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Brain Advance Access published online on May 30, 2006
Brain, doi:10.1093/brain/awl136
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received November 14, 2005
Revised March 31, 2006
Accepted April 20, 2006

Article

Genetic attributes of cerebrospinal fluid-derived HIV-1 env

Satish K. Pillai 1 *, Sergei L. Kosakovsky Pond 2, Yang Liu 3, Benjamin M. Good 4, Matthew C. Strain 2, Ronald J. Ellis 5, Scott Letendre 5, Davey M. Smith 4, Huldrych F. Günthard 6, Igor Grant 5, Thomas D. Marcotte 5, J. Allen McCutchan 5, Douglas D. Richman 4, and Joseph K. Wong 1

1 University of California, San Diego, La Jolla, CA, USA; University of California, San Francisco, San Francisco, CA, USA; VA Medical Center San Francisco, San Francisco, CA, USA
2 University of California, San Diego, La Jolla, CA, USA
3 Monogram Biosciences, Inc., South San Francisco, CA, USA
4 University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA
5 University of California, San Diego, La Jolla, CA, USA; HIV Neurobehavioral Research Center, San Diego, CA, USA
6 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland

* To whom correspondence should be addressed.
Satish K. Pillai, E-mail: satish.pillai{at}ucsf.edu


  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.

Keywords: HIV; CNS; neurovirulence; evolution; compartmentalization.
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