| Publication Abstract Display | | Type: Published Manuscript | | Title: Genetic attributes of cerebrospinal fluid-derived HIV-1 env. | | Authors: Pillai SK, Pond SL, Liu Y, Good BM, Strain MC, Ellis RJ, Letendre S, Smith DM, Gunthard HF, Grant I, Marcotte TD, McCutchan JA, Richman DD, Wong JK | | Contact: University of California San Diego, Department of Medicine/NCIRE, La Jolla, CA 94121, USA. satish.pillai@ucsf.edu | | Year: 2006 | | Publication: Brain | | Volume: 129 Issue: Pt 7 Pages: 1872-83 | | 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. | | Funding: NIAID:AI 5K23AI055276, NIAID:AI AI047745, NIAID:AI AI27670, NIAID:AI AI29164, NIAID:AI AI36214, NIAID:AI AI38858, NIAID:AI AI43638, NIAID:AI AI43752, NIMH:MH MH58076, NIMH:MH MH63512, NINDS:NS NS51132, NINDS:NS R01 NS51132, NIAID:AI T32 AI07305 | | Keywords: Amino Acid Sequence, CD4 Lymphocyte Count, Cerebrospinal Fluid, Cognition Disorders, Evolution, Molecular, Genes, env, Glycosylation, HIV Antibodies, HIV Infections, HIV-1, Humans, Molecular Sequence Data, Neuropsychological Tests, Phylogeny, RNA, Viral, Research Support, N.I.H., Extramural, Research Support, U.S. Gov''t, Non-P.H.S., Sequence Homology, Amino Acid, Variation (Genetics), Virulence |
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