HIV-associated Neurocognitive Dysfunction Research Articles

Plasma Derived Extracellular Vesicles Modulate Monocyte IL-18, IFN-α and IL-10 responses in Adults with HIV-related Cognitive Impairment

Abstract Background: HIV-associated neurocognitive dysfunction persists despite suppressive antiretroviral therapy (ART). Extracellular vesicles (EVs) are emerging modulators of immunological responses. We have previously shown that EVs expressing monocyte activation and neuronal markers associated with HIV associated cognitive impairment (CI). Whether these EV changes observed in people with HIV (PWH) influence innate cellular function among those with CI remains unclear. Method: Purified EV samples from 58 HIV-infected individuals on ART with either cognitive impairment (CI, n=48) or normal cognition (NC, n=10) and 8 uninfected controls were isolated using differential centrifugation and co-cultured with PBMCs from a single uninfected donor for 18 hrs. Eight intracellular cytokines and 13 surface chemokines and myeloid differentiation markers were assessed by spectral flow cytometry. Non-parametric statistical T tests were used. Result: Monocytes (mono) showed differential effects on multiple cytokine responses and cell surface receptors after exposure to EVs from HIV-infected individuals with or without CI. Levels of mono IL-18 were significantly lower after incubation with EVs derived from HIV-infected individuals compared to uninfected controls. Based on cognitive status, EVs from HIV-CI group significantly lower % of IL-18 mono responses and lower IFN-α and higher IL-10 responses on a per cell basis when compared to the NC group. Conclusion: These results suggest EVs can modulate mono function irrespective of HIV status. PWH with CI exhibited altered EV driven mono cytokine responses. Our data support interventions that target EVs to reverse or restore mono perturbations and limit neuropathology in PWH on ART. Supported by grants from NIH (R21NS106970 and R01NS117458)

Cognition, Coping, and Psychological Distress in HIV.

Interrelationships among HIV-associated neurocognitive dysfunction, avoidant coping, cognitively-oriented coping, and psychological distress were examined using structural equation modelingin an ethnically diverse sample of 209 adults predominantly in the mid-range of illness. Global neurocognitive deficits, assessed with the HIV-dementia scale, were associated with higher levels of avoidant coping, lower levels of cognitive coping, and a higher avoidant/cognitive coping ratio, which were each in turn associated with higher psychological distress measured by a latent factor comprising symptoms of depression, anxiety, and HIV-related distressing thoughts. There were significant indirect effects through avoidant coping and a higher avoidant/cognitive coping ratio. Results suggest the presence ofHIV-associated neurocognitive deficits may interfere withtheutilization of cognitive-based coping strategies andincreasereliance on more maladaptivestrategies,whichin turn may translate to elevated reports ofpsychological distress. Findings may help inform interventions aimed at reducing avoidant coping and psychological distress, two factors associated with accelerated HIVdisease progression.

HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System.

Antiretroviral therapy (ART) has transformed HIV into a chronic condition, lengthening and improving the lives of individuals living with this virus. Despite successful suppression of HIV replication, people living with HIV (PLWH) are susceptible to a growing number of comorbidities, including neuroHIV that results from infection of the central nervous system (CNS). Alterations in the dopaminergic system have long been associated with HIV infection of the CNS. Studies indicate that changes in dopamine concentrations not only alter neurotransmission, but also significantly impact the function of immune cells, contributing to neuroinflammation and neuronal dysfunction. Monocytes/macrophages, which are a major target for HIV in the CNS, are responsive to dopamine. Therefore, defining more precisely the mechanisms by which dopamine acts on these cells, and the changes in cellular function elicited by this neurotransmitter are necessary to develop therapeutic strategies to treat neuroHIV. This is especially important for vulnerable populations of PLWH with chemically altered dopamine concentrations, such as individuals with substance use disorder (SUD), or aging individuals using dopamine-altering medications. The specific neuropathologic and neurocognitive consequences of increased CNS dopamine remain unclear. This is due to the complex nature of HIV neuropathogenesis, and logistical and technical challenges that contribute to inconsistencies among cohort studies, animal models and in vitro studies, as well as lack of demographic data and access to human CNS samples and cells. This review summarizes current understanding of the impact of dopamine on HIV neuropathogenesis, and proposes new experimental approaches to examine the role of dopamine in CNS HIV infection. Graphical abstract HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System. Both substance abuse disorders and the use of dopaminergic medications for age-related diseases are associated with changes in CNS dopamine concentrations and dopaminergic neurotransmission. These changes can lead to aberrant immune function, particularly in myeloid cells, which contributes to the neuroinflammation, neuropathology and dysfunctional neurotransmission observed in dopamine-rich regions in HIV+ individuals. These changes, which are seen despite the use antiretroviral therapy (ART), in turn lead to further dysregulation of the dopamine system. Thus, in individuals with elevated dopamine, the bi-directional interaction between aberrant dopaminergic neurotransmission and HIV infection creates a feedback loop contributing to HIV associated neurocognitive dysfunction and neuroHIV. However, the distinct contributions and interactions made by HIV infection, inflammatory mediators, ART, drugs of abuse, and age-related therapeutics are poorly understood. Defining more precisely the mechanisms by which these factors influence the development of neurological disease is critical to addressing the continued presence of neuroHIV in vulnerable populations, such as HIV-infected older adults or drug abusers. Due to the complexity of this system, understanding these effects will require a combination of novel experimental modalities in the context of ART. These will include more rigorous epidemiological studies, relevant animal models, and in vitro cellular and molecular mechanistic analysis.

Neurological disorders in HIV in Africa: a review.

Neurological disorders in HIV infection are a common cause of morbidity and mortality. The aim of this paper is to provide a narrative overview of up to date information concerning neurological disorders affecting HIV infected persons in Africa. Seminal research concerning neurological disorders among HIV-infected adults in sub-Saharan Africa from prior to 2000 was combined with an in-depth search of PubMed to identify literature published from 2000 to 2017. The following Mesh terms were used. "Nervous System Diseases" "HIV Infections" and "Africa South of the Sahara" and "Seizures" or "Spinal Cord Diseases" or "Peripheral Nervous System Diseases" or "AIDS Dementia Complex" or "Opportunistic Infections" or "Immune Reconstitution Inflammatory Syndrome" or "Stroke". Only those articles written in English were used. A total of 352 articles were identified, selected and reviewed and 180 were included in the study. These included case series, observational studies, interventional studies, guidelines and reviews with metanalyses. The author also included 15 publications on the subject covering the earlier phase of the HIV epidemic in Africa from 1987 to 1999 making a total of 195 references in the study. This was combined with extensive personal experience diagnosing and treating these neurological disorders. Neurological disorders were common, typically occurring in WHO stages III/IV. These were in three main categories: those arising from opportunistic processes mostly infections, direct HIV infection and autoimmunity. The most common were those arising from direct HIV infection occurring in >50%. These included HIV-associated neurocognitive dysfunction (HAND), neuropathy and myelopathy. Opportunistic infections occurred in >20% and frequently had a 6-9-month mortality rate of 60-70%. The main causes were cryptococcus, tuberculosis, toxoplasmosis and acute bacterial meningitis. Concurrent systemic tuberculosis occurred in almost 50%. Neurological disorders are common in HIV in Africa and the main CNS opportunistic infections result in high mortality rates. Strategies aimed at reducing their high burden, morbidity and mortality include early HIV diagnosis and anti-retroviral therapy (ART), screening and chemoprophylaxis of main opportunistic infections, improved clinical diagnosis and management and programme strengthening.

Evaluation of Vascular Event Risk while on Long-term Anti-retroviral Suppressive Therapy [EVERLAST]: Protocol for a prospective observational study.

Background & objectiveCardiovascular disease (CVD) risk among the HIV population is high due to a combination of accelerated atherosclerosis from the pro-inflammatory milieu created by chronic HIV infection and the potentially adverse metabolic side effects from cART (combination antiretroviral therapy) medications. Although sub-Saharan Africa (SSA) bears 70% of the global burden of HIV disease, there is a relative paucity of studies comprehensively assessing CVD risk among people living with HIV on the continent. The overarching objective of the Evaluation of Vascular Event Risk while on Long-term Anti-retroviral Suppressive Therapy (EVERLAST) Study is to characterize the burden of CVD among HIV patients on ART in Ghana, and explore factors influencing it.MethodsThe EVERLAST study incorporates prospective CVD risk assessments and a convergent mixed methods approach. This prospective study will evaluate CVD risk by measuring Carotid Intimal Media Thickness (CIMT) and presence of traditional medical and lifestyle vascular risk among 240 Ghanaian HIV patients on antiretroviral therapy compared with age- and sex-matched HIV uninfected (n = 240) and HIV positive ART naïve controls (n = 240). A contextual qualitative analysis will also be conducted to determine attitudes/perceptions of various key local stakeholders about CVD risk among HIV patients. The primary outcome measure will be CIMT measured cross-sectionally and prospectively among the three groups. A host of secondary outcome variables including CVD risk factors, CVD risk equations, HIV associated neurocognitive dysfunction and psychological well-being will also be assessed.ConclusionEVERLAST will provide crucial insights into the unique contributions of ART exposure and environmental factors such as lifestyle, traditional beliefs, and socio-economic indicators to CVD risk among HIV patients in a resource-limited setting. Ultimately, findings from our study will be utilized to develop interventions that will be tested in a randomized controlled trial to provide evidence to guide CVD risk management in SSA.

Brain PET Imaging: Value for Understanding the Pathophysiology of HIV-associated Neurocognitive Disorder (HAND).

The purpose of this review is to summarize recent developments in PET imaging of neuropathologies underlying HIV-associated neurocognitive dysfunction (HAND). We concentrate on the recent post antiretroviral era (ART), highlighting clinical and preclinical brain PET imaging studies. In the post ART era, PET imaging has been used to better understand perturbations of glucose metabolism, neuroinflammation, the function of neurotransmitter systems, and amyloid/tau protein deposition in the brains of HIV-infected patients and HIV animal models. Preclinical and translational findings from those studies shed a new light on the complex pathophysiology underlying HAND. The molecular imaging capabilities of PET in neuro-HIV are great complements for structural imaging modalities. Recent and future PET imaging studies can improve our understanding of neuro-HIV and provide biomarkers of disease progress that could be used as surrogate endpoints in the evaluation of the effectiveness of potential neuroprotective therapies.

Study on the prevalence and influencing factors of depression and anxiety symptoms in HIV/AIDS patients

Objective To understand the prevalence of depression and anxiety symptoms in human immunodeficiency virus/anxiety symptoms in acquired immunodeficiency syndrome (HIV/AIDS) patients, and the possible factors of depression and anxiety symptoms, to provide the basis for promoting the physical and mental health of HIV/AIDS patients. Methods Cross-sectional survey of 1384 cases of HIV/AIDS outpatient and inpatient in Changsha Hospital affiliated to University of South China were carried out by using the the self-rating depression scale (SDS) and the self-rating anxiety scale (SAS), and the influencing factors of depression and anxiety symptoms were analyzed with logistic regression. Results In 1384 HIV/AIDS patients, the detection rate of depression and anxiety symptoms was 36.6%, and 198 patients was diagnosed the depression and anxiety (14.3%). Multi-factor regression analysis showed sex (OR=2.632, 95% CI: 1.814-3.817), cognitive function (OR=3.006, 95% CI: 2.043-4.424), combined diseases (OR=4.009, 95% CI: 3.036-5.295), adverse drug reactions (OR=2.580, 95% CI: 1.736-3.834), opportunistic infections (OR=6.994, 95% CI: 4.863-10.060) are the risk factors of depression and anxiety symptoms in HIV/AIDS patients. Platelet count (OR=0.610, 95% CI: 0.390-0.954) is the protective factor of depression and anxiety symptoms in HIV/AIDS patients. Conclusions Depression and anxiety are common in HIV/AIDS patients. Women, HIV associated neurocognitive dysfunction (HAND), combined with other diseases, opportunistic infections, and adverse drug reactions to HIV/AIDS patients are more likely to have depression and anxiety, and should be paid attention to in the follow-up process. Key words: Acquired immunodeficiency syndrome/CO; HIV infections/CO; Depression/ET; Anxiety/ET; Factor analysis, statistical

Cognitive deficits persist in the combination antiretroviral era: Preliminary results from the Co-morBidity in Relation to AIDS (COBRA) collaboration London cohort

Background: HIV is a neurotropic virus that if left untreated leads to a frank dementia in a significant proportion of patients. Modern combination antiretroviral therapy (cART) has transformed HIV into a chronic disease with life expectancy approaching normal. The more severe forms of HIV associated neurocognitive dysfunction (HAND) are now rarely seen but there have been many reports of more subtle cognitive deficits occurring in up to 50% of patients in the modern era. Unfortunately many previous studies have had heterogeneous patient groups or lacked appropriate controls making extrapolation to well treated patients, common in current practice, difficult. This study set out to investigate the true prevalence of cognitive dysfunction and the mechanisms underlying it in an older group of HIV positive individuals on effect cART. Methods: To date 46 participants (33 HIV-positive patients and 13 HIV-negative controls) have been recruited into the London cohort of the COBRA observational study. All participants were aged over 50 (mean age 61 ± 7.7 years) and were predominantly male (87%). All HIV positive patients were on fully suppressive stable cART > 12 months. The two groups were well matched in terms of age, gender, sexual orientation, ethnicity and educational attainment. Subjects underwent a full cognitive battery in addition to MRI scanning with a 64-direction diffusion protocol. Mean FA (fractional anisotropy) for the major white matter tracts was calculated using a white matter skeleton created from the centre of tracts common to the group and standard atlases. Results: Poorer performance on trail making tests A and B (p = 0.007 and < 0.001 respectively), the Stroop test (p = 0.006), grooved peg board test (p = 0.004) and the Wisconsin card sort test (p = 0.002) were observed in the HIV-positive group compared to the control group. After adjusting for age the mean white matter skeleton FA was highly significantly correlated (p < 0.01) with all the abnormal cognitive tests. Significantly lower FA values were observed in 24% of the major white matter tracts of the HIV-positive group compared to controls. Conclusions: Cognitive deficits in a variety of domains persist despite full suppression of HIV replication (at least in the plasma compartment) when compared to well matched controls. The reduction in cognitive performance observed is mediated in part by decreased white matter integrity manifested as lower FA values in numerous major white matter tracts. Further analysis of other MRI modalities and lumbar puncture findings of the same cohort are awaited and these may shed light further on the pathophysiology of HAND in those on fully suppressive therapy.

Evidence of the innate antiviral and neuroprotective properties of progranulin.

BackgroundCompelling data exist that show that normal levels of progranulin (PGRN) are required for successful CNS aging. PGRN production is also modulated by inflammation and infection, but no data are available on the production and role of PGRN during CNS HIV infection.MethodsTo determine the relationships between PGRN and HIV disease, neurocognition, and inflammation, we analyzed 107 matched CSF and plasma samples from CHARTER, a well-characterized HIV cohort. Levels of PGRN were determined by ELISA and compared to levels of several inflammatory mediators (IFNγ, IL-6, IL-10, IP-10, MCP-1, TNFα, IL-1β, IL-4 and IL-13), as well as clinical, virologic and demographic parameters. The relationship between HIV infection and PGRN was also examined in HIV-infected primary human microglial cultures.ResultsIn plasma, PGRN levels correlated with the viral load (VL, p<0.001). In the CSF of subjects with undetectable VL, lower PGRN was associated with neurocognitive impairment (p = 0.046). CSF PGRN correlated with CSF IP-10, TNFα and IL-10, and plasma PGRN correlated with plasma IP-10. In vitro, microglial HIV infection increased PGRN production and PGRN knockdown increased HIV replication, demonstrating that PGRN is an innate antiviral protein.ConclusionsWe propose that PGRN plays dual roles in people living with HIV disease. With active HIV replication, PGRN is induced in infected macrophages and microglia and functions as an antiviral protein. In individuals without active viral replication, decreased PGRN production contributes to neurocognitive dysfunction, probably through a diminution of its neurotrophic functions. Our results have implications for the pathogenesis, biomarker studies and therapy for HIV diseases including HIV-associated neurocognitive dysfunction (HAND).

Neurocognitive dysfunction among HIV positive patients using International HIV dementia scale

Background: HIV associated neurocognitive dysfunction (HAND) ranges from asymptomatic neurocognitive impairment (ANI) to mild neurocognitive disorders (MND) to HIV associated dementia (HAD). Cognitive impairment may impact medication adherence which will ultimately affect morbidity and mortality. Aim: This study was undertaken to evaluate neurocognitive dysfunction among HIV positive patients using the International HIV Dementia scale(IHDS). Materials and Methods: This cross sectional study was conducted in a tertiary care hospital attached to a medical college that caters to a large number of HIV positive patients. The subjects for this study included HIV positive patients belonging to WHO stage 1 or 2. Data collection was done using a pre tested questionnaire. The International HIV Dementia scale(IHDS) was used to assess HAND. Results: Out of the 101 patients studied, 69(68.3%) were males and 32(31.7%) were females. Among these patients, 88 (87.1%) were receiving antiretroviral therapy (ART), 84 (83.2%) were in WHO stage 1. 91 (90.1%) patients had HAND. There were statistically significant differences in the gender and educational level between patients with or without HAND. As age advanced the percentage of patients having HAND also increased. Conclusion: There was high prevalence of HIV associated neurocognitive dysfunction among HIV positive individuals in our study. Also there was an increase in HIV associated neurocognitive dysfunction with increase in age. DOI: http://dx.doi.org/10.3126/ajms.v5i4.8724 Asian Journal of Medical Sciences 2014 Vol.5(4); 61-64

Circulating plasmablasts of HIV-infected individuals dominantly produce polyreactive antibodies including anti-NMDAR antibodies contributing to HAND and HAD (P3037)

Abstract In the post-HAART stage, a substantial percent of HIV patients develop HIV-Associated Neurocognitive Dysfunction and HIV-Associated Dementia. Finding early biomarkers is essential to diagnose and prevent these diseases. HIV infection causes B cell dysfunctions. To evaluate the functional antibody repertoire during HIV infection, we cloned the paired IgH and IgL genes from single circulating plasmablasts of 5 HIV patients and expressed 80 recombinant antibodies to determine their functions. We also expressed 80 antibodies from 5 donors without HIV infection as control. Analyses of antibodies from HIV-infected individuals showed that 30% of them weakly bind to gp120. Surprisingly, about 72% of the antibodies cloned from HIV-infected individuals were polyreactive, which is sharp contrast to the 16% of polyreactive antibodies from control donors. Up to 60% of them cross-reacted with the DWDYS peptide present in NMDA receptor. We found 17% of antibodies bound to SH-SY5Y or U251 cell surface antigens. Detailed analyses of one such antibody HIV201P5B2 derived from HIV patients showed that it induced NMDAR clustering and internalization and eventually caused neuronal cell apoptosis. Taken together, the dominant production of polyreactive antibodies in the plasmablasts of HIV patients revealed an abnormal alteration of B cell function during HIV infection. Anti-NDMAR antibodies generated in HIV patients may provide a new diagnostic biomarker for HAND and HAD in AIDS patient.

Detection of anti-tat antibodies in CSF of individuals with HIV-associated neurocognitive disorders

Despite major advances in the development of antiretroviral therapies, currently available treatments have no effect on the production of HIV-Tat protein once the proviral DNA is formed. Tat is a highly neurotoxic and neuroinflammatory protein, but its effects may be modulated by antibody responses against it. We developed an indirect enzyme-linked immunosorbent assay and measured anti-Tat antibody titers in CSF of a well characterized cohort of 52 HIV-infected and 13 control individuals. We successfully measured anti-Tat antibodies in CSF of HIV-infected individuals with excellent sensitivity and specificity, spanning a broad range of detection from 10,000 to over 100,000 relative light units. We analyzed them for relationship to cognitive function, CD4 cell counts, and HIV viral load. Anti-Tat antibody levels were higher in those without neurocognitive dysfunction than in those with HIV-associated neurocognitive dysfunction (HAND) and in individuals with lower CD4 cell counts and higher viral loads. We provide details of an assay which may have diagnostic, prognostic, or therapeutic implications for patients with HAND. Active viral replication may be needed to drive the immune response against Tat protein, but this robust immune response against the protein may be neuroprotective.

MECHANISMS OF CEREBRAL DAMAGE IN PATIENTS WITH HIV-INFECTION

Mechanisms of HIV transportation through blood-brain barrier, vascular plexus and interaction with cerebral cells having CD-4-receptors, CCR-5- and CXCR-4-coreceptors were studied. Cerebral damage developed through latent and acute periods also known as HIV-encephalopathy, HIV-associated neurocognitive dysfunction etc. Cerebral lesions are caused by a variety of chemical agents from pro-inflammatory cytokines to toxic HIV-proteins resulting in development of HIV-dementia through several years. Even early stage of this process revealed significant disturbances of glucose metabolism and evoked potentials EEG alterations which can serve as a marker of HIV-infection. Genetic differences of HIV in blood and spinal liquor with different drug resistance were revealed implying a new approach to therapy development.

HIV treatment: mechanisms of neurotoxicity and implications for targeted therapy

Correspondence: Chengxiang Wu Departments of Microbiology and Public Health Sciences, University of Hawai’i at Manoa, 1960 East-West Road, Biomed Bldg, D105, Honolulu, HI 96822, USA Tel +1 808 956 2684 Fax +1 808 956 5818 Email chengxia@hawaii.edu Abstract: The central nervous system is known to act as a unique compartment where the human immunodeficiency virus (HIV) can replicate independently from the plasma and as a sanctuary in which the virus is largely protected from the host immune system and combination antiretroviral therapy. Although combination antiretroviral therapy has dramatically decreased the rate of HIV-caused mortality and associated diseases, neurological complications are increasingly common. However, our knowledge of the complicated pathogenesis and clinical symptoms of HIV-associated neurocognitive dysfunction is limited by a lack of complete understanding of the biology of HIV and its interaction with host cells in the central nervous system. This review focuses on the mechanisms of HIV entry and replication in the central nervous system, neurotoxicity caused by viral proteins and cytokine/chemokines derived from affected host cells, their implications for targeted therapy, and advances in the development of animal models for novel therapeutics in the context of combination antiretroviral therapy regimens.

Relationship of ethnicity, age, education, and reading level to speed and executive function among HIV+ and HIV– women: The Women's Interagency HIV Study (WIHS) Neurocognitive Substudy

Use of neuropsychological tests to identify HIV-associated neurocognitive dysfunction must involve normative standards that are well suited to the population of interest. Norms should be based on a population of HIV-uninfected individuals as closely matched to the HIV-infected group as possible and must include examination of the potential effects of demographic factors on test performance. This is the first study to determine the normal range of scores on measures of psychomotor speed and executive function among a large group of ethnically and educationally diverse HIV-uninfected, high-risk women, as well as their HIV-infected counterparts. Participants (n = 1,653) were administered the Trail Making Test Parts A and B (Trails A and Trails B), the Symbol Digit Modalities Test (SDMT), and the Wide Range Achievement Test–3 (WRAT–3). Among HIV-uninfected women, race/ethnicity accounted for almost 5% of the variance in cognitive test performance. The proportions ofvariance in cognitive test performance accounted for by age (13.8%), years of school (4.1%), and WRAT–3 score (11.5%) were each significant, but did not completely account for the effect of race (3%). HIV-infected women obtained lower scores than HIV-uninfected women on time to complete Trails A and B, SDMT total correct, and SDMT incidental recall score, but after adjustment for age, years of education, racial/ethnic classification, and reading level, only the difference on SDMT total correct remained significant. Results highlight the need to adjust for demographic variables when diagnosing cognitive impairment in HIV-infected women. Advantages of demographically adjusted regression equations developed using data from HIV-uninfected women are discussed.

The persistence of HIV-associated neurocognitive dysfunction and the effects of comorbidities

Despite the effectiveness of combination antiretroviral therapy (CART), many HIV-infected patients continue to experience cognitive problems.1 The study by Heaton et al.2 in this issue of Neurology ® examined HIV-associated neurocognitive disorder (HAND) in a large national cohort from the multicenter CHARTER study, which assesses the changes in presentation of HIV neurologic complications in the modern era of HIV treatment. Only 2% of the cohort exhibited dementia, confirming clinical observations that severe functional decline is now relatively rare.1 Yet 47% of the sample without major comorbidities met criteria for HAND. It is notable that the latter prevalence is similar to those reported in studies conducted before modern antiretroviral therapy.3 It is likely that this is partly attributable to the fact that HIV-infected patients are living longer with effective treatment, such that aging contributes to the prevalence of neurocognitive deficits. Nevertheless, the results provide clear evidence that HAND continues to be common despite the effectiveness of CART, and the prevalence of neurocognitive impairment is even greater when factoring in people with significant comorbidities commonly experienced by HIV-infected …

Developing Neuroprotective Strategies for Treatment of HIV-Associated Neurocognitive Dysfunction

Important advances have been made in recent years in identifying the molecular mechanisms of HIV neuropathogenesis. Defining the pathways leading to HIV dementia has created an opportunity to therapeutically target many steps in the pathogenic process. HIV itself rarely infects neurons, but significant neuronal damage is caused both by viral proteins and by inflammatory mediators produced by the host in response to infection. Highly active antiretroviral therapy (HAART) does not target these mediators of neuronal damage, and the prevalence of HIV-associated neurocognitive dysfunction has actually been rising in the post-HAART era. This review will briefly summarize our current understanding of the mechanisms of HIV-induced neurological disease, and emphasize translation of this basic research into potential clinical applications.