Genetic attributes of cerebrospinal fluid-derived HIV-1 env.

TitleGenetic attributes of cerebrospinal fluid-derived HIV-1 env.
Publication TypeJournal Article
Year of Publication2006
AuthorsPillai SK, Pond SLKosakovs, Liu Y, Good BM, Strain MC, Ellis RJ, Letendre S, Smith DM, Günthard HF, Grant I, Marcotte TD, J McCutchan A, Richman DD, Wong JK
JournalBrain
Volume129
IssuePt 7
Pagination1872-83
Date Published2006 Jul
ISSN1460-2156
KeywordsAmino Acid Sequence, CD4 Lymphocyte Count, Cerebrospinal Fluid, Cognition Disorders, Evolution, Molecular, Genes, env, Genetic Variation, Glycosylation, HIV Antibodies, HIV Infections, HIV-1, Humans, Molecular Sequence Data, Neuropsychological Tests, Phylogeny, RNA, Viral, Sequence Homology, Amino Acid, Virulence
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.

DOI10.1093/brain/awl136
Alternate JournalBrain
PubMed ID16735456
Grant List5K23AI055276 / AI / NIAID NIH HHS / United States
AI047745 / AI / NIAID NIH HHS / United States
AI27670 / AI / NIAID NIH HHS / United States
AI29164 / AI / NIAID NIH HHS / United States
AI36214 / AI / NIAID NIH HHS / United States
AI38858 / AI / NIAID NIH HHS / United States
AI43638 / AI / NIAID NIH HHS / United States
AI43752 / AI / NIAID NIH HHS / United States
MH58076 / MH / NIMH NIH HHS / United States
MH63512 / MH / NIMH NIH HHS / United States
NS51132 / NS / NINDS NIH HHS / United States
R01 NS51132 / NS / NINDS NIH HHS / United States
T32 AI07305 / AI / NIAID NIH HHS / United States