The role of viral coreceptors and enhanced macrophage tropism in human immunodeficiency virus type 1 disease progression.
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.
Gorry
Paul R
PR
Macfarlane Burnet Institute for Medical Research and Public Health, Australia. gorry@burnet.edu.au
Sterjovski
Jasminka
J
Churchill
Melissa
M
Witlox
Kristie
K
Gray
Lachlan
L
Cunningham
Anthony
A
Wesselingh
Steven
S
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*
D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV