The elevated level of pro-inflammatory cytokines and chemokines, such as C-C Chemokine Ligand 5 (CCL5/RANTES), is one of the ways of causing HIV-1-mediated neuroinflammation. C-C Chemokine Receptor 5 (CCR5) is the main coreceptor for viral entry into host cells and for mediating induction of CCL5/RANTES. CCR5 and CCL5 are part of a correlated axis of immune pathways used for effective protection against the HIV-1 virus. The purpose of this paper was to review the literary knowledge about the immunopathological relationship between this immune complex and neuroAIDS. A systematic review of the literature was conducted based on the selection and search of articles, available in English, Spanish, or Portuguese in the time frame of 1990–2022, of primary and secondary types in the PUBMED, Science Direct, SciELO, and LILACS databases through descriptors (MeSH) together with “AND”: “CCR5”; “CCL5”; “neurological manifestations”; or “HIV”. The methodological quality of the articles was assessed using the JBI Checklists and the PRISMA 2020 writing guidelines were followed. A total of 36 articles were included in the final composition of the review. The main cells of the CNS affected by neuroAIDS are: neurons; microglia; astrocytes; and oligodendrocytes. Molecular devices and their associations with cellular injuries have been described from the entry of the virus into the host’s CNS cell to the generation of mental disorders. Furthermore, divergent results were found about the levels of CCL5/RANTES secretion and the generation of immunopathogenesis, while all condensed research for CCR5 indicated that elevation of this receptor causes more neurodegenerative manifestations. Therefore, new therapeutic and interventional strategies can be conditioned on the immunological direction proposed in this review for the disease.


Introduction
The human immunodeficiency virus (HIV) can impair the immune system by targeting the CD4+ T lymphocyte cells, which causes the acquired immune deficiency syndrome (AIDS) [1].Type 1 HIV (HIV-1) has been shown to produce a wide range of neurological diseases and penetrates the central nervous system (CNS) shortly after infection [2,3].Patients with HIV-1 infection have a significant frequency of HIV-associated neurocognitive disorders (HAND) [4,5].
Currently, combined antiretroviral therapy (cART) is the standard of care for HIVpositive patients who are following the right treatment regimens.Although it has improved the quality of life of people with HIV, cART is unable to eliminate the virus' latent reservoir [6].As a result, HIV/AIDS is now considered a chronic condition requiring continuing treatment rather than a fatal disease.At least half of patients receiving cART exhibit HIVassociated neurocognitive disorders (HAND), which have been linked to HIV-1 infection severity and its replication in the CNS, despite substantial viral load reduction [7].
Primary HIV neurological disease occurs when HIV is both necessary and sufficient to cause the illness [5].Besides that, primary HIV-related CNS disease is driven by the viral load and inflammation in the brain at the time the CD4+ count is drawn, and it will function largely independently of other variables like HIV disease stage, viral load, or dyslipidemia [8].The occurrence of a specific neurological illness in an HIV-positive individual is the result of a series of circumstances that are influenced by the features of HIV itself, such as the genetic makeup of the host, immunological features, and interactions with the environment (including therapy) [9,10].
HIV can interact with additional pathogens to cause tumors and opportunistic infections (OI), secondary or opportunistic neurological disease, and treatment-related neurological disease (like immune reconstitution inflammatory syndrome, or IRIS).Some examples of HIV-infected cells include microglia, monocytes, macrophages, astrocytes, and the choroid plexus.Infections are expected to impact neurons and oligodendrocytes seldom, if at all, and "indirect" processes are assumed to oversee the bulk of damage.However, this is still up for discussion [11].
Since C-C chemokine receptor 5 (CCR5) is the main coreceptor that allows HIV-1 infection when coupled with the viral glycoprotein 120 (gp120), it has been identified as a possible target for anti-HIV therapies [12].Immune cells (such as T cells), smooth muscle endothelial cells, epithelial cells, CNS cells, even parenchymal cells, and other cells exhibit CCR5, also known as CD195, a G-protein-coupled receptor (GPCR) whose expression is regulated by cAMP response element-binding (CREB)-18 protein [13].When it comes to the processes that start HIV-1 infections, virions attach to the surface of target cells to start the adsorption phase.This is accomplished by a high affinity contact between the CD4+ T lymphocyte being the primary receptor and the extracellular domain of the viral glycoprotein gp120.Following this glycoprotein's attachment to the CD4+ T receptor, the cell membrane undergoes structural modifications that allow for interaction with coreceptors like CCR5, which facilitates the fusing of the viral envelope with the host cell membrane and, ultimately, facilitates viral entrance [14].
In this sense, the polarization of cells with immunological expression and the activation of lymphocytes can be both mediated by C-C Motif Chemokine Ligand 5 (CCL5/regulated on activation, normal T-cell expressed and secreted-RANTES), which binds to G protein receptors [15].CCL5/RANTES has the greatest affinity with CCR5, but it may also connect to CCR1, CCR3, and CCR4.Most inflammatory cells, mainly T cells and macrophages, are capable of producing CCL5/RANTES [16].As a critical regulator of T-cell migration to inflammatory sites, CCL5/RANTES is a chemokine that directs T-cell migration to damaged or infected regions [17].Additionally, research suggests that CCL5/RANTES controls T-cell differentiation through type 1 of T helper (Th1) cells recruitment [18].
CCL5/RANTES may disrupt the interaction between the HIV-1 Env gp120 and the receptor, which is necessary for viral entry, by competitively binding to CCR5 [19].This can prevent HIV-1 cells from entering and replicating in those cells.Furthermore, CCL5/RANTES might cause the internalization of the bound receptor, which in turn reduces the expression of CCR5 on the cell surface [20].Chronic HIV-1 infection can cause neurological illness, often known as neuroAIDS.The elevated level of pro-inflammatory cytokines and chemokines, such as CCL5/RANTES, is one of the ways of causing HIV-1mediated neuroinflammation, leading to HIV-1-mediated neurotoxicity (neuroAIDS) [21].Research evidence demonstrated that HAND has a positive relationship with immunological activation and had a more wide spectrum of cognitive abnormalities that may overlap with other brain disorders [22].Then, this work had the purpose of systemizing the immunopathological relationship between the CCL5-CCR5 immune axis and neu-roAIDS progression.

Study Design
This systematic review was performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [23].The PICO technique was employed to formulate the guiding question, corresponding the anagram for population (P), intervention (I), comparison (C), and outcome (O).In this regard, it was produced from the following: P-patients with HAND; I-assess CCL5-CCR5 immune response; C-CCL5-CCR5 via and HAND biological effects; O-neuroAIDS advancement in CNS [24].It led to the formulation of the guiding question: "What immunopathological components within the CCL5-CCR5 axis are involved in the progression of HAND in CNS?".

Search Strategy
The identification and selection of articles were performed in the databases Science Direct (https://www.sciencedirect.com/;accessed on 20 November 2023), the National Library of Medicine National Institutes of Health of the USA-PUBMED (https: //pubmed.ncbi.nlm.nih.gov/;accessed on 21 November 2023), Scientific Electronic Library Online-SciELO (https://www.scielo.br/;accessed on 26 November 2023), and Latin American and Caribbean Literature in Health Sciences-LILACS (https://lilacs.bvsalud.org/; accessed on 26 November 2023), using the descriptors: "CCL5", "CCR5", "neurological manifestations" and "HIV", together with the Boolean operator "AND".The period included in the analysis was between January 1990 and December 2022.The information was gathered on 21 August 2023.This search strategy only considered English, Portuguese, and Spanish languages.
If a study satisfied all three criteria, it was deemed to be eligible: (i) dealt specifically with HIV-1; (ii) reported information on the biological effects of CCR5 and/or CCL5 on the progression of neuroAIDS; and (iii) had data on the CNS.Before selecting the data to be extracted, the study titles and abstracts were reviewed.

Data Extraction
All information deemed pertinent, including discrepancies and ambiguities discovered in the publications, was separately extracted by the two authors (MJAS and CSS), with the assistance of a third author (RLM) in circumstances where the selection of the data was discordant.The data that were extracted comprised the author's name, publication year, title, method, database, and outcomes.
Data gathering and a review of the publications' methodological quality were performed at the same time.Joanna Briggs Institute (JBI) checklists were used to conduct a methodological quality assessment [25].Pre-defined criteria from the literature were used to include two articles through their methodologies [26,27].A third author (TPB) discussed any discrepancies regarding the study's inclusion between the two researchers' analyses (MJAS and CSS).

Literature Search
The search in four databases identified 125 articles, with only 3 duplicated or incomplete works.Based on titles and abstracts that were unrelated to the topic's focus, 40 publications were subsequently eliminated from consideration.Consequently, 82 articles were chosen for thorough reading, of which 46 were dropped for deviating from the subject.A total of 36 studies fit this criterion (Figure 1), and they were included.
publications were subsequently eliminated from consideration.Consequently, 82 articles were chosen for thorough reading, of which 46 were dropped for deviating from the subject.A total of 36 studies fit this criterion (Figure 1), and they were included.

Characteristics of the Studies
Table 1 describes the characteristics of the 36 studies included in this systematic review.The majority came from the PUBMED database (n = 36; 100%), of American origin (n = 22; 61.11%) and of the experimental type (n = 18; 50%).All presented high methodological quality within the score acquired in the JBI Checklist for each specific type of study included.

Characteristics of the Studies
Table 1 describes the characteristics of the 36 studies included in this systematic review.The majority came from the PUBMED database (n = 36; 100%), of American origin (n = 22; 61.11%) and of the experimental type (n = 18; 50%).All presented high methodological quality within the score acquired in the JBI Checklist for each specific type of study included.Apoptosis and neuronal damage are brought on by HIV-1 proteins like gp120, which drive macrophages to generate neurotoxins.Additionally, the two main HIV co-receptors, the chemokine receptors CCR5 and CXCR4, have a wide range of physiological uses and are expressed in cells other than immune cells, such as those in the brain.Transgenic mice with HIV gp120 expression in the brain resemble NeuroAIDS brains in various pathogenic ways.Among CCR5-expressing and CCR5-deficient animals, there does not appear to be a difference in peripheral production of the chemokines CCL5/RANTES, CCL3/MIP-1, or CCL4/MIP-1ß.However, in contrast to wild-type controls, CCR5 Knockout (KO) mice exhibit improved humoral or cell-mediated immune responses, depending on the antigen trigger.

8
Autophagy is increased in postmortem brains of persons with HIV-1-associated encephalitis.
Zhou; Masliah; Spector (2011) [35]/ PUBMED/JBI (9/10) Case-control In neural cells exposed to either CXCR4-or CCR5-tropic HIV-1 gp120, levels of autophagic proteins and autophagosomes were elevated.The etiology of neuroAIDS is significantly influenced by the dysregulation of autophagy during HIV infection.In neural cells exposed to either CXCR4-or CCR5-tropic HIV-1 gp120, levels of autophagic proteins and autophagosomes were elevated.CCR5 expression on CD4+ cells was considerably decreased with Gp1a therapy in both immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL) and HIVE mice, according to flow cytometric studies.Between the treatment and control groups, the levels of CCR5 expression on CD8+ cells were not substantially different.Although neurons do not support HIV-1 infection or replication, they do express several cell-surface receptors (such as CCR5, CXCR4, NMDAR, etc.) that make them vulnerable to insults from viral proteins (such as Tat, gp120), inflammatory cytokines (such as TNF-alpha, IL-1), and small metabolites (such as nitric oxide, arachidonic acid, etc.) secreted by immune cells in the brain.The N-methyl-D-aspartate receptors (NMDAR), the low-density lipoprotein receptor-related protein (LRP), the chemokine receptors CCR5 and CXCR4, and the dopamine transporter are the key mediators of this susceptibility.HIV-1 gp120 can bind to either CCR5 or CXCR4 and cause neuroblastoma cell death.Gp120 can directly bind to CCR5 or CXCR4, starting a signaling cascade driven by p38-MAPK that causes neuronal death.The natural ligands of both CCR5 (such as CCL5, CCL3) and CXCR4 (such as CXCL12) were discovered to be neuroprotective against gp120 neurotoxicity.

Effects of HIV-1 Infection on Cellular and Molecular Pathways from the Perspective of the CCL5-CCR5 Immune Axis
Immune response against HIV-1 infection in the brain initiates with action of APC cells, such as macrophages, dendritic cells, and CD4+ T cells in the bloodstream, which recognize pathogen-associated molecular patterns (PAMPs) and pathogen-associated molecular damage (DAMPs) of the virus through virus recognition receptors patterns (PRRs), such as toll-like receptors (TLRs) to initiate an innate immune response through factors, such as inflammatory mediators [63].In this instance, CCR5 acts to fuse the viral membrane with that of the host cell and introduce viral particles into the cell to begin the viral replication process [64].
The process of neurotoxicity related to HAND was related to a series of viral pathogenic elements inside the affected cell that guide and drive the progression of the infection, whether directly or indirectly [65].The neurotoxicity of HIV-1 and HIV-1 proteins, such as gp120, Tat, and Nef, is what causes the direct effects of CNS infection with HIV-1 [28,33,40,41,57,60].In contrast, toxic mediators like quinolinic acid and arachidonic acid metabolites, as well as pro-inflammatory cytokines, are secreted by microglia or astrocytes that are either infected with HIV-1 or exposed to HIV-1 proteins, causing indirect neurotoxicity [38].Astrocytes make up around 70% of the brain, and these cells are prone to non-productive HIV-1 infection as well as low levels of productive infection [39,41,49].Since these cells oversee preserving brain homeostasis, they are crucial in mediating the neurotoxic consequences of CNS HIV-1 infection.As a result, there is the phosphorylation of molecules related to the activation of the NF-kB pathway, which release, in the nucleus, molecules related to the subsequent increased release of CCL5/RANTES, correlated with the increase in neuroinflammation and cellular damages in the brain [62].The main cells of the CNS affected by neuroAIDS, as described in the literary scene, are: neurons; microglia; astrocytes; and oligodendrocytes [32,40,42,[51][52][53]56,60,66].These tissue injuries cause clinical problems in affected individuals [67].
Neurocognitive deficits including diminished attention/concentration, psychomotor speed, memory, learning, information processing, and executive function are some of the neurocognitive symptoms of this process that are clinically manifest [68].Also present are motor slowness, incoordination, and tremor, which can develop into paraparesis, debilitating weakness, spasticity, and extrapyramidal movement disorders [69].Apathy and impatience are only a couple of the possible behavioral side effects.It is also possible to have psychomotor slowness, which is linked to frontal-striatal system injury [70].Clinically, this process can range in severity from asymptomatic neurocognitive impairment (ANI) to moderate neurocognitive disorder (MND) to full-blown HIV-associated dementia (HAD) [71].Since the initial diagnosis of AIDS dementia complex (ADC), HIV-associated cognitivemotor complex (HIVCMC), and most recently HIV-associated neurocognitive disorders (HAND), a variety of clinical nosologies have been used to describe this process [72].
Figure 2 describes the main findings of the articles included in this review regarding the process of HAND from the perspective of the CCL5-CCR5 pathway, considering the viral pathological effects since viral entry into the host's CNS cells.It demonstrates how devices induced by the pathogen molecularly deregulate the immune response of the affected cell to the point of affecting the pathway and leading to a worse mental prognosis in humans with cell death and neural damage.
devices induced by the pathogen molecularly deregulate the immune response of the affected cell to the point of affecting the pathway and leading to a worse mental prognosis in humans with cell death and neural damage.

Discussion
Research using postmortem tissue from AIDS patients, in situ hybridization [73], and immunohistochemical methods [74] have been used to show the presence of HIV-1 in the brain.Brain is a key location for viral infection and replication, which can happen in the early stages of HIV-1 sickness [75].It has been established that the release of CCL5/RANTES plays a critical role in modifying HIV-1 replication in mononuclear phagocytes in the blood and lung, and that the expression of CCR5 on T cell surfaces determines vulnerability to HIV/AIDS through variation in its activation [30].
Key immune activity regulators of the host can be represented by chemokines and their accompanied chemokine receptors [51,76].Homeostatic and inflammatory are the two kinds of main families of the chemokines [77].In immune homeostasis, homeostatic chemokines are primarily expressed in lymphoid organs and control leukocyte trafficking to these locations, whereas inflammatory chemokines (such as CCL5/RANTES) are

Discussion
Research using postmortem tissue from AIDS patients, in situ hybridization [73], and immunohistochemical methods [74] have been used to show the presence of HIV-1 in the brain.Brain is a key location for viral infection and replication, which can happen in the early stages of HIV-1 sickness [75].It has been established that the release of CCL5/RANTES plays a critical role in modifying HIV-1 replication in mononuclear phagocytes in the blood and lung, and that the expression of CCR5 on T cell surfaces determines vulnerability to HIV/AIDS through variation in its activation [30].
Key immune activity regulators of the host can be represented by chemokines and their accompanied chemokine receptors [51,76].Homeostatic and inflammatory are the two kinds of main families of the chemokines [77].In immune homeostasis, homeostatic chemokines are primarily expressed in lymphoid organs and control leukocyte trafficking to these locations, whereas inflammatory chemokines (such as CCL5/RANTES) are induced at infected/damaged tissues and draw leukocytes to areas that have experienced an inflammatory insult [17].
The CCL5-CCR5 axis prevents tissue macrophages from dying from virus-induced cell death, hence providing antiapoptotic signals for macrophage survival during infection [35].
CCL5-CCR5 association is a key regulator of endothelial progenitor cells' homing during wound healing, suggesting that CCL5 may be significant as a general B cell coactivator [14].Additionally, the interaction between CCL5 and its derivatives with CCR5 is thought to be a possible treatment axis for HIV-1 since the gp120 protein of HIV-1 binds to chemokine receptors CCR5 [15] or CXCR4 [12] as a major phase of HIV-1 entrance into the host cell.
Chemokine receptors play crucial functions in the attraction and placement of immune cells within tissues and have been linked to a variety of CNS inflammatory illnesses [55].Correlative research links the CCR5-chemokine axis to a variety of illnesses, including cerebral malaria, Rasmussen encephalitis, progressive multifocal leukoencephalopathyassociated immune reconstitution inflammatory syndrome, and HAND issues [58].In addition, it has been demonstrated that CCL5/RANTES contributes to the development of Parkinson Disease and multiple sclerosis, i.e., other neurodegenerative illnesses [78,79].In this context, this work sought to review the AIDS neuropathogenesis induced by the CCL5-CCR5 immune pathway and build an illustration in the article for didactic visualization of related immune and biological processes.
Many viral proteins can cause direct harm to neurons.Numerous neuronal cell surface receptors, including the N-methyl-D-aspartate receptors (NMDAR), the low-density lipoprotein receptor-related protein (LRP), the chemokine receptors CCR5 and CXCR4, and the dopamine transporter, play a major role in mediating this sensitivity [79,80].The most prevalent neurotransmitter in the brain, glutamate, is responsible for facilitating the transmission of excitatory signals by binding to NMDAR and opening cation-specific channels in cell membranes, which permit the entry of sodium, calcium, and potassium ions while blocking the exit of other ions [81].LRP is involved in the movement of cholesterol inside neurons, as well as signaling and preventing apoptosis in these cells [82].
Dopamine receptors and transporters are less common than NMDAR, but they are still significant because they are present in regions of the brain that are vulnerable to HIV-1 infection, such as the striatum and substantia nigra, which are involved in executive function and the behavioral reward system [50].Additionally, dopamine transporter expression is lower in the striatum of HIV patients with cognitive deficits [11].The two main viral proteins, Tat and gp120, interact with the receptors to harm neurons.Both monomeric and oligomeric gp120 have neurotoxic properties [48,60], and transgenic mice producing gp120 show a variety of neuronal and glial alterations reflecting abnormalities in the brains of HIV-1-infected people [34].
The expression of genes including CCR5, CXCR4, CD4, and CypA, as well as factors that inhibit viral replication like TRIM5 and APOBEC3G, take on greater significance in this research area [83].They produce human proteins (such as the chemokines) that are directly related to the host's immune response against the pathogen [84].Additionally, it is known that genetic polymorphisms in the HIV-1 coreceptors (such as in CCR5) and their ligands (like RANTES/CCL5) affect several aspects in immune response, including the severity of the infection [85,86].
Recent meta-analysis by Silva et al. (2023) conducted analysis of genetic variants, more precisely three functional single nucleotide polymorphisms (SNPs) of CCL5/RANTES and demonstrated that reduced expression of this gene decreases the level of CCL5 protein production and increases risk of HIV-1 progressing to AIDS [87].Previous meta-analyses and systematic reviews carried out to evaluate SNPs and insertions and deletions (Indels) in the CCR5 gene (such as the CCR5-delta32 variant) also claimed that increased expression of this viral coreceptor in host cells and increases the susceptibility and severity of AIDS [85,88].The study by Tamamis and Floudas (2016) with bioinformatics methods predicted the potential benefits of the CCL5-CCR5 immune axis and provides insights into the blocking mechanism of HIV-1 by CCL5/RANTES [20].
Although studies have already been carried out relating variants of these genes to the worse prognosis of HIV-1 disease, to date, no epidemiological association study between genetic polymorphisms of CCL5/RANTES and/or CCR5 has specifically sought relationships for cohorts of individuals.with neuroAIDS.Thus, the research conducted so far regarding both gene and protein expression suggests that the elevation of these factors conditioned to CCL5/RANTES appears to mitigate the clinical evolution of general AIDS, and vice versa [89].
According to the results found in this present study, divergent data were found regarding the expression levels of the chemokine CCL5/RANTES and its role in neuroinflammation, while all research that analyzed CCR5 in patients with neurological manifestations associated with AIDS, there were positive associations between increased receptor synthesis and greater brain damage, so as reported by previous research [90,91].
In this case, unlike what has already been proposed about the associations between the regulation of gene expression and, consequently, the production of the CCL5/RANTES protein related to the susceptibility and/or progression of HIV-1 infection, high levels of CCL5/RANTES may be related to both pro-and anti-inflammatory roles against apoptosis in neuroAIDS.However, it was also noted in this review that all studies that reported a direct relationship in their results between increased CCL5 and greater neurotoxicity in these patients had a serum concentration of CCL5/RANTES > 20 nM (156 ng/mL).
Therefore, it is suggested the existence of a relative threshold between CCL5/RANTES expression levels in the CNS of the infected individual for their effective immune response against the pathogen, through the CCL5-CCR5 axis, as many studies in this review also concluded a beneficial organic role in the evolution of the neurological clinical picture related to the elevation of the levels of this chemokine (all at a concentration of CCL5/RANTES ≤ 20 nM) in the blood of individuals with AIDS.
In this sense, inflammation is a defense device necessary for an immune response required in disease, while an excessive amount is deleterious.An example of these cases are severe cases of COVID-19, in which these individuals develop, at an advanced stage of the disease, a molecular positive feedback condition that exacerbates the inflammatory condition in the body, which can generate multiple organ dysfunction.However, this inflammatory response triggered in the initial immune response to SARS-CoV-2 in initial cases of infection is crucial to avoid a worsening prognosis and inflammatory progression to the point of causing organic disorders, through inflammatory manifestations, such as a cytokine storm [92].
In this context, this article makes a pioneering hypothesis about the possible cause of the divergence already reported through observations of similar data from the included studies.If this hypothesis is confirmed by new primary studies on the disease, one of the possible causes for the greater cerebral pathogenesis in these cases could be hypercytokinemia correlated with a hyperinflammatory condition.
Regarding CCR5, desensitization, internalization, and recycling or receptor degradation all play a role in the control of its expression.According to Oppermann (2004), these pathways are started by either homologous or heterologous phosphorylation of the receptor/ligand complex by protein kinase C (PKC) or G protein-coupled receptor kinases [93].Therefore, several studies have already reported the effectiveness of CCR5 antagonist drugs in proposing measures against HIV-1 infection, corroborating the findings of this review for associated with factors, such as neurological complications [94].Besides that, although neuronal death is associated with HAND (which is usually thought of as severe cognitive impairment), the more relevant importance of inflammation in the era of ART is in the minor cognitive impairment that is seen in up to 25% of those infected with HIV.In these cases, there is no sign of neuronal death and the cognitive impairment is thought to be a direct effect of inflammation resulting in neuron dysfunction [4,95].
In addition to CCR5 antagonists, CCR5-ligand chemokine RANTES serves as an appropriate molecular building block for the development of effective HIV drugs.In the search for new HIV-1 entry inhibitors, RANTES-engineering techniques have been extremely valuable through the formulation of potential CCL5/RANTES derivatives [96].The ongoing development of chosen molecular leads is being driven by a "mixed" strategy that combines structure-guided design with empirical testing.HIV microbicides based on CCL5/RANTES might be given exogenously and generated in a gel carrier to sustain protective concentrations for a long time [97].
As an alternative, bacterial systems that can produce recombinant CCL5/RANTES derivatives endogenously following colonization of the female genital tract (live microbicides) might be created.When safe and efficient RANTES derivatives that may prevent HIV-1 transmission to intraepithelial CD4+ T cells and mononuclear phagocytic cells in the vaginal canal become available, the field of microbicides may benefit the most [98].Therefore, this present study can provide support for therapeutic applications and new forms of treatment, although primary studies are still needed to confirm the information described about the role of CCL5/RANTES levels in neuroAIDS [99,100].
Some previous reviews [101,102] have already been conducted regarding the association between this immune axis and neuropathogenesis caused by AIDS disease.However, this review is a pioneer in presenting a scheme in image format relating immunopathology to the CCL5-CCR5 complex.The study limitations identified were: (1) each study's respective definition of HIV-1 infection based on case identification; (2) each study's respective definition of neuroAIDS severity based on case identification; (3) the methodology applied in each study; (4) the need for different HIV-1 variants to evaluate data from these included studies; (5) the methodology adopted for this systematic review.Future epidemiological studies with cohorts of diverse populations aimed at identifying new molecular pathways involved and characterizing the CCL5-CCR5 complex in these individuals are essential for defining new panoramas of health strategies [103].

Conclusions
Host factors that mediate the neurotoxic damage set on by the CNS being subjected to HIV-1-infected cells, HIV-1, or certain HIV-1 proteins.Different diseases have varying degrees of severity due to different neurotoxic pathways, such as the CCL5-CCR5 axis.Astrocytes, neurons, and microglia all express the chemokine receptor CCR5.CCR5 directly affects the progression of the neurological condition.It was shown that CCL5 can have distinct impacts on viral infectivity and neurotoxicity when it comes to neuroAIDS.
This review also concludes that greater attention should be given to subsequent studies aiming at therapeutic improvement, through the observation and association between clinical-epidemiological factors of individuals with neuroAIDS and the molecular concentrations of CCL5/RANTES and CCR5 in the blood, aiming to create a new molecular biomarker for monitoring and monitoring these patients.
Then, it was suggested here that there are several ways to precisely counteract the neurotoxicity of viral and host proteins, as well as possible neuroprotective elements that may be strengthened to lessen the detrimental effects of HIV-1 on the brain.Direct neuronal death, abnormal control of essential neuronal support cells, and dendritic arbor loss are the main factors that cause HAND.Therefore, new therapeutic and interventional strategies can be conditioned on the immunological direction proposed in this review for the disease.
Author Contributions: M.J.A.S. was responsible for the conceptualization, formal analysis, data curation, methodology, investigation, validation, visualization, and roles/writing-original draft, editing.R.L.M. performed the data curation, investigation, visualization, and roles/writing-original draft, editing.Y.C.R. performed the supervision, validation, visualization, and writing-review and editing.T.P.B. performed the data curation, methodology, and validation.P.A.S.D.S. performed the data curation, methodology, and validation.C.S.S. was responsible for the resources, software, and validation.D.M.S. performed the validation, visualization, and writing-review and editing.K.V.B.L. was responsible for the supervision, visualization, and writing-review and editing.L.N.G.C.L. performed the conceptualization, investigation, project administration, supervision, visualization, and writing-review and editing.All authors have read and agreed to the published version of the manuscript.

Funding:
The authors received no external funding.
Institutional Review Board Statement: Not applicable.

Figure 1 .
Figure 1.PRISMA flowchart of the stages of selection of the articles within this systematic review.

Figure 1 .
Figure 1.PRISMA flowchart of the stages of selection of the articles within this systematic review.

Figure 2 .
Figure 2. CCL5-CCR5 axis induction by HIV-1 infection and HIV-1 neurotoxicity effects in molecular and cellular levels of the central nervous system (CNS).Their stages are indicated in chronological order of events by letters (A-F).It describes the stages of immune processes in the human body from viral entry into the CNS cells and the processes of adhesion and recognition by APCs (A), viral replication process releases viral proteins that exacerbate the inflammatory process (B), and the activation of cell signaling pathways (C): in the cellular cytoplasm, viral proteins act on joint pathways for secretion of co-stimulatory molecules of this inflammation (C1); toll-like receptors (TLRs) activate other protein pathways that induce phosphorylation of molecules related to the activation of the NF-kB pathway (C2-C4); with subsequent increased release of CCL5/RANTES and matrix metalloproteinases (MMPs) associated with neuroinflammation (C5); other viral proteins act by increasing the viral load and generating an inflammatory cycle (C6).Ultimately, they generate reactive astrocytes, affected oligodendrocytes, and neurons, and ROS, RNS, inflammatory mediators and neurotoxins determine apoptosis, inflammation of neurons, and other CNS cells (in the absence of cell death), and damage to neuronal cells (D-F).

Figure 2 .
Figure 2. CCL5-CCR5 axis induction by HIV-1 infection and HIV-1 neurotoxicity effects in molecular and cellular levels of the central nervous system (CNS).Their stages are indicated in chronological order of events by letters (A-F).It describes the stages of immune processes in the human body from viral entry into the CNS cells and the processes of adhesion and recognition by APCs (A), viral replication process releases viral proteins that exacerbate the inflammatory process (B), and the activation of cell signaling pathways (C): in the cellular cytoplasm, viral proteins act on joint pathways for secretion of co-stimulatory molecules of this inflammation (C1); toll-like receptors (TLRs) activate other protein pathways that induce phosphorylation of molecules related to the activation of the NF-kB pathway (C2-C4); with subsequent increased release of CCL5/RANTES and matrix metalloproteinases (MMPs) associated with neuroinflammation (C5); other viral proteins act by increasing the viral load and generating an inflammatory cycle (C6).Ultimately, they generate reactive astrocytes, affected oligodendrocytes, and neurons, and ROS, RNS, inflammatory mediators and neurotoxins determine apoptosis, inflammation of neurons, and other CNS cells (in the absence of cell death), and damage to neuronal cells (D-F).

Table 1 .
Data analyzed of the articles included in this review.
nanomoles (nM) (equal to 78.76 ng/mL), promoting neuronal survival under pro-apoptotic conditions.However, the maximal levels of CCL5 induction by gp120 in the current investigation were only 3 ng/mL, preventing the concentration from being protective.CCL5 rise mediated by Gp120 can only be understood as responsible for a neuroinflammatory response.A particular NF-kB inhibitor and siRNA might partially stop the elevated CCL5 synthesis.
CohortIt implies that RANTES can activate signaling pathways through an alternate receptor or receptors that are GAG dependent, but which are presumably not known, particular GPCR chemokine receptors, at both low, physiologically appropriate concentrations and at greater, potentially supraphysiological concentrations.At a post entry stage of the viral life cycle, the subsequent activation of MAPK at high RANTES concentrations can improve the efficacy of HIV-1 replication.Protein tyrosine kinases (PTK)-and MAPK-dependent signaling pathway is activated by the interaction of CCL5/RANTES with cell surface, glycosaminoglycans (GAGs).