CROI 2020 Abstract eBook
previous findings that CSF sCD30 rises after ART in chronic HIV and warrants further investigation to assess a possible distinct impact of very early ART.
432 QUANTITATION OF CEREBROSPINAL FLUID PLEOCYTOSIS AND HIV-1 RNA DURING ACUTE INFECTION Phillip Chan 1 , Camilla Muccini 2 , Carlo Sacdalan 1 , Eugène Kroon 1 , Donn J. Colby 1 , Nitiya Chomchey 1 , Peeriya Prueksakaew 1 , Suteeraporn Pinyakorn 3 , Nittaya Phanuphak 1 , Linda Jagodzinski 3 , Victor Valcour 4 , Sandhya Vasan 3 , Jintanat Ananworanich 1 , Serena S. Spudich 5 , for the RV254 Study Team 1 SEARCH, Bangkok, Thailand, 2 San Raffaele Vita-Salute University, Milan, Italy, 3 US Military HIV Research Program, Bethesda, MD, USA, 4 University of California San Francisco, San Francisco, CA, USA, 5 Yale University, New Haven, CT, USA Background: HIV-1 RNA can be detected in cerebrospinal fluid (CSF) within days after viral transmission. CSF leukocyte level (clinically determined as white blood cell count, or WBC) is linked with levels of systemic and CSF HIV-1 RNA in untreated chronic HIV infection. We quantitated CSF WBC and investigated its associations with HIV-1 in blood and CSF during untreated acute HIV infection (AHI). Methods: Individuals with AHI were enrolled in the RV254 cohort in Bangkok, Thailand. A subset underwent optional lumbar puncture (LP). We measured WBC, protein and glucose in whole CSF. HIV-1 RNA was tested in CSF supernatant by Roche COBAS TaqMan HIV-1 V2.0 with a lower limit of quantification (LLQ) of 80 copies/mL. A level of 79 copies/mL was assigned to samples with levels below LLQ. Logistic regression was used to determine factors predicting CSF pleocytosis (WBC>5 cells/mm 3 ). Results: FromMarch 2016 to March 2019, 61/246 RV254 participants underwent LP. 60 (98%) were male, and median age was 26, CD4 count 335 (IQR 247-553) and CD8 count 540 (IQR 357-802) cells/ul. 22 (37%) presented at Fiebig stage I & II and 36 (59%) had acute retroviral syndrome but none had overt neurologic signs or symptoms. 7 had untreated syphilis and 2 had hepatitis C. 16 (26%) CSF samples had HIV-1 RNA below LLQ. Median HIV-1 RNA levels in plasma and CSF were 6.10 (IQR 5.15-6.78) and 3.15 (IQR 1.90-4.11) log 10 copies/ml respectively. The median CSF WBC was 2 (IQR 1-8; range 0-105) cells/ mm 3 . Median CSF protein and glucose were 27 (IQR 23.2-31.9) mg/dL and 62 (IQR 57-69) mmol/L respectively. 20 (33%) CSF samples had pleocytosis. Four extreme outliers had levels >40 cells/mm 3 of whom 2 were later diagnosed with neurosyphilis. Paring plasma and CSF HIV-1 RNA with CSF WBC by Fiebig stages revealed that CSF pleocytosis lagged behind the rise in CSF HIV-1 (Figure). In the multivariate analysis, CSF pleocytosis was independently predicted by CSF HIV-1 levels (adjust odd ratio (aOR)=2.69 (95%CI 1.44 – 5.04); p=0.002) and CD8 T-cells (aOR=1.24 )(95%CI 1.00 – 1.54); p=0.046). Conclusion: CSF pleocytosis is present in one third of neuroasymptomatic individuals during AHI. It appears to emerge temporally after CSF viremia, suggesting that marked CSF lymphocytosis is not necessary to early CNS viral transmigration. Future studies should examine the functionality of the excessive T-cells among those with CSF pleocytosis and whether the presence of pleocytosis may impact central nervous system outcomes in long term follow up after ART.
433 EVOLUTION OF IMMUNE ACTIVATION BIOMARKERS IN CSF IN FIEBIG I-V ACUTE HIV INFECTION Julian Weiss 1 , Phillip Chan 2 , Carlo Sacdalan 2 , Eugène Kroon 2 , Siriwat Akapirat 3 , Jennifer Chiarella 1 , Victor Valcour 4 , Nittaya Phanuphak 2 , Ningbo Jian 5 , Sandhya Vasan 5 , Jintanat Ananworanich 2 , Bonnie Slike 5 , Shelly J. Krebs 5 , Serena S. Spudich 1 , for the RV254/SEARCH 010 study 1 Yale University, New Haven, CT, USA, 2 SEARCH, Bangkok, Thailand, 3 Armed Forces Research Institute of Medical Sciences in Bangkok, Bangkok, Thailand, 4 University of California San Francisco, San Francisco, CA, USA, 5 US Military HIV Research Program, Silver Spring, MD, USA Background: The initial immune response in the central nervous system (CNS) during acute HIV infection (AHI) may set the trajectory for HIV-associated neurocognitive disorders (HAND). A better understanding of immune activation pathways and dynamics in the CNS during AHI could inform therapeutic modalities to lessen the neurological impacts of HIV. Methods: We analyzed 41 biomarkers of immune activation in the cerebrospinal fluid (CSF) in the RV254/SEARCH010 Thai AHI cohort prior to antiretroviral initiation. We compared biomarker levels across Fiebig stages by univariate analysis and explored bivariate correlations with CSF HIV RNA levels. Temporal expression patterns were visualized by heatmap analysis (Figure 1), and pathway kinetics were identified through hierarchical clustering using Spearman’s correlation of biomarkers differentially expressed between Fiebig stages. To quantify the heatmap data, post-hoc Dunn’s test was performed for pairwise comparisons of biomarker levels between stages. Results: CSF was collected for biomarker analysis from 78 enrollees (99%male, median age 28 (IQR 23-33) years, median duration of infection 18 (IQR 15-23) days, median CD4 T cells 400 (IQR 280-543) cells/mL, median log 10 plasma HIV RNA 5.69 (IQR 5.01-6.51) copies/mL). Analysis of median CSF biomarker levels across Fiebig stages revealed temporal patterns of immune activation. Univariate analysis showed a set of biomarkers with statistically significant increases at Fiebig II compared to Fiebig I, and continued to increase until peak CSF viremia, primarily at Fiebig IV. The diverse subset of markers exhibiting this pattern included IL-2, TNF-α and its receptors TNFR-1 and TNFR-2, and IL-6RA, among others. Most biomarkers that followed this induction pattern had strong positive associations with CSF HIV RNA level, such as IL-2 (R2=0.36, P<0.0001) and TNFR-2 (R2=0.20, P<0.0001). Others, such as IL-15 and MCP-1, were also induced following Fiebig I, but peaked prior to peak viremia with inconsistent correlations with CSF HIV RNA level. Conclusion: This analysis revealed temporal pathways of multiple CSF biomarkers with differential dynamics of immune activation during AHI. The predominant pattern displayed significant increases at Fiebig II compared to Fiebig I, with peak biomarker concentration occurring at peak CSF HIV RNA level during Fiebig IV. The levels of these CSF biomarkers correlated with CSF HIV RNA levels, and may provide insight into early immunological mechanisms contributing to HAND.
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