Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology

Maria F. Chen, Susan Westmoreland, Elena V. Ryzhova, Julio Martín-García, Samantha S. Soldan, Andrew Lackner, Francisco González-Scarano

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) gp160s obtained from the brain are often genetically distinct from those isolated from other organs, suggesting the presence of brain-specific selective pressures or founder effects that result in the compartmentalization of viral quasispecies. Whereas HIV has also been found to compartmentalize within different regions of the brain, the extent of brain-regional compartmentalization of SIV in rhesus macaques has not been characterized. Furthermore, much is still unknown about whether phenotypic differences exist in envelopes from different brain regions. To address these questions, DNA sequences were amplified from four SIVmac239-infected macaques and subjected to phylogenetic and phenetic analysis. The authors demonstrated that sequences from different areas of the brain form distinct clades, and that the long-term progressing macaques demonstrated a greater degree of regional compartmentalization compared to the rapidly progressing macaques. In addition, regional compartmentalization occurred regardless of the presence of giant-cell encephalitis. Nucleotide substitution rates at synonymous and nonsynonymous sites (ds:dn rates) indicated that positive selection varied among envelopes from different brain regions. In one macaque, envelopes from some but not all brain regions acquired changes in a conserved CD4-binding motif GGGDPE at amino acids 382 to 387. Furthermore, gp160s with the mutation G383E were able to mediate cell-to-cell fusion in a CD4-independent manner and were more susceptible to fusion inhibition by pooled plasma from infected macaques. Reversion of this mutation by site-directed mutagenesis resulted in reduction of CD4-independence and resistance to fusion inhibition in cell fusion assays. These studies demonstrate that SIV evolution within the brain results in a heterogeneous viral population with different phenotypes among different regions.

Original languageEnglish (US)
Pages (from-to)73-89
Number of pages17
JournalJournal of NeuroVirology
Volume12
Issue number2
DOIs
StatePublished - Apr 2006
Externally publishedYes

Fingerprint

Simian Immunodeficiency Virus
Macaca
Brain
Cell Fusion
HIV
Founder Effect
Neuropathology
Mutation
Encephalitis
Giant Cells
Site-Directed Mutagenesis
Macaca mulatta
Nucleotides
Phenotype
Amino Acids

Keywords

  • CD4-independence
  • CNS compartmentalization
  • gp160
  • SIV

ASJC Scopus subject areas

  • Virology
  • Clinical Neurology

Cite this

Chen, M. F., Westmoreland, S., Ryzhova, E. V., Martín-García, J., Soldan, S. S., Lackner, A., & González-Scarano, F. (2006). Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology. Journal of NeuroVirology, 12(2), 73-89. https://doi.org/10.1080/13550280600654565

Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology. / Chen, Maria F.; Westmoreland, Susan; Ryzhova, Elena V.; Martín-García, Julio; Soldan, Samantha S.; Lackner, Andrew; González-Scarano, Francisco.

In: Journal of NeuroVirology, Vol. 12, No. 2, 04.2006, p. 73-89.

Research output: Contribution to journalArticle

Chen, MF, Westmoreland, S, Ryzhova, EV, Martín-García, J, Soldan, SS, Lackner, A & González-Scarano, F 2006, 'Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology', Journal of NeuroVirology, vol. 12, no. 2, pp. 73-89. https://doi.org/10.1080/13550280600654565
Chen, Maria F. ; Westmoreland, Susan ; Ryzhova, Elena V. ; Martín-García, Julio ; Soldan, Samantha S. ; Lackner, Andrew ; González-Scarano, Francisco. / Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology. In: Journal of NeuroVirology. 2006 ; Vol. 12, No. 2. pp. 73-89.
@article{515485fe4b3a4a778838efdeb5b60dc3,
title = "Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology",
abstract = "Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) gp160s obtained from the brain are often genetically distinct from those isolated from other organs, suggesting the presence of brain-specific selective pressures or founder effects that result in the compartmentalization of viral quasispecies. Whereas HIV has also been found to compartmentalize within different regions of the brain, the extent of brain-regional compartmentalization of SIV in rhesus macaques has not been characterized. Furthermore, much is still unknown about whether phenotypic differences exist in envelopes from different brain regions. To address these questions, DNA sequences were amplified from four SIVmac239-infected macaques and subjected to phylogenetic and phenetic analysis. The authors demonstrated that sequences from different areas of the brain form distinct clades, and that the long-term progressing macaques demonstrated a greater degree of regional compartmentalization compared to the rapidly progressing macaques. In addition, regional compartmentalization occurred regardless of the presence of giant-cell encephalitis. Nucleotide substitution rates at synonymous and nonsynonymous sites (ds:dn rates) indicated that positive selection varied among envelopes from different brain regions. In one macaque, envelopes from some but not all brain regions acquired changes in a conserved CD4-binding motif GGGDPE at amino acids 382 to 387. Furthermore, gp160s with the mutation G383E were able to mediate cell-to-cell fusion in a CD4-independent manner and were more susceptible to fusion inhibition by pooled plasma from infected macaques. Reversion of this mutation by site-directed mutagenesis resulted in reduction of CD4-independence and resistance to fusion inhibition in cell fusion assays. These studies demonstrate that SIV evolution within the brain results in a heterogeneous viral population with different phenotypes among different regions.",
keywords = "CD4-independence, CNS compartmentalization, gp160, SIV",
author = "Chen, {Maria F.} and Susan Westmoreland and Ryzhova, {Elena V.} and Julio Mart{\'i}n-Garc{\'i}a and Soldan, {Samantha S.} and Andrew Lackner and Francisco Gonz{\'a}lez-Scarano",
year = "2006",
month = "4",
doi = "10.1080/13550280600654565",
language = "English (US)",
volume = "12",
pages = "73--89",
journal = "Journal of NeuroVirology",
issn = "1355-0284",
publisher = "Springer New York",
number = "2",

}

TY - JOUR

T1 - Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology

AU - Chen, Maria F.

AU - Westmoreland, Susan

AU - Ryzhova, Elena V.

AU - Martín-García, Julio

AU - Soldan, Samantha S.

AU - Lackner, Andrew

AU - González-Scarano, Francisco

PY - 2006/4

Y1 - 2006/4

N2 - Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) gp160s obtained from the brain are often genetically distinct from those isolated from other organs, suggesting the presence of brain-specific selective pressures or founder effects that result in the compartmentalization of viral quasispecies. Whereas HIV has also been found to compartmentalize within different regions of the brain, the extent of brain-regional compartmentalization of SIV in rhesus macaques has not been characterized. Furthermore, much is still unknown about whether phenotypic differences exist in envelopes from different brain regions. To address these questions, DNA sequences were amplified from four SIVmac239-infected macaques and subjected to phylogenetic and phenetic analysis. The authors demonstrated that sequences from different areas of the brain form distinct clades, and that the long-term progressing macaques demonstrated a greater degree of regional compartmentalization compared to the rapidly progressing macaques. In addition, regional compartmentalization occurred regardless of the presence of giant-cell encephalitis. Nucleotide substitution rates at synonymous and nonsynonymous sites (ds:dn rates) indicated that positive selection varied among envelopes from different brain regions. In one macaque, envelopes from some but not all brain regions acquired changes in a conserved CD4-binding motif GGGDPE at amino acids 382 to 387. Furthermore, gp160s with the mutation G383E were able to mediate cell-to-cell fusion in a CD4-independent manner and were more susceptible to fusion inhibition by pooled plasma from infected macaques. Reversion of this mutation by site-directed mutagenesis resulted in reduction of CD4-independence and resistance to fusion inhibition in cell fusion assays. These studies demonstrate that SIV evolution within the brain results in a heterogeneous viral population with different phenotypes among different regions.

AB - Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) gp160s obtained from the brain are often genetically distinct from those isolated from other organs, suggesting the presence of brain-specific selective pressures or founder effects that result in the compartmentalization of viral quasispecies. Whereas HIV has also been found to compartmentalize within different regions of the brain, the extent of brain-regional compartmentalization of SIV in rhesus macaques has not been characterized. Furthermore, much is still unknown about whether phenotypic differences exist in envelopes from different brain regions. To address these questions, DNA sequences were amplified from four SIVmac239-infected macaques and subjected to phylogenetic and phenetic analysis. The authors demonstrated that sequences from different areas of the brain form distinct clades, and that the long-term progressing macaques demonstrated a greater degree of regional compartmentalization compared to the rapidly progressing macaques. In addition, regional compartmentalization occurred regardless of the presence of giant-cell encephalitis. Nucleotide substitution rates at synonymous and nonsynonymous sites (ds:dn rates) indicated that positive selection varied among envelopes from different brain regions. In one macaque, envelopes from some but not all brain regions acquired changes in a conserved CD4-binding motif GGGDPE at amino acids 382 to 387. Furthermore, gp160s with the mutation G383E were able to mediate cell-to-cell fusion in a CD4-independent manner and were more susceptible to fusion inhibition by pooled plasma from infected macaques. Reversion of this mutation by site-directed mutagenesis resulted in reduction of CD4-independence and resistance to fusion inhibition in cell fusion assays. These studies demonstrate that SIV evolution within the brain results in a heterogeneous viral population with different phenotypes among different regions.

KW - CD4-independence

KW - CNS compartmentalization

KW - gp160

KW - SIV

UR - http://www.scopus.com/inward/record.url?scp=33746867131&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746867131&partnerID=8YFLogxK

U2 - 10.1080/13550280600654565

DO - 10.1080/13550280600654565

M3 - Article

C2 - 16798669

AN - SCOPUS:33746867131

VL - 12

SP - 73

EP - 89

JO - Journal of NeuroVirology

JF - Journal of NeuroVirology

SN - 1355-0284

IS - 2

ER -