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

Abstract

The ␣-chemokine receptor fusin (CXCR-4) and ␤-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 ␤-chemokine receptors, such as CCR2b and CCR3. A mutation of CCR5 (⌬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 ⌬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 ⌬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.

HIV-1 coreceptor preference is distinct from target cell tropism: a dual-parameter nomenclature to define viral phenotypes

“…Because of donor variability, cells from multiple independent donors must be evaluated. Because primary macrophages and lymphocytes express both CCR5 or CXCR4 (albeit for lymphocytes on somewhat different subsets), identification of the entry pathway(s) employed requires selective inhibition using coreceptor blocking agents and/or use of primary cells lacking CCR5 derived from individuals homozygous for the nonfunctional CCR5 ⌬32 deletion allele [29,65]. Specificity of coreceptor use for entry into mixed populations of Examples Source L-R5 JRCSF [68] cerebrospinal fluid/PI a NB13, NB17 [33] blood/PI L9, L11 [28] blood/PI NA20 LN8, NA118 LN33 [34] lymph node b M-R5…”

Possible influence of the mutant CCR5 allele on vertical transmission of HIV-1

“…⌬32ccr5 homozygotes do not express CCR5 on the cell surface but show no recognised clinical impairment due to this defect Zimmerman et al, 1997]. Increasing experimental and epidemiological data suggest that these individuals may be resistant to sexually and parenterally transmitted HIV-1 [Dean et al, 1996;Huang et al, 1996;Liu et al, 1996;Samson et al, 1996;Zimmerman et al, 1997;Rana et al, 1997].…”

Co‐receptor use by HIV and inhibition of HIV infection by chemokine receptor ligands

“…The reduced level of infection by such strains in D32D32 CCR5 macrophages is completely inhibited by ligands to CXCR4. Macrophage infection by different HIV-1 strains that together used at least eight different co-receptors was solely explained by the use of either CCR5 or CXCR4 (33,55,56). Thus, no evidence of alternative co-receptor use was found.…”