title: The role of viral coreceptors and enhanced macrophage tropism in human immunodeficiency virus type 1 disease progression.
abstract: Despite numerous studies on the impact of viral diversity, human immunodeficiency virus type 1 (HIV-1)-specific immune responses and host factors on disease progression, we still do not have a firm understanding of the long-term pathogenesis of HIV-1 infection. Rapid depletion of CD4+ T-lymphocytes has been associated with a switch in viral coreceptor usage from CCR5 to CXCR4 in approximately 40 to 50% of infected individuals. However, the majority of infected individuals who progress to AIDS harbour only CCR5-dependent (R5) viral strains. The progression of HIV-1 disease is associated with an enhanced tropism of R5 viral strains for monocyte/macrophage lineage cells (enhanced M-tropism). However, the underlying molecular mechanisms contributing to enhanced M-tropism by R5 HIV-1 strains, and how HIV-1 variants with enhanced M-tropism cause CD4+ T-cell depletion in vivo are unknown. This review examines the relationship between viral coreceptor usage, M-tropism, and pathogenicity of HIV-1. We highlight evidence supporting the hypothesis that enhanced M-tropism of R5 HIV-1 results from adaptive viral evolution, resulting in HIV-1 variants that have increased ability to utilise relatively low levels of CCR5 expressed on macrophages, by way of increased CCR5 affinity. The evidence also suggests that these late-emerging, R5 viral strains have reduced sensitivity to entry inhibitors, and increased ability to cause CD4+ T-lymphocyte loss. These variants are likely to impact HIV-1 disease progression, especially in patients who persistently harbour only R5 viral strains.
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Australia. gorry@burnet.edu.au
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: Jasminka
authors.initials: J
authors.lastname: Sterjovski
authors.forename: Melissa
authors.initials: M
authors.lastname: Churchill
authors.forename: Kristie
authors.initials: K
authors.lastname: Witlox
authors.forename: Lachlan
authors.initials: L
authors.lastname: Gray
authors.forename: Anthony
authors.initials: A
authors.lastname: Cunningham
authors.forename: Steven
authors.initials: S
authors.lastname: Wesselingh
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018450:Disease Progression; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D008264:Macrophages / Q000821:virology*; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015728:Receptors, HIV / Q000378:metabolism*
chemical_list: D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV