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Peripheral Immune Activation Modulates HIV RNA Entry to CSF in Early Acute Infection
Alexandra Schuetz1; Suteeraporn Pinyakorn2; Leah Le3; Yuwadee Phuang-Ngern1; Eugène Kroon4; Linda Jagodzinski5; Thep Chalermchai4; Victor Valcour6; Jintanat Ananworanich5; Serena S. Spudich3; for the RV254/SEARCH 010 Study Group
1US AFRIMS, Bangkok, Thailand;2US Military HIV Rsr Prog, Walter Reed Army Inst of Rsr, Silver Spring, MD, USA;3Yale Univ Sch of Med, New Haven, CT, USA;4SEARCH, Bangkok, Thailand;5Military HIV Rsr Prog, Bethesda, MD, USA;6Univ of California San Francisco, San Francisco, CA, USA
The mechanisms determining the magnitude of initial HIV entry into the nervous system during acute HIV infection (AHI) are largely unknown. We examined whether peripheral blood and mucosal cellular immune activation were independently associated with the level of HIV RNA detected in cerebrospinal fluid (CSF) during the earliest stages of HIV infection (Fiebig I to III).
Concurrent blood, CSF and sigmoid biopsy samples were obtained at the time of AHI diagnosis (8 Fiebig I, 11 Fiebig II and 19 Fiebig III) in the context of an observational study of AHI in Bangkok, Thailand (RV254/SEARCH 010). CSF and plasma HIV RNA levels were measured by Roche Amplicor HIV-1 Monitor and Roche COBAS TaqMan HIV-1 tests. Multiparameter flow cytometry was performed using frozen and fresh samples to determine systemic and mucosal immune activation (Ki67+ and CD38+/HLA-DR+), respectively. CSF chemokine levels (IP-10 and neopterin) were quantified by ELISA. Mann Whitney U test was used for comparisons and linear regression and Pearson’s Correlation to evaluate associations.
Among 38 early AHI subjects, 90% were MSM, the median age was 29 years, mean CD4 count was 438 cells/mm3, and estimated duration since exposure was 15 days. During early AHI, plasma (p<0.001) and CSF HIV RNA (p<0.001), CSF neopterin levels (p=0.003) and the frequency of activated CD8+ T cell in blood (p=0.002) and sigmoid mucosa (p<0.001) increased with progression from Fiebig I to Fiebig III. In univariate analyses of the overall group, CSF HIV RNA was associated with CSF IP-10 levels (r=0.37, p=0.04), CSF neopterin levels (r=0.61, p<0.001), the frequency of CD8+Ki67+ T cells in the blood (r=0.56, p=0.001) and the frequency of CD8+Ki67+ (r=0.48, p=0.008) and CD8+CD38+HLA-DR+ (r=0.46, p=0.01) T cells in the mucosa. Moreover, when adjusting for levels of plasma HIV RNA, the frequency of peripheral CD8+Ki67+ T cells remained a significant predictor of CSF HIV RNA (adjusted r=0.78, p<0.001; Figure 1).
During early AHI, CSF inflammation and peripheral and mucosal immune activation are present and increase with progression of Fiebig stage from I to III. The correlation between CSF HIV RNA and frequency of activated CD8+ T cells in the blood independent from plasma HIV RNA supports the hypothesis that peripheral immune activation modulates the amount of HIV entering the CNS during this earliest stage of infection.