A human immunodeficiency virus type 1 isolate from an infected person homozygous for CCR5Delta32 exhibits dual tropism by infecting macrophages and MT2 cells via CXCR4.
The mechanisms of human immunodeficiency virus (HIV) infection of a man (VH) homozygous for the CCR5Delta32 mutation were investigated, and coreceptors other than CCR5 used by HIV type 1 (HIV-1) isolated from this individual were identified. In contrast to previous reports, this individual's rate of disease progression was not accelerated. Homozygosity for CCR5Delta32 mutation was demonstrated by PCR and DNA sequencing (R. Biti et al., Nat. Med. 3:252-253, 1997). CCR5 surface expression was absent on T lymphocytes and macrophages. HIV was isolated by coculture with peripheral blood mononuclear cells (PBMCs) from siblings who were homozygous (VM) or wild type (WT) for the CCR5Delta32 mutation. The virus demonstrated dual tropism for infection of MT2 cell line and primary macrophages. Sequencing of the full HIV genome directly from the patient's PBMCs revealed 21 nucleotide insertions in the V1 region of gp120. The VH envelope sequence segregated apart from both the T-cell-line-adapted tropic strains NL4-3 and SF2 and M-tropic strain JRFL or YU2 by phylogenetic tree analysis. VH was shown to utilize predominantly CXCR4 for entry into T lymphocytes and macrophages by HOS.CD4 cell infection assay, direct envelope protein fusion, and inhibition by anti-CXCR4 monoclonal antibody (12G5), SDF-1, and AMD3100. Microsatellite mapping demonstrated the separate inheritance of CXCR4 by both homozygote brothers (VH and VM). Our study demonstrates the ability of certain strains of HIV to readily use CXCR4 for infection or entry into macrophages, which is highly relevant to the pathogenesis of late-stage disease and presumably also HIV transmission.
Naif
Hassan M
HM
Centre for Virus Research. Institute of Immunology and Allergy Research, The Westmead Millennium Institute, The University of Sydney, Sydney, New South Wales, Australia. hassan_naif@wmi.usyd.edu.au
Cunningham
Anthony L
AL
Alali
Mohammed
M
Li
Shan
S
Nasr
Najla
N
Buhler
Marc M
MM
Schols
Dominique
D
de Clercq
Erik
E
Stewart
Graeme
G
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006720:Homozygote; D006801:Humans; D008264:Macrophages / Q000821:virology; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D019713:Receptors, CCR5 / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000378:metabolism; D018523:Tropism; D014779:Virus Replication
D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D019718:Receptors, CXCR4