Inflammation and tissue influx of activated T cells affects the compartmentalization and dynamics of HIV viral replication, but the role of compartmentalized virus populations in the emergence of drug resistant mutations (DRMs) and virological failure is uncertain. Herein, we describe viral escape with high viral RNA levels and DRMs in CSF during an episode of unmasking PML-IRIS
PBMCs and CSF mononuclear cells were used for immunophenotyping along with a flow cytometric T cells responses assay to JC virus (JCV), BKV and CMV. Plasma and CSF ARV concentrations were measured by tandem mass spectrometry. Phylogenetic analysis of CSF, plasma, rectal mucosa and cervical lymph node HIV variants was performed
A man with HIV/AIDS [CD4: 6 cells/μL, HIV plasma viral load (VL): 716531 c/mL, CSF VL: 1200 c/mL, no DRMs] presenting with PCP, achieved prompt clinical improvement after TMP-SMX, Prednisone and cEVG/TAF/FTC initiation. 12 weeks after starting ARV, with suppressed HIV VL <40c/mL (bLOD) in plasma and CSF, he developed new ataxia and dysmetria with multiple parenchymal enhancing lesions on MRI. JCV DNA was detectable in CSF, HIV VL remained bLOD and unmasking PML-IRIS was diagnosed, which resolved with addition of Prednisone, Maraviroc and Mirtazapine. After Prednisone was tapered, PML-IRIS flared with new hand tremor: CSF analysis revealed pleocytosis with CSF HIV VL of 15441 c/mL and plasma VL to 185 c/mL. HIV genotype in CSF revealed a new E92Q DRM in Integrase (INT) and M184V/I in RT. Prednisone was restarted with clinical improvement and suppression of both plasma and CSF HIV VL bLOD. Follow-up monitoring of plasma VL showed a progressive increase up to 509 c/mL with the new appearance of E92Q INT and M184I/V RT in plasma. Retrospective drug level analysis documented subtherapeutic EVG concentration in CSF (5.5 ng/ml), which was >300 fold lower than concurrent plasma EVG (1730 ng/mL). Robust specific CD4 T cells responses to JCV, but not to BKV or CMV were documented in CNS and peripheral blood at the time of PML-IRIS flare
Rebound viremia with DRMs emerged in the setting of CNS immune activation from PML-IRIS and suboptimal CSF EVG levels. HIV-1 RNA was >100 fold higher in CSF than plasma, suggesting selection of resistant variants in CNS and consequent dissemination to peripheral blood and lymphnode. The case highlights the role of localized inflammatory processes and trafficking of immune cells in shaping HIV populations in CNS, plasma and lymphoid tissue