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Title: HIV-1 tropism for the central nervous system: Brain-derived envelope glycoproteins with lower CD4 dependence and reduced sensitivity to a fusion inhibitor

Abstract

We previously described envelope glycoproteins of an HIV-1 isolate adapted in vitro for growth in microglia that acquired a highly fusogenic phenotype and lower CD4 dependence, as well as resistance to inhibition by anti-CD4 antibodies. Here, we investigated whether similar phenotypic changes are present in vivo. Envelope clones from the brain and spleen of an HIV-1-infected individual with neurological disease were amplified, cloned, and sequenced. Phylogenetic analysis demonstrated clustering of sequences according to the tissue of origin, as expected. Functional clones were then used in cell-to-cell fusion assays to test for CD4 and co-receptor utilization and for sensitivity to various antibodies and inhibitors. Both brain- and spleen-derived envelope clones mediated fusion in cells expressing both CD4 and CCR5 and brain envelopes also used CCR3 as co-receptor. We found that the brain envelopes had a lower CD4 dependence, since they efficiently mediated fusion in the presence of low levels of CD4 on the target cell membrane, and they were significantly more resistant to blocking by anti-CD4 antibodies than the spleen-derived envelopes. In contrast, we observed no difference in sensitivity to the CCR5 antagonist TAK-779. However, brain-derived envelopes were significantly more resistant than those from spleen to the fusion inhibitor T-1249 andmore » concurrently showed slightly greater fusogenicity. Our results suggest an increased affinity for CD4 of brain-derived envelopes that may have originated from in vivo adaptation to replication in microglial cells. Interestingly, we note the presence of envelopes more resistant to a fusion inhibitor in the brain of an untreated, HIV-1-infected individual.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [3]
  1. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States). E-mail: julio.martin-garcia@drexelmed.edu
  2. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States)
  3. (United States)
Publication Date:
OSTI Identifier:
20779463
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 346; Journal Issue: 1; Other Information: DOI: 10.1016/j.virol.2005.10.031; PII: S0042-6822(05)00726-9; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIDS VIRUS; ANTIBODIES; BRAIN; CELL MEMBRANES; GLYCOPROTEINS; IN VITRO; IN VIVO; INHIBITION; NERVOUS SYSTEM DISEASES; PHENOTYPE; RECEPTORS; SENSITIVITY; SPLEEN

Citation Formats

Martin-Garcia, Julio, Cao, Wei, Varela-Rohena, Angel, Plassmeyer, Matthew L., Gonzalez-Scarano, Francisco, and Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. HIV-1 tropism for the central nervous system: Brain-derived envelope glycoproteins with lower CD4 dependence and reduced sensitivity to a fusion inhibitor. United States: N. p., 2006. Web. doi:10.1016/J.VIROL.2005.1.
Martin-Garcia, Julio, Cao, Wei, Varela-Rohena, Angel, Plassmeyer, Matthew L., Gonzalez-Scarano, Francisco, & Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. HIV-1 tropism for the central nervous system: Brain-derived envelope glycoproteins with lower CD4 dependence and reduced sensitivity to a fusion inhibitor. United States. doi:10.1016/J.VIROL.2005.1.
Martin-Garcia, Julio, Cao, Wei, Varela-Rohena, Angel, Plassmeyer, Matthew L., Gonzalez-Scarano, Francisco, and Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Wed . "HIV-1 tropism for the central nervous system: Brain-derived envelope glycoproteins with lower CD4 dependence and reduced sensitivity to a fusion inhibitor". United States. doi:10.1016/J.VIROL.2005.1.
@article{osti_20779463,
title = {HIV-1 tropism for the central nervous system: Brain-derived envelope glycoproteins with lower CD4 dependence and reduced sensitivity to a fusion inhibitor},
author = {Martin-Garcia, Julio and Cao, Wei and Varela-Rohena, Angel and Plassmeyer, Matthew L. and Gonzalez-Scarano, Francisco and Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104},
abstractNote = {We previously described envelope glycoproteins of an HIV-1 isolate adapted in vitro for growth in microglia that acquired a highly fusogenic phenotype and lower CD4 dependence, as well as resistance to inhibition by anti-CD4 antibodies. Here, we investigated whether similar phenotypic changes are present in vivo. Envelope clones from the brain and spleen of an HIV-1-infected individual with neurological disease were amplified, cloned, and sequenced. Phylogenetic analysis demonstrated clustering of sequences according to the tissue of origin, as expected. Functional clones were then used in cell-to-cell fusion assays to test for CD4 and co-receptor utilization and for sensitivity to various antibodies and inhibitors. Both brain- and spleen-derived envelope clones mediated fusion in cells expressing both CD4 and CCR5 and brain envelopes also used CCR3 as co-receptor. We found that the brain envelopes had a lower CD4 dependence, since they efficiently mediated fusion in the presence of low levels of CD4 on the target cell membrane, and they were significantly more resistant to blocking by anti-CD4 antibodies than the spleen-derived envelopes. In contrast, we observed no difference in sensitivity to the CCR5 antagonist TAK-779. However, brain-derived envelopes were significantly more resistant than those from spleen to the fusion inhibitor T-1249 and concurrently showed slightly greater fusogenicity. Our results suggest an increased affinity for CD4 of brain-derived envelopes that may have originated from in vivo adaptation to replication in microglial cells. Interestingly, we note the presence of envelopes more resistant to a fusion inhibitor in the brain of an untreated, HIV-1-infected individual.},
doi = {10.1016/J.VIROL.2005.1},
journal = {Virology},
number = 1,
volume = 346,
place = {United States},
year = {Wed Mar 01 00:00:00 EST 2006},
month = {Wed Mar 01 00:00:00 EST 2006}
}