Neurological manifestation with special reference to HIV-associated neurocognitive disorder (HAND) among people on anti-retroviral treatment in India.

OBJECTIVE: The neurological manifestations and their severity in patients on antiretroviral treatment (ART) are currently unexplained. We aimed at studying the prevalence of HIV Associated Neurological Disorders (HAND) among people on antiretroviral treatment, using the International HIV Dementia Scale (IHDS). PATIENTS AND METHODS: A predesigned and pretested proforma including the International HIV Dementia Scale (IHDS) was administered to 100 HIV patients attending to ART center of KIMS teaching Hospital (Koppal, Karnataka) from January 2020 to March 2020. The data was analyzed SPSS version 15 software. Descriptive statistics were used for demographic characteristics. The Student's t-test and chi-square test methods were applied to determine the relationship between qualitative characteristics. RESULTS: The prevalence was found to be 59%. Out of 100, 57 HIV patients scored less than 10 whereas 43 HIV patients scored ≥10 on the IHDS scale. The mean age of the study population was 39.14 ±13.01 years; the total IHDS score was 9.96±1.53 and the CD4 count was 427.91±226.0. This study demonstrated that the patients with CD4 count more than 350 (i.e., 63.60%) had a better IHDS score. CONCLUSIONS: Neurocognitive disorder was found to be more common than anticipated. All ICTC Centers need to consider assessing HIV-associated neurocognitive disability (HAND), and the International HIV Dementia Scale (IHDS) as one instrument for such assessment.

HIV-Associated Neurotoxicity: The Interplay of Host and Viral Proteins.

HIV-1 can incite activation of chemokine receptors, inflammatory mediators, and glutamate receptor-mediated excitotoxicity. The mechanisms associated with such immune activation can disrupt neuronal and glial functions. HIV-associated neurocognitive disorder (HAND) is being observed since the beginning of the AIDS epidemic due to a change in the functional integrity of cells from the central nervous system (CNS). Even with the presence of antiretroviral therapy, there is a decline in the functioning of the brain especially movement skills, noticeable swings in mood, and routine performance activities. Under the umbrella of HAND, various symptomatic and asymptomatic conditions are categorized and are on a rise despite the use of newer antiretroviral agents. Due to the use of long-lasting antiretroviral agents, this deadly disease is becoming a manageable chronic condition with the occurrence of asymptomatic neurocognitive impairment (ANI), symptomatic mild neurocognitive disorder, or HIV-associated dementia. In-depth research in the pathogenesis of HIV has focused on various mechanisms involved in neuronal dysfunction and associated toxicities ultimately showcasing the involvement of various pathways. Increasing evidence-based studies have emphasized a need to focus and explore the specific pathways in inflammation-associated neurodegenerative disorders. In the current review, we have highlighted the association of various HIV proteins and neuronal cells with their involvement in various pathways responsible for the development of neurotoxicity.

Cerebrospinal fluid immune markers and HIV-associated neurocognitive impairments: A systematic review.

HIV-1 is responsible for the development of a spectrum of cognitive impairments known as HIV-associated neurocognitive disorder (HAND). In the era of antiretroviral therapy (ART), HAND remains prevalent in people living with HIV (PLWH), despite low or undetectable viral loads. Persistent neuroinflammation likely plays an important role in the contributing biological mechanisms. Multiple cerebrospinal fluid (CSF) immune markers have been studied but it is unclear which markers most consistently correlate with neurocognitive impairment. We therefore conducted a systematic review of studies of the association of CSF immune markers with neurocognitive performance in ART-experienced PLWH. We aimed to synthesize the published data to determine consistent findings and to indicate the most noteworthy CSF markers of HAND. Twenty-nine studies were included, with 20 cross-sectional studies and 9 longitudinal studies. From the group of markers most often assayed, specific monocyte activation (higher levels of Neopterin, sCD163, sCD14) and neuroinflammatory markers (higher levels of IFN-γ, IL-1α, IL-7, IL-8, sTNFR-II and lower levels of IL-6) showed a consistent direction in association with HIV-associated neurocognitive impairment. Furthermore, significant differences exist in CSF immune markers between HIV-positive people with and without neurocognitive impairment, regardless of viral load and nadir/current CD4+ count. These markers may be useful in furthering our understanding of the neuropathology, diagnosis and prognosis of HAND. Studies using prospective designs (i.e. pre- and post-interventions), "multi-modal" methods (e.g. imaging, inflammation and neurocognitive evaluations) and utilizing a combination of the markers most commonly associated with HAND may help delineate the mechanisms of HAND.

Plasma anti-CD4 IgG is associated with brain abnormalities in people with HIV on antiretroviral therapy.

Anti-CD4 IgG autoantibodies have been implicated in CD4+ T cell reconstitution failure, leaving people with HIV (PWH) at heightened risk of HIV-associated comorbidities, such as neurocognitive impairment. Seventeen PWH on stable anti-retroviral therapy (ART) and 10 HIV seronegative controls had plasma anti-CD4 IgG antibodies measured by enzyme-linked immunosorbent assay. Neuropsychological (NP) tests assessed cognitive performance, and brain volumes were measured by structural magnetic resonance imaging. Anti-CD4 IgG levels were elevated (p = 0.04) in PWH compared with controls. Anti-CD4 IgG correlated with global NP z-scores (rho = - 0.51, p = 0.04). A relationship was observed between anti-CD4 IgG and putamen (ß = - 0.39, p = 0.02), pallidum (ß = - 0.38, p = 0.03), and amygdala (ß = - 0.42, p = 0.05) regional brain volumes. The results of this study suggest the existence of an antibody-mediated relationship with neurocognitive impairment and brain abnormalities in an HIV-infected population.

Effects of HIV gp120 on Neuroinflammation in Immunodeficient vs. Immunocompetent States.

HIV affects 37 million people worldwide, 25-69% of which develop HIV-associated neurocognitive disorders (HAND) regardless of antiviral treatment. HIV infection of the brain decreases cognitive function, disrupts/impairs learning and memory, and reduces quality of life for those affected. HIV-induced neuroinflammation has been associated with viral proteins such as gp120 and Tat, which remain elevated in the CNS even in patients with low peripheral viremia counts. In this study, we examined the effects of gp120 on neuroinflammation in immunodeficient vs. immunocompetent states by examining neuroinflammatory markers in gp120tg mice with or without systemic immunodeficiency caused by murine retroviral administration (LP-BM5 murine AIDS). Changes in inflammatory cytokine/chemokine mRNA expression was complex and dependent upon expression of gp120 protein, immunodeficiency status, brain region (hippocampus, frontal lobe, or striatum), and age. Gp120 expression reduced hippocampal synaptophysin expression but did not affect animals' learning/memory on the spontaneous T-maze test in our experimental conditions. Our results emphasize the critical role of the neuroinflammatory micro-environment and the peripheral immune system context in which gp120 acts. Multiple factors, particularly system-level differences in the immune response of different brain regions, need to be considered when developing treatment for HAND. Graphical Abstract.

HIV-associated neurocognitive disorder and HIV-associated myelopathy in a patient with a preserved CD4, but high viral load-a rarely reported phenomenon: a case report and literature review.

BACKGROUND: Despite widespread use of combination antiretroviral therapy (cART), HIV-associated neurocognitive disorder (HAND) and HIV-associated myelopathy (HAM) are not showing significant reduction in there occurrence. The HAM is a progressive myelopathy that often occur synchronously with severe form of the HAND in patients' having advanced immunosuppression. However, co-existence of less severe form of the HAND and HAM in patient with relatively preserved CD4 cells is rarely reported clinical entity in post cART era. CASE PRESENTATION: We report a 16-year old male, acquired HIV infection vertically, was on second line regimen because of virological failure since 3 years. His current CD4 lymphocyte count is 835 cells/uL with viral RNA level of 33,008 copies/mL. Currently presented with progressive forgetfulness, gait imbalance, and a frequent staring episodes without loss of postural tone. Neurological examination was pertinent for cognitive dysfunction with score of 6 on International HIV Dementia Scale (motor speed = 3, psychomotor speed = 2, and memory recall = 1). Lower limbs power is 4-/5, increased deep tendon reflexes, and unsteady gait. Brain MRI revealed diffuse both cortical and white matter T2 and FLAIR hyperintense lesions. Thoracic MRI showed abnormal T2 signal prolongation spanning from mid thoracic cord to conus. Electroencephalography study showed severe generalized slowing with evidence of focal dysrhythmia in bilateral frontotemporal regions. Unremarkable serum vitamin B 12 level (286 ng/mL). Virological failure with the HAND, HAM and seizure was considered. Dolutegravir +3TC + ATV/r regimen and valproate for seizure disorder was started. On 6 months follow up evaluation, he is clinically stable with significant improvement of his symptoms related to seizure disorders and modest improvement of his cognitive dysfunction, as he is now attending his school regularly. However, less improvement was observed reading his gait abnormality. CONCLUSION: This case supports the current understanding regarding the persistent occurrence of HIV-associated neurocognitive disorder and HIV-associated myelopathy even decades after introduction of cART. Therefore, it's important to screen HIV+ patients for the HAND and HAM even if they have relatively preserved immunity. Because patient can be easily shifted to ART drugs with better CNS penetrating potential to achieve acceptable virological suppression level, to observe sound clinical improvement.

CD8 + T-lymphocyte Encephalitis: A Systematic Review.

The increase of CD8 + T lymphocytes in the perivascular spaces of patients with HIV encephalopathy has been reported in some studies. CD8 + T lymphocyte encephalitis was first described in 2013 and then a few other similar cases were published. We proposed to analyze the clinical, MR imaging, and histopathology findings of CD8 + T lymphocyte encephalitis. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyzes protocol using the PubMed, Scopus, Lilacs, and IBECS databases up to February 3, 2018. Seven articles were included, two case series and five case reports. A total of 19 individuals were evaluated. MRI showed alterations in the white matter signal in all cases. Histopathology showed a predominance of CD8 + T lymphocytes. The findings described so far may resemble the inflammatory immune reconstitution syndrome. New studies on the subject are needed in an attempt to characterize the differences between these two entities.

Plasma CXCL10 correlates with HAND in HIV-infected women.

HIV-associated neurocognitive disorder (HAND) is characterized by chronic immune activation. We aimed to identify biomarkers associated with HAND and to investigate their association with cognitive function and sex, in a homogenous cohort of HIV-infected (HIV+) young adults, parenterally infected during early childhood. One hundred forty-four HIV+ Romanian participants (51% women) without major confounders underwent standardized neurocognitive and medical evaluation in a cross-sectional study. IFN-γ, IL-1ß, IL-6, CCL2, CXCL8, CXCL10, and TNF-α were measured in plasma in all participants and in cerebrospinal fluid (CSF) in a subgroup of 56 study participants. Biomarkers were compared with neurocognitive outcomes, and the influence of sex and HIV disease biomarkers was assessed. In this cohort of young adults (median age of 24 years), the rate of neurocognitive impairment (NCI) was 36.1%. Median current CD4+ count was 479 cells/mm3 and 36.8% had detectable plasma viral load. Women had better HIV-associated overall status. In plasma, controlling for sex, higher levels of IL-6 and TNF-α were associated with NCI (p < 0.05). Plasma CXCL10 showed a significant interaction with sex (p = 0.02); higher values were associated with NCI in women only (p = 0.02). Individuals with undetectable viral load had significantly lower plasma CXCL10 (p < 0.001) and CCL2 (p = 0.02) levels, and CSF CXCL10 (p = 0.01), IL-6 (p = 0.04), and TNF-α (p = 0.04) levels. NCI in young men and women living with HIV was associated with higher IL-6 and TNF-α in plasma, but not in the CSF. CXCL10 was identified as a biomarker of NCI specifically in women with chronic HIV infection.

Limited correlation between systemic biomarkers and neurocognitive performance before and during HIV treatment.

The AIDS Clinical Trials Group (ACTG) study A5303 investigated the associations between neuropsychological performance (NP) and inflammatory biomarkers in HIV-infected participants. Fifteen NP tests were administered at baseline and week 48 to 233 ART naïve participants randomized to maraviroc- or tenofovir-containing ART. Neurocognition correlated modestly with markers of lymphocyte activation and inflammation pre-ART (percent CD38+/HLA-DR+(CD4+) (r = - 0.22, p = 0.02) and percent CD38+/HLA-DR+(CD8+) (r = - 0.25, p = 0.02)), and with some monocyte subsets during ART (r = 0.25, p = 0.02). Higher interleukin-6 and percent CD38+/HLA-DR+(CD8+) were independently associated with worse severity of HIV-associated neurocognitive disorders (HAND) (p = 0.04 and 0.01, respectively). More studies to identify HAND biomarkers are needed.

Cognitive impairment and CSF proteome modification after oral bacteriotherapy in HIV patients.

OBJECTIVE: To investigate whether a probiotic supplementation to cART patients modifies the cerebrospinal fluid (CSF) proteome and improves neurocognitive impairment. METHODS: 26 CSF samples from 13 HIV-positive patients [six patients living with HIV (PLHIV) and seven patients with a history of AIDS (PHAIDS)] were analyzed. All patients underwent to neurocognitive evaluation and blood sampling at baseline and after 6 months of oral bacteriotherapy. Immune phenotyping and activation markers (CD38 and HLA-DR) were evaluated on peripheral blood mononuclear cells (PBMC). Plasma levels of IL-6, sCD14, and MIP-1ß were detected, by enzyme-linked immunosorbent assay (ELISA). Functional proteomic analysis of CSF sample was conducted by two-dimensional electrophoresis; a multivariate analysis was performed by principal component analysis (PCA) and data were enriched by STRING software. RESULTS: Oral bacteriotherapy leads to an improvement on several cognitive test and neurocognitive performance in both groups of HIV-positive subjects. A reduction in the percentage of CD4+CD38+HLA-DR+ T cells was also observed at peripheral level after the probiotic intake (p = 0.008). In addition, the probiotic supplementation to cART significantly modifies protein species composition and abundance at the CSF level, especially those related to inflammation (ß2-microglobulin p = 0.03; haptoglobin p = 0.06; albumin p = 0.003; hemoglobin p = 0.003; immunoglobulin heavy chains constant region p = 0.02, transthyretin p = 0.02) in PLHIV and PHAIDS. CONCLUSIONS: Our results suggest that oral bacteriotherapy as a supplement to cART could exert a role in the amelioration of inflammation state at peripheral and CNS level.

Interleukin-6 is associated with mortality and neuropsychiatric outcomes in antiretroviral-naïve adults in Rakai, Uganda.

Serum interleukin-6 (IL-6) and D-dimer have been associated with multiple adverse outcomes in HIV-infected (HIV+) individuals, but their association with neuropsychiatric outcomes, including HIV-associated neurocognitive disorder (HAND) and depression, headaches, and peripheral neuropathy have not been investigated. Three hundred ninety-nine HIV+ antiretroviral therapy (ART)-naïve adults in Rakai, Uganda, were enrolled in a longitudinal cohort study and completed a neurological evaluation, neurocognitive assessment, and venous blood draw. Half of the participants had advanced immunosuppression (CD4 count < 200 cells/µL), and half had moderate immunosuppression (CD4 count 350-500 cells/µL). All-cause mortality was determined by verbal autopsy within 2 years. HAND was determined using Frascati criteria, and depression was defined by the Center for Epidemiologic Studies-Depression (CES-D) scale. Neuropathy was defined as the presence of > 1 neuropathy symptom and > 1 neuropathy sign. Headaches were identified by self-report. Serum D-dimer levels were determined using ELISA and IL-6 levels using singleplex assays. Participants were 53% male, mean age 35 + 8 years, and mean education 5 + 3 years. Participants with advanced immunosuppression had significantly higher levels of IL-6 (p < 0.001) and a trend toward higher D-dimer levels (p = 0.06). IL-6 was higher among participants with HAND (p = 0.01), with depression (p = 0.03) and among those who died within 2 years (p = 0.001) but not those with neuropathy or headaches. D-dimer did not vary significantly by any outcome. Systemic inflammation as measured by serum IL-6 is associated with an increased risk of advanced immunosuppression, all-cause mortality, HAND, and depression but not neuropathy or headaches among ART-naïve HIV+ adults in rural Uganda.

Role of the inflammasomes in HIV-associated neuroinflammation and neurocognitive disorders.

HIV associated neurocognitive disorders (HAND) is a unique form of neurological impairment that stems from HIV. This disease and its characteristics can be accredited to incorporation of DNA and mRNA of HIV-1 into the CNS. A proper understanding of the intricacies of HAND and the underlying mechanisms associated with corresponding immune reactions are vital for the potential development of a reliable treatment for HAND. A common phenomenon observed in CNS cells, specifically microglia, that are infected with HAND is inflammation, which is a consequence of the activation of innate immune response due to a variety of stimuli, in this case, being the HIV infection. The CNS based inflammation is mediated by the production of cytokines, chemokines, reactive oxygen species, and secondary messengers, which occurs at CNS glia, endothelial cells and peripherally derived immune cells. Inflammasomes play a significant role with regard to neuroinflammation due to their ability to dictate the activation of various inflammatory responses. Certain stimuli can result in the activation of caspase-1; hence, leading to the processing of interleukin-1ß and interleukin-18 pro-inflammatory cytokines. The processed IL-1ß and IL-18 activate signaling pathways that begin the process of neuroinflammation. Due to the fact that the NLRP3 inflammasome is the most abundant in the CNS, it is the most extensively investigated inflammasome with regard to the nervous system. Due to the importance of neuroinflammation in the evolution of HAND and proliferation of neuroinflammation due to HAND, it can be concluded that there exists a relationship between HAND and inflammasomes. The aim of our review is to consolidate current knowledge of important mechanisms in HAND, specifically related to its relationship with neuroinflammation and inflammasomes to shed light on a possible improved treatment for HAND.

Epitranscriptomics: Correlation of N6-methyladenosine RNA methylation and pathway dysregulation in the hippocampus of HIV transgenic rats.

Internal RNA modifications have been known for decades, however their roles in mRNA regulation have only recently started to be elucidated. Here we investigated the most abundant mRNA modification, N6-methyladenosine (m6A) in transcripts from the hippocampus of HIV transgenic (Tg) rats. The distribution of m6A peaks within HIV transcripts in HIV Tg rats largely corresponded to the ones observed for HIV transcripts in cell lines and T cells. Host transcripts were found to be differentially m6A methylated in HIV Tg rats. The functional roles of the differentially m6A methylated pathways in HIV Tg rats is consistent with a key role of RNA methylation in the regulation of the brain transcriptome in chronic HIV disease. In particular, host transcripts show significant differential m6A methylation of genes involved in several pathways related to neural function, suggestive of synaptodendritic injury and neurodegeneration, inflammation and immune response, as well as RNA processing and metabolism, such as splicing. Changes in m6A methylation were usually positively correlated with differential expression, while differential m6A methylation of pathways involved in RNA processing were more likely to be negatively correlated with gene expression changes. Thus, sets of differentially m6A methylated, functionally-related transcripts appear to be involved in coordinated transcriptional responses in the context of chronic HIV. Altogether, our results support that m6A methylation represents an additional layer of regulation of HIV and host gene expression in vivo that contributes significantly to the transcriptional effects of chronic HIV.

CSF concentrations of soluble TREM2 as a marker of microglial activation in HIV-1 infection.

Objective: To explore changes in CSF sTREM2 concentrations in the evolving course of HIV-1 infection. Methods: In this retrospective cross-sectional study, we measured concentrations of the macrophage/microglial activation marker sTREM2 in CSF samples from 121 HIV-1-infected adults and 11 HIV-negative controls and examined their correlations with other CSF and blood biomarkers of infection, inflammation, and neuronal injury. Results: CSF sTREM2 increased with systemic and CNS HIV-1 disease severity, with the highest levels found in patients with HIV-associated dementia (HAD). In untreated HIV-1-infected patients without an HAD diagnosis, levels of CSF sTREM2 increased with decreasing CD4+ T-cell counts. CSF concentrations of both sTREM2 and the neuronal injury marker neurofilament light protein (NFL) were significantly associated with age. CSF sTREM2 levels were also independently correlated with CSF NFL. Notably, this association was also observed in HIV-negative controls with normal CSF NFL. HIV-infected patients on suppressive antiretroviral treatment had CSF sTREM2 levels comparable to healthy controls. Conclusions: Elevations in CSF sTREM2 levels, an indicator of macrophage/microglial activation, are a common feature of untreated HIV-1 infection that increases with CD4+ T-cell loss and reaches highest levels in HAD. The strong and independent association between CSF sTREM2 and CSF NFL suggests a linkage between microglial activation and neuronal injury in HIV-1 infection. CSF sTREM2 has the potential of being a useful biomarker of innate CNS immune activation in different stages of untreated and treated HIV-1 infection.

Type I Interferons in NeuroHIV.

Infection with Human Immunodeficiency Virus (HIV)-1 continues to cause HIV-associated neurocognitive disorders despite combined antiretroviral therapy. Interferons (IFNs) are important for any antiviral immune response, but the lasting production of IFNα causes exhaustive activation leading eventually to progression to AIDS. Expression of IFNα in the HIV-exposed central nervous system has been linked to cognitive impairment and inflammatory neuropathology. In contrast, IFNß exerts anti-inflammatory effects, appears to control, at least temporarily, lentiviral infection in the brain and provides neuroprotection. The dichotomy of type I IFN effects on HIV-1 infection and the associated brain injury will be discussed in this review, because the underlying mechanisms require further investigation to allow harnessing these innate immune factors for therapeutic purposes.

FACTORS AFFECTING THE FATAL OUTCOME IN HIV-INFECTED PATIENTS WITH ENCEPHALITIS.

Despite the successful use of ART up to 40-70% of HIV(+) individuals have neurologic complications caused both by the HIV itself and by the reactivation of OIs on the background of severe immunodeficiency. Nowadays, there are no universally recognized criteria that allow predicting the outcome of encephalitis caused by OIs in this category of patients. The aim of our study was to assess factors affecting the fatal outcome in HIV(+) patients with CNS involvement. Retrospectively we selected 53 HIV(+) patients with confirmed encephalitis due to OIs. Depending on the outcome of the disease, patients were divided into groups: non-survivors (n=22) and survivors (n=31), after compared their clinical manifestation, history of the disease and life, CSF results in the first days of admission. It has been established that the factors affecting the fatal outcome in HIV(+) patients with encephalitis are: the severity of the patient's condition upon admission, acuteness of the onset of the disease, the severity of neurologic symptoms, the degree of co-morbidity, the level of immunosuppression and viral load, absence of ART.

Peripheral and cerebrospinal fluid immune activation and inflammation in chronically HIV-infected patients before and after virally suppressive combination antiretroviral therapy (cART).

Cerebrospinal fluid (CSF)/plasma HIV-RNA ratio has been associated with residual neurocognitive impairment on cART, leading us to hypothesize a specific peripheral and/or CSF immune feature in patients with high CSF/plasma ratio (≥ 1). In patients with diverse pre-cART CSF/plasma ratio (61/70 with CSF/plasma ratio < 1, L-CSF, 9/70 with CSF/plasma ratio ≥ 1, H-CSF), we investigated the effects of 12 months of effective cART on peripheral and CSF inflammatory markers, on T cell activation/maturation and HIV/CMV-specific intracellular cytokine pattern. We also studied the possible clinical association between peripheral/CSF pro-inflammatory milieu and neurocognitive screening tests (MMSE, FAB, IHDS). Prior to cART, the two groups were comparable for peripheral and CSF inflammation, T cell activation/proliferation and maturation, and HIV/CMV-specific response. Upon cART initiation, both H-CSF and L-CSF featured a significant reduction in plasma TNF-α and circulating CD8 activation, with a redistribution of memory/naïve T cell subsets in L-CSF alone. In the CSF compartment, cART seemed able to reduce pro-inflammatory cytokine/chemokine levels in both H-CSF and L-CSF patients. Interestingly, despite a reduction in the pro-inflammatory milieu, no changes were shown in neurocognitive screening tests in both patients' groups. We hereby show that 12-month cART is able to reduce intratechal and peripheral pro-inflammatory burden; a longer cART exposure and a more comprehensive neuropsychological evaluation might be necessary to gain a broader insight into the possible effects on neurocognitive performance.

Frontline Science: Buprenorphine decreases CCL2-mediated migration of CD14+ CD16+ monocytes.

HIV infection of the CNS causes neuroinflammation and damage that contributes to the development of HIV-associated neurocognitive disorders (HAND) in greater than 50% of HIV-infected individuals, despite antiretroviral therapy (ART). Opioid abuse is a major risk factor for HIV infection. It has been shown that opioids can contribute to increased HIV CNS pathogenesis, in part, by modulating the function of immune cells. HIV enters the CNS within two weeks after peripheral infection by transmigration of infected monocytes across the blood brain barrier (BBB). CD14+ CD16+ monocytes are a mature subpopulation that is increased in number in the peripheral blood of HIV-infected people. Mature monocytes can be productively infected with HIV, and they transmigrate preferentially across the BBB in response to CCL2, a chemokine elevated in the CNS and CSF of HIV-infected people even with ART. Buprenorphine, an opioid derivate, is an opioid replacement therapy for heroin addiction. It is a partial agonist of µ-opioid receptor and full antagonist of κ-opioid receptor. The effects of buprenorphine on CCL2-mediated CD14+ CD16+ monocytes transmigration across the BBB, a critical mechanism that promotes neuroinflammation and HAND, have not been characterized. We showed for the first time that buprenorphine decreases several steps of CCL2-mediated human mature monocyte transmigration. We propose that buprenorphine treatment in the context of HIV infection could serve a dual purpose, to treat opioid addiction and also to reduce neuroinflammation. Additionally, buprenorphine may be used as a treatment for HAND not only in the context of opioid abuse.

Neuropathogenesis of human immunodeficiency virus infection.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain a common end-organ manifestation of viral infection. Subclinical and mild symptoms lead to neurocognitive and behavioral abnormalities. These are associated, in part, with viral penetrance and persistence in the central nervous system. Infections of peripheral blood monocytes, macrophages, and microglia are the primary drivers of neuroinflammation and neuronal impairments. While current antiretroviral therapy (ART) has reduced the incidence of HIV-associated dementia, milder forms of HAND continue. Depression, comorbid conditions such as infectious liver disease, drugs of abuse, antiretroviral drugs themselves, age-related neurodegenerative diseases, gastrointestinal maladies, and concurrent social and economic issues can make accurate diagnosis of HAND challenging. Increased life expectancy as a result of ART clearly creates this variety of comorbid conditions that often blur the link between the virus and disease. With the discovery of novel biomarkers, neuropsychologic testing, and imaging techniques to better diagnose HAND, the emergence of brain-penetrant ART, adjunctive therapies, longer life expectancy, and better understanding of disease pathogenesis, disease elimination is perhaps a realistic possibility. This review focuses on HIV-associated disease pathobiology with an eye towards changing trends in the face of widespread availability of ART.

Animal models of HIV-associated disease of the central nervous system.

It is difficult to study the pathogenesis of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) in living patients because central nervous system (CNS) tissues are only available post mortem. Rodent and nonhuman primate (NHP) models of HAND allow for longitudinal analysis of HIV-associated CNS pathology and efficacy studies of novel therapeutics. Rodent models of HAND allow for studies with large sample sizes, short duration, and relatively low cost. These models include humanized mice used to study HIV-associated neuropathogenesis and transgenic mice used to study neurotoxic effects of viral proteins without infection. Simian immunodeficiency virus (SIV)-infected NHP are the premier model of neuroAIDS; SIV-associated CNS pathology is similar to HIV-associated CNS pathology with HAND. Additionally, the size, lifespan of NHP, and time to acquired immune deficiency syndrome (AIDS) progression make SIV-infected NHP models optimal for studies of viral latency and reservoirs, and assessing novel therapeutics for neuroAIDS. NHP models of neuroAIDS generally include conventional progressors (AIDS within 2-3 years) and those that have rapid disease (AIDS within 150 days). Rapid AIDS models are achieved by immune modulation and/or infection with neurovirulent and neurosuppressive viral strains and result in a high incidence of SIV-associated encephalitis. In this chapter, we briefly review rodent and NHP models of neuroAIDS, including contributions made using these models to our understanding of HIV-associated CNS disease.