Role of CCR5 in infection of primary macrophages and lymphocytes by macrophage-tropic strains of human immunodeficiency virus: resistance to patient-derived and prototype isolates resulting from the delta ccr5 mutation

J Virol. 1997 Apr;71(4):3219-27. doi: 10.1128/JVI.71.4.3219-3227.1997.

Abstract

The alpha-chemokine receptor fusin (CXCR-4) and beta-chemokine receptor CCR5 serve as entry cofactors for T-cell (T)-tropic and macrophage (M)-tropic human immunodeficiency virus type 1 (HIV-1) strains, respectively, when expressed with CD4 in otherwise nonpermissive cells. Some M-tropic and dual-tropic strains can also utilize other beta-chemokine receptors, such as CCR2b and CCR3. A mutation of CCR5 (delta ccr5) was recently found to be common in certain populations and appears to confer protection against HIV-1 in vivo. Here, we show that this mutation results in a protein that is expressed intracellularly but not on the cell surface. Primary CD4 T cells from delta ccr5 homozygous individuals were highly resistant to infection with prototype M-tropic HIV-1 strains, including an isolate (YU-2) that uses CCR5 and CCR3, but were permissive for both a T-tropic strain (3B) and a dual-tropic variant (89.6) that uses CXCR-4, CCR5, CCR3, or CCR2b. These cells were also resistant to M-tropic patient isolates but were readily infected by T-tropic patient isolates. Primary macrophages from delta ccr5 homozygous individuals were also resistant to infection with M-tropic strains, including YU-2, but the dual-tropic strain 89.6 was able to replicate in them even though macrophages are highly resistant to CXCR-4-dependent T-tropic isolates. These data show that CCR5 is the essential cofactor for infection of both primary macrophages and T lymphocytes by most M-tropic strains of HIV-1. They also suggest that CCR3 does not function for HIV-1 entry in primary lymphocytes or macrophages, but that a molecule(s) other than CCR5 can support entry into macrophages by certain virus isolates. These studies further define the cellular basis for the resistance to HIV-1 infection of individuals lacking functional CCR5.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CD4 Antigens / immunology
  • CD8 Antigens / immunology
  • Cells, Cultured
  • HIV-1 / immunology
  • HIV-1 / physiology*
  • Humans
  • Lymphocytes / cytology
  • Lymphocytes / virology*
  • Macrophages / cytology
  • Macrophages / virology*
  • Mutagenesis
  • Receptors, CCR3
  • Receptors, CCR5
  • Receptors, Chemokine*
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / immunology
  • Receptors, Cytokine / physiology*
  • Receptors, HIV / genetics
  • Receptors, HIV / immunology
  • Receptors, HIV / physiology*
  • Species Specificity
  • Virus Replication

Substances

  • CCR3 protein, human
  • CD4 Antigens
  • CD8 Antigens
  • Receptors, CCR3
  • Receptors, CCR5
  • Receptors, Chemokine
  • Receptors, Cytokine
  • Receptors, HIV