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Astrocyte and Microglial Activation in Acute and Chronic HIV Pre- and Post-cART
Michael Peluso1, Victor G. Valcour2, Jintanat Ananworanich3, James L. Fletcher4, Somporn Tipsuk4, Bonnie Slike3, Nittaya Phanuphak4, Magnus Gisslén5, Henrik Zetterberg5, Serena Spudich6
1 Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. 2 University of California San Francisco, San Francisco, CA, United States. 3 Military HIV Research Program, Walter Reed Army Institute of Research, Bethesda, MD, United States. 4 SEARCH, Thai Red Cross AIDS Research Centre, Bangkok, Thailand. 5 University of Gothenburg, Gothenburg, Sweden. 6 Neurology, Yale University, New Haven, CT, United States.
Background: Cerebrospinal fluid (CSF) YKL-40, a putative marker of astrocyte and microglial activation associated with Alzheimer's disease and multiple sclerosis, is a potentially useful biomarker of processes occurring within the central nervous system (CNS) of HIV-infected individuals. To explore the impact of early HIV infection and early versus later initiation of combination antiretroviral therapy (cART) on the CNS, we measured CSF YKL-40 in subjects with acute HIV infection (AHI) before and after initiation of cART and compared the results with individuals initiating cART during chronic HIV infection (CHI) and HIV-uninfected Thai controls.
Methods: AHI (n=33), CHI (n=34) and control (n=18) Thai subjects naïve to cART underwent blood and CSF sampling, followed by immediate cART initiation. CHI subjects met Thai criteria for initiating cART at baseline, having advanced disease typically with CD4 count <300. CSF was sampled at 24 (n=25) and 96 weeks (n=14) in the AHI and at 48 weeks (n=10) in the CHI subjects, and HIV RNA levels and soluble biomarkers were measured at each visit. Cross-sectional analyses employed the Mann-Whitney and Spearman tests; paired analyses were used to compare subjects across time points.
Results: At initial sampling, median CD4 T cell count was 401 and 228 cells/uL in the AHI and CHI groups, respectively (p<0.0001). At baseline (median 18 days post estimated date of infection in AHI and unknown duration in CHI), median CSF YKL-40 was elevated in CHI (96,844 ng/L) compared with AHI subjects (80,754 ng/L; p=0.01) and controls (86,612 ng/L; p=0.07). In CHI but not AHI subjects, YKL-40 correlated with CSF neurofilament light chain (NFL; r=0.56, p<0.001), CSF neopterin (r=0.51, p=0.003), and CSF interferon-gamma-inducible protein 10 (IP-10; r=0.44, p=0.010). There were no correlations with HIV RNA or other soluble immune biomarkers in either group. After at >6 months of sustained cART (24 weeks in AHI and 48 weeks in CHI), the AHI group had a lower median CSF YKL-40 than CHI subjects (66,130 ng/L versus 87,414 ng/L, p=0.003).
Conclusions: Elevations in CSF YKL-40 suggestive of reactive astrocytes and microglial activation were present in CHI but not AHI subjects at baseline. YKL-40 declined after cART in CHI subjects, but remained elevated after treatment as compared to values in AHI participants after cART. YKL-40 correlation with NFL supports a role for astrocyte and/or microglial activation during CHI in neuronal injury that might be mitigated by early cART initiation.