Plasma Galectin-9 relates to cognitive performance and inflammation among adolescents with vertically acquired HIV.

OBJECTIVE: Adolescents with perinatally-acquired HIV (AWH) are at an increased risk of poor cognitive development but the underlying mechanisms remain unclear. Circulating galectin-9 (Gal-9) has been associated with increased inflammation and multi-morbidity in adults with HIV despite anti-retroviral therapy (ART), however, relationship between Gal-9 in AWH and cognition remain unexplored. DESIGN: A cross-sectional study of two independent age-matched cohorts from India [AWH on ART (n = 15), ART-naïve (n = 15), and adolescents without HIV (AWOH; n = 10)] and Myanmar [AWH on ART (n = 54) and AWOH (n = 22)] were studied. Adolescents from Myanmar underwent standardized cognitive tests. METHODS: Plasma Gal-9 and soluble mediators were measured by immunoassays and cellular immune markers by flow cytometry. We used Mann-Whitney U tests to determine group-wise differences, Spearman's correlation for associations and machine learning (ML) to identify a classifier of cognitive status (impaired vs. unimpaired) built from clinical (age, sex, HIV status) and immunological markers. RESULTS: Gal-9 levels were elevated in ART-treated AWH compared to AWOH in both cohorts (all p < 0.05). Higher Gal-9 in AWH correlated with increased levels of inflammatory mediators (sCD14, TNFα, MCP-1, IP-10, IL-10) and activated CD8 T cells (all p < 0.05). Irrespective of HIV status, higher Gal-9 levels correlated with lower cognitive test scores in multiple domains (verbal learning, visuospatial learning, memory, motor skills (all p < 0.05). ML classification identified Gal-9, CTLA-4, HVEM, and TIM-3 as significant predictors of cognitive deficits in adolescents (mean AUC = 0.837). CONCLUSION: Our results highlight a potential role of Gal-9 as a biomarker of inflammation and cognitive health among adolescents with perinatally acquired HIV.

Pathogen and Antibody Identification in Children with Encephalitis in Myanmar.

OBJECTIVE: Prospective studies of encephalitis are rare in regions where encephalitis is prevalent, such as low middle-income Southeast Asian countries. We compared the diagnostic yield of local and advanced tests in cases of pediatric encephalitis in Myanmar. METHODS: Children with suspected subacute or acute encephalitis at Yangon Children's Hospital, Yangon, Myanmar, were prospectively recruited from 2016-2018. Cohort 1 (n = 65) had locally available diagnostic testing, whereas cohort 2 (n = 38) had advanced tests for autoantibodies (ie, cell-based assays, tissue immunostaining, studies with cultured neurons) and infections (ie, BioFire FilmArray multiplex Meningitis/Encephalitis multiplex PCR panel, metagenomic sequencing, and pan-viral serologic testing [VirScan] of cerebrospinal fluid). RESULTS: A total of 20 cases (13 in cohort 1 and 7 in cohort 2) were found to have illnesses other than encephalitis. Of the 52 remaining cases in cohort 1, 43 (83%) had presumed infectious encephalitis, of which 2 cases (4%) had a confirmed infectious etiology. Nine cases (17%) had presumed autoimmune encephalitis. Of the 31 cases in cohort 2, 23 (74%) had presumed infectious encephalitis, of which one (3%) had confirmed infectious etiology using local tests only, whereas 8 (26%) had presumed autoimmune encephalitis. Advanced tests confirmed an additional 10 (32%) infections, 4 (13%) possible infections, and 5 (16%) cases of N-methyl-D-aspartate receptor antibody encephalitis. INTERPRETATION: Pediatric encephalitis is prevalent in Myanmar, and advanced technologies increase identification of treatable infectious and autoimmune causes. Developing affordable advanced tests to use globally represents a high clinical and research priority to improve the diagnosis and prognosis of encephalitis. ANN NEUROL 2023;93:615-628.

HIV-Related Cognitive Impairment of Orphans in Myanmar With Vertically Transmitted HIV Taking Antiretroviral Therapy.

OBJECTIVE: We determined the effect of perinatally acquired HIV on neurocognition in Myanmar children treated with antiretroviral therapy by comparison to demographically matched seronegative children. BACKGROUND: Myanmar has one of the highest HIV-1 prevalence rates in Southeast Asia. Studies from other resource-poor countries have shown that HIV-infected children differ in socioeconomic, nutritional and caregiver status compared to normal controls. Some vertically infected orphans in Myanmar reside separately from HIV-uninfected children in separate orphanages, thus the demographic variables of interest are naturally controlled. This study provides a unique evaluation of the neurocognitive effects of HIV in children, with control over key demographic variables. We hypothesized that HIV-infected orphans would perform significantly worse on cognitive indices compared with HIV-negative orphans. DESIGN/METHODS: A battery of cognitive tests sensitive to HIV-associated impairments in children was administered to 28 perinatally acquired HIV-positive children and 31 HIV-negative children from two orphanages in Myanmar; 21 children from each cohort underwent testing at baseline and again after 12 months. RESULTS: Baseline comparison of the two groups indicated that the HIV-infected children performed poorly across all tests, with significant group differences in executive function, visuospatial reasoning, fine motor dexterity, and visual motor integration. On subsequent testing, both cohorts of children showed improvements across multiple domains, with no significant effect of age at treatment initiation. CONCLUSIONS: Our results demonstrate a strong effect of HIV infection on specific neurocognitive deficits in vertically infected children. Understanding viral and host determinants and timing and choice of antiretroviral therapy on cognition will be critical to preventing cognitive impairment of children with HIV.