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 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.
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. julio.martin-garcia@drexelmed.edu
authors.forename: Julio
authors.initials: J
authors.lastname: Martín-García
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.forename: Angel
authors.initials: A
authors.lastname: Varela-Rohena
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Plassmeyer
authors.forename: Francisco
authors.initials: F
authors.lastname: González-Scarano
mesh_terms: D015526:AIDS Dementia Complex / Q000821:virology*; D000595:Amino Acid Sequence; D001921:Brain / Q000821:virology*; D015704:CD4 Antigens / Q000378:metabolism*; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000150:complications / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification / Q000472:pathogenicity*; D006801:Humans; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D015728:Receptors, HIV / Q000378:metabolism; D013154:Spleen / Q000821:virology
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D015728:Receptors, HIV