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.
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.
Peters
Paul J
PJ
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
Duenas-Decamp
Maria J
MJ
Sullivan
W Matthew
WM
Brown
Richard
R
Ankghuambom
Chiambah
C
Luzuriaga
Katherine
K
Robinson
James
J
Burton
Dennis R
DR
Bell
Jeanne
J
Simmonds
Peter
P
Ball
Jonathan
J
Clapham
Paul R
PR
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*
D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; C514793:gp120 protein, Human immunodeficiency virus 1