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HIV-1 tropism for the central nervous system: Brain-derived envelope glycoproteins with lower CD4 dependence and reduced sensitivity to a fusion inhibitor
Journal article   Open access   Peer reviewed

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

Julio Martín-García, Wei Cao, Angel Varela-Rohena, Matthew L Plassmeyer and Francisco González-Scarano
Virology (New York, N.Y.), v 346(1)
01 Mar 2006
DOI: https://doi.org/10.1016/j.virol.2005.10.031
PMID: 16309726
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1016/j.virol.2005.10.031View
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Abstract

HIV Envelope Protein gp120 - genetics Spleen - virology Amino Acid Sequence HIV Envelope Protein gp41 - genetics HIV-1 - pathogenicity Membrane Fusion HIV-1 - drug effects HIV Infections - virology Humans Drug Resistance, Viral Brain - virology HIV Envelope Protein gp41 - metabolism Molecular Sequence Data HIV Envelope Protein gp41 - chemistry HIV Fusion Inhibitors - pharmacology HIV Envelope Protein gp120 - metabolism Receptors, HIV - metabolism HIV-1 - isolation & purification HIV Infections - complications AIDS Dementia Complex - virology HIV Envelope Protein gp120 - chemistry CD4 Antigens - metabolism
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.

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Collaboration types
Domestic collaboration
Web of Science research areas
Virology
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