title: Variation in HIV-1 R5 macrophage-tropism correlates with sensitivity to reagents that block envelope: CD4 interactions but not with sensitivity to other entry inhibitors.
abstract: BACKGROUND
  HIV-1 R5 viruses cause most of the AIDS cases worldwide and are preferentially transmitted compared to CXCR4-using viruses. Furthermore, R5 viruses vary extensively in capacity to infect macrophages and highly macrophage-tropic variants are frequently identified in the brains of patients with dementia. Here, we investigated the sensitivity of R5 envelopes to a range of inhibitors and antibodies that block HIV entry. We studied a large panel of R5 envelopes, derived by PCR amplification without culture from brain, lymph node, blood and semen. These R5 envelopes conferred a wide range of macrophage tropism and included highly macrophage-tropic variants from brain and non-macrophage-tropic variants from lymph node.
  
  
  RESULTS
  R5 macrophage-tropism correlated with sensitivity to inhibition by reagents that inhibited gp120:CD4 interactions. Thus, increasing macrophage-tropism was associated with increased sensitivity to soluble CD4 and to IgG-CD4 (PRO 542), but with increased resistance to the anti-CD4 monoclonal antibody (mab), Q4120. These observations were highly significant and are consistent with an increased affinity of envelope for CD4 for macrophage-tropic envelopes. No overall correlations were noted between R5 macrophage-tropism and sensitivity to CCR5 antagonists or to gp41 specific reagents. Intriguingly, there was a relationship between increasing macrophage-tropism and increased sensitivity to the CD4 binding site mab, b12, but decreased sensitivity to 2G12, a mab that binds a glycan complex on gp120.
  
  
  CONCLUSIONS
  Variation in R5 macrophage-tropism is caused by envelope variation that predominantly influences sensitivity to reagents that block gp120:CD4 interactions. Such variation has important implications for therapy using viral entry inhibitors and for the design of envelope antigens for vaccines.
authors.affiliation: Center for AIDS Research, Program in Molecular Medicine and Department of Molecular Genetics and Microbiology, 373 Plantation Street, University of Massachusetts Medical School, Worcester, MA 01605, USA. Paul.Peters@umassmed.edu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Peters
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Duenas-Decamp
authors.forename: W Matthew
authors.initials: WM
authors.lastname: Sullivan
authors.forename: Richard
authors.initials: R
authors.lastname: Brown
authors.forename: Chiambah
authors.initials: C
authors.lastname: Ankghuambom
authors.forename: Katherine
authors.initials: K
authors.lastname: Luzuriaga
authors.forename: James
authors.initials: J
authors.lastname: Robinson
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Jeanne
authors.initials: J
authors.lastname: Bell
authors.forename: Peter
authors.initials: P
authors.lastname: Simmonds
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ball
authors.forename: Paul R
authors.initials: PR
authors.lastname: Clapham
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology; D001921:Brain / Q000821:virology; D002460:Cell Line; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D007223:Infant; D020128:Inhibitory Concentration 50; D008198:Lymph Nodes / Q000821:virology; D008264:Macrophages / Q000821:virology*; D009500:Neutralization Tests; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; C514793:gp120 protein, Human immunodeficiency virus 1