title: Genetic attributes of cerebrospinal fluid-derived HIV-1 env.
abstract: HIV-1 often invades the CNS during primary infection, eventually resulting in neurological disorders in up to 50% of untreated patients. The CNS is a distinct viral reservoir, differing from peripheral tissues in immunological surveillance, target cell characteristics and antiretroviral penetration. Neurotropic HIV-1 likely develops distinct genotypic characteristics in response to this unique selective environment. We sought to catalogue the genetic features of CNS-derived HIV-1 by analysing 456 clonal RNA sequences of the C2-V3 env subregion generated from CSF and plasma of 18 chronically infected individuals. Neuropsychological performance of all subjects was evaluated and summarized as a global deficit score. A battery of phylogenetic, statistical and machine learning tools was applied to these data to identify genetic features associated with HIV-1 neurotropism and neurovirulence. Eleven of 18 individuals exhibited significant viral compartmentalization between blood and CSF (P < 0.01, Slatkin-Maddison test). A CSF-specific genetic signature was identified, comprising positions 9, 13 and 19 of the V3 loop. The residue at position 5 of the V3 loop was highly correlated with neurocognitive deficit (P < 0.0025, Fisher's exact test). Antibody-mediated HIV-1 neutralizing activity was significantly reduced in CSF with respect to autologous blood plasma (P < 0.042, Student's t-test). Accordingly, CSF-derived sequences exhibited constrained diversity and contained fewer glycosylated and positively selected sites. Our results suggest that there are several genetic features that distinguish CSF- and plasma-derived HIV-1 populations, probably reflecting altered cellular entry requirements and decreased immune pressure in the CNS. Furthermore, neurological impairment may be influenced by mutations within the viral V3 loop sequence.
authors.affiliation: University of California San Diego, Department of Medicine/NCIRE, La Jolla, CA 94121, USA. satish.pillai@ucsf.edu
authors.forename: Satish K
authors.initials: SK
authors.lastname: Pillai
authors.forename: Sergei L Kosakovsky
authors.initials: SL
authors.lastname: Pond
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Good
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Strain
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Ellis
authors.forename: Scott
authors.initials: S
authors.lastname: Letendre
authors.forename: Davey M
authors.initials: DM
authors.lastname: Smith
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.forename: Igor
authors.initials: I
authors.lastname: Grant
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Marcotte
authors.forename: J Allen
authors.initials: JA
authors.lastname: McCutchan
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Richman
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wong
mesh_terms: D000595:Amino Acid Sequence; D018791:CD4 Lymphocyte Count; D002555:Cerebrospinal Fluid / Q000821:virology; D003072:Cognition Disorders / Q000821:virology*; D019143:Evolution, Molecular; D015752:Genes, env; D014644:Genetic Variation; D006031:Glycosylation; D015483:HIV Antibodies / Q000276:immunology; D015658:HIV Infections / Q000523:psychology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D008969:Molecular Sequence Data; D009483:Neuropsychological Tests; D010802:Phylogeny; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid; D017386:Sequence Homology, Amino Acid; D014774:Virulence
chemical_list: D015483:HIV Antibodies; D012367:RNA, Viral