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HIV-1 PERSISTS IN CSF CELLS IN HALF OF INDIVIDUALS ON LONG-TERM ART
Serena S. Spudich1, Rajesh T. Gandhi2, Joshua C. Cyktor3, Christina Lalama4, Ronald Bosch4, Bernard J. Macatangay3, Charles Rinaldo3, Kevin Robertson5, Ann Collier6, Catherine Godfrey7, Evelyn Hogg8, Joseph J. Eron5, Deborah McMahon3, John W. Mellors3
1Yale University, New Haven, CT, USA,2Massachusetts General Hospital, Boston, MA, USA,3University of Pittsburgh, Pittsburgh, PA, USA,4Harvard University, Boston, MA, USA,5University of North Carolina Chapel Hill, Chapel Hill, NC, USA,6University of Washington, Seattle, WA, USA,7NIAID, Bethesda, MD, USA,8Social &Scientific Systems, Silver Spring, MD, USA
The frequency of HIV persistence in the cerebrospinal fluid (CSF) and the factors associated with persistence in individuals on long-term antiretroviral therapy (ART) are incompletely understood.
Participants who initiated ART during chronic HIV infection with documented sustained long-term viral suppression in ACTG A5321 underwent paired lumbar puncture and blood collection. Cell-associated (CA) HIV DNA and RNA were measured by qPCR assays in PBMCs and cell pellets derived from ~13 mls of CSF and normalized by amplifiable CCR5 cell equivalents. Cell-free HIV RNA was quantified by single copy assay (SCA) in 3-5 mls of CSF supernatant and blood plasma. Inflammatory biomarkers (IL-6, IP-10, neopterin, MCP-1, sCD14, sCD163) were measured in cell-free CSF and plasma.
69 participants (97% male) had median age 50 years, current CD4 696 cells/mm3, pre-ART CD4 288 cells/mm3 and 8.6 (range 5.4-16.4) years on ART. In CSF, cell-free RNA was detected in only 4% of participants (at 0.4, 0.7, and 1.2 cps/mL), while CA-RNA was detected in 9% (6/69) and CA-DNA in 48% (33/69) (Figure). Among those with detectable CA-DNA in CSF, median levels were 2.1 (0.12 -7.00) cps/103 cells. Participants with detectable cell-free HIV RNA in CSF had higher levels of plasma HIV RNA by SCA than those with undetectable CSF HIV RNA (median plasma VL, 5.9 vs < 0.4 cps/ml, p=0.007). By contrast, detection of CA-DNA in CSF was not associated with HIV DNA levels in PBMCs. CSF inflammatory biomarkers, especially indicators of myeloid cell activation, correlated within CSF and between CSF and plasma, but not with CSF CA-DNA, CA-RNA or cell-free HIV RNA. Higher CSF neopterin, IP-10, MCP-1, sCD14 and sCD163 correlated with older age (p≤0.016); higher CSF neopterin correlated with lower pre-ART CD4:CD8 ratio (r=−0.29, p=0.017). Plasma HIV RNA by SCA correlated with CSF sCD14 (r=0.34, p=0.004) and sCD163 (r=0.29, p=0.017).
Almost half of individuals on long-term ART have HIV-infected mononuclear cells in CSF; transcribed HIV RNA is detectable in CSF cells in a small subset. Persistence of HIV-infected cells in CSF was not associated with higher levels of HIV DNA in blood or with levels of inflammation in blood or CSF, but the level of residual plasma viremia was associated with both cell-free HIV RNA and myeloid cell activation in CSF. These findings highlight the need to develop interventions in addition to ART to clear persistently infected cells from the CSF compartment.