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.

Natural Bioactives as a potential Therapeutic Modality against NeuroAIDS

: With the introduction of antiretroviral therapy, the worldwide AIDS-related deaths have decreased, and life expectancy has increased, so has the prevalence of AIDS-related neurological disorders or neuroAIDS. HIV associated neurocognitive disorder such as mild neurocognitive disorder and asymptomatic neurocognitive impairment have largely remained stable or increased among the HIV infected individuals in the combination antiretroviral therapy era and with the emerging evidence that antiretrovirals with high CNS penetration effectiveness score contribute to the neurotoxicity and HIV associated neurocognitive disorder. have ushered the search for natural, nontoxic bioactive constituents having pre-established neuroprotective, anti-inflammatory and restorative neurocognitive activity. In this review, we have highlighted the probable mechanism of neuroAIDS infection, the problem with the existing antiretroviral therapy, along with various bioactive constituents with in vivo, in vitro, or ex vivo evidence of their neuroprotective activity that can be used as an adjuvant with the current combination antiretroviral therapy regimen or can even serve as an alternate to the antiretrovirals for treatment of HIV associated neurocognitive disorder.

Prevalence and 1-year incidence of HIV-associated neurocognitive disorder (HAND) in adults aged ≥50 years attending standard HIV clinical care in Kilimanjaro, Tanzania

Objectives: HIV-associated neurocognitive disorders (HANDs) are prevalent in older people living with HIV (PLWH) worldwide. HAND prevalence and incidence studies of the newly emergent population of combination antiretroviral therapy (cART)-treated older PLWH in sub-Saharan Africa are currently lacking. We aimed to estimate HAND prevalence and incidence using robust measures in stable, cART-treated older adults under long-term follow-up in Tanzania and report cognitive comorbidities. Design: Longitudinal study Participants: A systematic sample of consenting HIV-positive adults aged ≥50 years attending routine clinical care at an HIV Care and Treatment Centre during March–May 2016 and followed up March–May 2017. Measurements: HAND by consensus panel Frascati criteria based on detailed locally normed low-literacy neuropsychological battery, structured neuropsychiatric clinical assessment, and collateral history. Demographic and etiological factors by self-report and clinical records. Results: In this cohort (n = 253, 72.3% female, median age 57), HAND prevalence was 47.0% (95% CI 40.9–53.2, n = 119) despite well-managed HIV disease (Mn CD4 516 (98-1719), 95.5% on cART). Of these, 64 (25.3%) were asymptomatic neurocognitive impairment, 46 (18.2%) mild neurocognitive disorder, and 9 (3.6%) HIV-associated dementia. One-year incidence was high (37.2%, 95% CI 25.9 to 51.8), but some reversibility (17.6%, 95% CI 10.0–28.6 n = 16) was observed. Conclusions: HAND appear highly prevalent in older PLWH in this setting, where demographic profile differs markedly to high-income cohorts, and comorbidities are frequent. Incidence and reversibility also appear high. Future studies should focus on etiologies and potentially reversible factors in this setting.

Early prediction of putamen imaging features in HIV-associated neurocognitive impairment syndrome

Background To explore the correlation between the volume of putamen and brain cognitive impairment in patients with HIV and to predict the feasibility of early-stage HIV brain cognitive impairment through radiomics. Method Retrospective selection of 90 patients with HIV infection, including 36 asymptomatic neurocognitive impairment (ANI) patients and 54 pre-clinical ANI patients in Beijing YouAn Hospital. All patients received comprehensive neuropsychological assessment and MRI scanning. 3D Slicer software was used to acquire volume of interest (VOI) and radiomics features. Clinical variables and volume of putamen were compared between patients with ANI and pre-clinical ANI. The Kruskal Wallis test was used to analysis multiple comparisons between groups. The relationship between cognitive scores and VOI was compared using linear regression. For radiomics, principal component analysis (PCA) was used to reduce model overfitting and calculations and then a support vector machine (SVM) was used to build a binary classification model. For model performance evaluation, we used an accuracy, sensitivity, specificity and receiver operating characteristic curve (ROC). Result There were no significant differences in clinical variables between ANI group and pre-clinical-ANI group (P>0.05). The volume of bilateral putamen was significantly different between AHI group and pre-clinical group (P<0.05), but there was only a trend in the left putamen between ANI-treatment group and pre-clinical treatment group(P = 0.063). Reduced cognitive scores in Verbal Fluency, Attention/Working Memory, Executive Functioning, memory and Speed of Information Processing were negatively correlated with the increased VOI (P<0.05), but the correlation was relatively low. In diagnosing the ANI from pre-clinical ANI, the mean area under the ROC curves (AUC) were 0.85 ± 0.22, the mean sensitivity and specificity were 63.12 ± 5.51 and 94.25% ± 3.08%. Conclusion The volumes of putamen in patients with ANI may be larger than patients with pre-clinical ANI, the change of the volume of the putamen may have a certain process; there is a relationship between putamen and cognitive impairment, but the exact mechanism is unclear. Radiomics may be a useful tool for predicting early stage HAND in patients with HIV.

Atypical Resting-State Functional Connectivity Dynamics Correlate With Early Cognitive Dysfunction in HIV Infection

Purpose: Previous studies have shown that HIV affects striato-cortical regions, leading to persisting cognitive impairment in 30–70% of the infected individuals despite combination antiretroviral therapy. This study aimed to investigate brain functional dynamics whose deficits might link to early cognitive decline or immunologic deterioration.Methods: We applied sliding windows and K-means clustering to fMRI data (HIV patients with asymptomatic neurocognitive impairment and controls) to construct dynamic resting-state functional connectivity (RSFC) maps and identify states of their reoccurrences. The average and variability of dynamic RSFC, and the dwelling time and state transitioning of each state were evaluated.Results: HIV patients demonstrated greater variability in RSFC between the left pallidum and regions of right pre-central and post-central gyri, and between the right supramarginal gyrus and regions of the right putamen and left pallidum. Greater variability was also found in the frontal RSFC of pars orbitalis of the left inferior frontal gyrus and right superior frontal gyrus (medial). While deficits in learning and memory recall of HIV patients related to greater striato-sensorimotor variability, deficits in attention and working memory were associated with greater frontal variability. Greater striato-parietal variability presented a strong link with immunologic function (CD4+/CD8+ ratio). Furthermore, HIV-infected patients exhibited longer time and reduced transitioning in states typified by weaker connectivity in specific networks. CD4+T-cell counts of the HIV-patients were related to reduced state transitioning.Conclusion: Our findings suggest that HIV alters brain functional connectivity dynamics, which may underlie early cognitive impairment. These findings provide novel insights into our understanding of HIV pathology, complementing the existing knowledge.

Association between HIV infection and neurocognitive disorders: a review

Background: HIV-associated neurocognitive disorders (HAND) are characterized by impairment in at least two cognitive domains with a prevalence of up to 50% in people living with HIV (PLHIV). HAND is subdivided into asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) and HIV-associated dementia (HAD). Objectives: Demonstrate the impact of HAND and possible pathogenic mechanisms by relating them to the prevalence of subtypes Design and Setting: Review of the literature. Methods: Review made from PubMed with the descriptors “neurocognitive disorder”, “HIV”, “review”. Twelve articles were selected, among systematic reviews and meta-analysis published since 2017. Results: Before Highly Active Antiretroviral Therapy (HAART) HAD cases had a higher prevalence, probably due to the high viral load causing intense brain inflammation. Today the percentage of HAD has decreased, but the cases of ANI and MND continue to increase. HAART increases life expectancy and reduces viral load, but it may be related to the increase in ANI / MND associated with early brain aging and mild inflammatory processes resulting from primary infection. Conclusions: HAND is a concern for its impact on the quality of life and life expectancy of PLHIV. Therefore, neuropsychological assessment is an important tool for early diagnosis and disease management. The change in prevalence of different HAND subtypes raises doubts about the pathogenesis of these conditions and further studies are needed to elucidate this issue and develop therapeutic solutions.

Improvement of HIV-associated neurocognitive disorders after antiretroviral therapy intensification: the Neuro+3 study

Objectives Despite the effectiveness of antiretroviral (ARV) therapy to control HIV infection, HIV-associated neurocognitive disorders (HAND) remain frequent. The Neuro+3 study assessed the cognitive improvement associated with ARV intensification based on increased CNS penetration effectiveness (CPE) scoring ≥+3 and total CPE score ≥9. Methods Thirty-one patients, aged 18–65 years, with confirmed diagnosis of HAND and effective ARV therapy were included. The cognitive improvement was measured using Frascati three-stage classification and global deficit score (GDS) after 48 and 96 weeks of ARV intensification. Ultrasensitive HIV-RNA, neopterin, soluble CD14, CCL2, CXCL10, IL6, IL8 and NF-L were measured in plasma and cerebrospinal fluid at Day 0 (baseline), Week 48 (W48) and W96. Results The intensified ARV was associated with a median (IQR) CPE score increase from 6 (4–7) at baseline to 10 (9–11). From baseline to W96, the median (IQR) GDS decreased from 1.4 (0.8–2.2) to 1.0 (0.6–2.0) (P = 0.009); HAND classification improved from 2 to 1 HIV-associated dementia, 22 to 8 mild neurocognitive disorders, 7 to 17 asymptomatic neurocognitive impairment and 0 to 5 patients without any neurocognitive alterations (P = 0.001). In multivariable linear regression analysis, GDS improvement at W96 was significantly associated with CPE score ≥9 after intensification (P = 0.014), CD4 lymphocyte increase at W48 (P &lt; 0.001) and plasma CXCL10 decrease at W96 (P = 0.001). Conclusions In patients with HAND, a significant cognitive improvement was observed after the ARV intensification strategy, with a higher CPE score. Cognitive improvement was more often observed in the case of a switch of two drug classes, arguing for better control of CNS HIV immune activation.

Global prevalence and burden of HIV-associated neurocognitive disorder

ObjectiveTo characterize the prevalence and burden of HIV-associated neurocognitive disorder (HAND) and assess associated factors in the global population with HIV.MethodsWe searched PubMed and Embase for cross-sectional or cohort studies reporting the prevalence of HAND or its subtypes in HIV-infected adult populations from January 1, 1996, to May 15, 2020, without language restrictions. Two reviewers independently undertook the study selection, data extraction, and quality assessment. We estimated pooled prevalence of HAND by a random effects model and evaluated its overall burden worldwide.ResultsOf 5,588 records identified, we included 123 studies involving 35,513 participants from 32 countries. The overall prevalence of HAND was 42.6% (95% confidence interval [CI] 39.7–45.5) and did not differ with respect to diagnostic criteria used. The prevalence of asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia were 23.5% (20.3–26.8), 13.3% (10.6–16.3), and 5.0% (3.5–6.8) according to the Frascati criteria, respectively. The prevalence of HAND was significantly associated with the level of CD4 nadir, with a prevalence of HAND higher in low CD4 nadir groups (mean/median CD4 nadir <200 45.2% [40.5–49.9]) vs the high CD4 nadir group (mean/median CD4 nadir ≥200 37.1% [32.7–41.7]). Worldwide, we estimated that there were roughly 16,145,400 (95% CI 15,046,300–17,244,500) cases of HAND in HIV-infected adults, with 72% in sub-Saharan Africa (11,571,200 cases, 95% CI 9,600,000–13,568,000).ConclusionsOur findings suggest that people living with HIV have a high burden of HAND in the antiretroviral therapy (ART) era, especially in sub-Saharan Africa and Latin America. Earlier initiation of ART and sustained adherence to maintain a high-level CD4 cell count and prevent severe immunosuppression is likely to reduce the prevalence and severity of HAND.