In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4-mediated killing of uninfected CD4 T cells.
The destruction of the immune system by progressive loss of CD4 T cells is the hallmark of AIDS. CCR5-dependent (R5) human immunodeficiency virus type 1 (HIV-1) isolates predominate in the early, asymptomatic stages of HIV-1 infection, while CXCR4-dependent (X4) isolates typically emerge at later stages, frequently coinciding with a rapid decline in CD4 T cells. Lymphocyte killing in vivo primarily occurs through apoptosis, but the importance of apoptosis of HIV-1-infected cells relative to apoptosis of uninfected bystander cells is controversial. Here we show that in human lymphoid tissues ex vivo, apoptosis of uninfected bystander CD4 T cells is a major mechanism of lymphocyte depletion caused by X4 HIV-1 strains but is only a minor mechanism of depletion by R5 strains. Further, X4 HIV-1-induced bystander apoptosis requires the interaction of the viral envelope glycoprotein gp120 with the CXCR4 coreceptor on CD4 T cells. These results emphasize the contribution of bystander apoptosis to HIV-1 cytotoxicity and suggest that in association with a coreceptor switch in HIV disease, T-cell killing evolves from an infection-restricted stage to generalized toxicity that involves a high degree of bystander apoptosis.
Gladstone Institute of Virology and Immunology, University of California at San Francisco, San Francisco, California 94141-9100, USA. ajekle@gladstone.ucsf.edu
Andreas
A
Jekle
Oliver T
OT
Keppler
Erik
E
De Clercq
Dominique
D
Schols
Mark
M
Weinstein
Mark A
MA
Goldsmith
D017209:Apoptosis; D024201:Bystander Effect; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D019143:Evolution, Molecular; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D014066:Palatine Tonsil / Q000276:immunology / Q000821:virology; D019718:Receptors, CXCR4 / Q000378:metabolism*; D014774:Virulence
D017252:CD3 Complex; D019718:Receptors, CXCR4