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EXPRESSION OF UNIQUE AND DIVERSE HIV VARIANTS IN CEREBROSPINAL FLUID DURING ART
Jeffrey A. Johnson1, Sarah Malik1, Sam Nightingale2, Jin-fen Li1, Apostolos Beloukas2, Tom Solomon2, Saye Khoo3, Anna Maria Geretti2
1CDC, Atlanta, GA, USA,2Univ of Liverpool, Liverpool, UK,3Univ of Liverpool Inst of Translational Med, Liverpool, UK
The central nervous system (CNS) may become a sanctuary site for HIV during stable antiretroviral therapy (ART). The determinants and mechanisms of viral persistence in CNS remain poorly understood. Using a particle immunocapture algorithm targeting cell proteins within HIV envelopes, we investigated the possible cellular sources of HIV persisting in cerebrospinal fluid (CSF) and examined the phylogenetic relatedness of plasma and CSF viruses.
From the PARTITION Study, we examined 6 HIV-positive persons on stable ART who underwent lumbar puncture for neurological disease (n=4) or a history of intermittent plasma viremia (n=2). Virions expressed in CSF were segregated by source cell type by targeting 10 different host cell proteins that may embed in HIV envelopes during budding. Virions from each capture step were sequenced for evidence of reverse transcriptase (RT) drug-resistant variants (DRVs), and for relatedness to other viruses in the CSF and in plasma. Drug concentrations in plasma and CSF were measured by HPLC.
At sampling, HIV-1 RNA levels in CSF were median 1.2 log10 c/ml (range 0.4-2.0) higher than in paired plasma (Table). The captures identified distinct HIV variants in the CSF of 4/6 individuals. Two subjects (ID 01A and 14A) with no reported NNRTI exposure expressed NNRTI-DRVs in CSF, while plasma viremia was suppressed. One person on an efavirenz (EFV)-containing regimen (ID 04A) expressed 3 different NNRTI-DRVs in the CSF, with no evidence of plasma DRVs. One person with prior abacavir (ABC)/lamivudine (3TC) and current emtricitabine (FTC) exposure (ID 01B) expressed M184I in CSF, whereas one other individual with prior ABC exposure (ID 14A) had a K65E variant. CSF DRVs found in captures were associated with CD45RA-/CD45RO+ and CD3-/CD2+ and/or CD10+ particles, suggesting perivascular macrophage or TH17 cells and NK cells, respectively, as the sources. ID 10A with unsuppressed viremia had phylogenetically distant wildtype viruses in the plasma and CSF, and ART drugs were undetectable.
We found evidence of diverse CSF HIV variants that were distinct from plasma viruses suggesting CNS HIV evolution and maintenance that is separate from blood. Lower CNS drug concentrations and/or activity may allow for compartmentalized selection, persistence and evolution of drug-resistant variants. The capture data suggest different resident cell types were lending to ongoing CNS HIV expression under ART.