title: Early Antiretroviral Therapy Is Associated with Lower HIV DNA Molecular Diversity and Lower Inflammation in Cerebrospinal Fluid but Does Not Prevent the Establishment of Compartmentalized HIV DNA Populations.
abstract: Even when antiretroviral therapy (ART) is started early after infection, HIV DNA might persist in the central nervous system (CNS), possibly contributing to inflammation, brain damage and neurocognitive impairment. Paired blood and cerebrospinal fluid (CSF) were collected from 16 HIV-infected individuals on suppressive ART: 9 participants started ART <4 months of the estimated date of infection (EDI) ("early ART"), and 7 participants started ART >14 months after EDI ("late ART"). For each participant, neurocognitive functioning was measured by Global Deficit Score (GDS). HIV DNA levels were measured in peripheral blood mononuclear cells (PBMCs) and CSF cell pellets by droplet digital (dd)PCR. Soluble markers of inflammation (sCD163, IL-6, MCP-1, TNF-α) and neuronal damage (neurofilament light [NFL]) were measured in blood and CSF supernatant by immunoassays. HIV-1 partial C2V3 env deep sequencing data (Roche 454) were obtained for 8 paired PBMC and CSF specimens and used for phylogenetic and compartmentalization analysis. Median exposure to ART at the time of sampling was 2.6 years (IQR: 2.2-3.7) and did not differ between groups. We observed that early ART was significantly associated with lower molecular diversity of HIV DNA in CSF (p<0.05), and lower IL-6 levels in CSF (p = 0.02), but no difference for GDS, NFL, or HIV DNA detectability compared to late ART. Compartmentalization of HIV DNA populations between CSF and blood was detected in 6 out of 8 participants with available paired HIV DNA sequences (2 from early and 4 from late ART group). Phylogenetic analysis confirmed the presence of monophyletic HIV DNA populations within the CSF in 7 participants, and the same population was repeatedly sampled over a 5 months period in one participant with longitudinal sampling. Such compartmentalized provirus in the CNS needs to be considered for the design of future eradication strategies and might contribute to the neuropathogenesis of HIV.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Michelli F
authors.initials: MF
authors.lastname: Oliveira
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Antoine
authors.initials: A
authors.lastname: Chaillon
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakazawa
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Milenka
authors.initials: M
authors.lastname: Vargas
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.|HIV Neurobehavioral Research Center, San Diego, California, United States of America.
authors.forename: Scott L
authors.identifier: 0000-0003-3490-4975
authors.initials: SL
authors.lastname: Letendre
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Strain
authors.affiliation: HIV Neurobehavioral Research Center, San Diego, California, United States of America.|Departments of Neurosciences and Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ronald J
authors.identifier: 0000-0003-4931-752X
authors.initials: RJ
authors.lastname: Ellis
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Morris
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Little
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.|Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America.
authors.forename: Davey M
authors.initials: DM
authors.lastname: Smith
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Gianella
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002490:Central Nervous System / Q000821:virology*; D003071:Cognition; D060825:Cognitive Dysfunction / Q000821:virology*; D004279:DNA, Viral / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D011446:Prospective Studies; D012367:RNA, Viral / Q000134:cerebrospinal fluid; D055502:Secondary Prevention
chemical_list: D015415:Biomarkers; D004279:DNA, Viral; D012367:RNA, Viral