Pathogenesis of primary R5 human immunodeficiency virus type 1 clones in SCID-hu mice.
We studied the replication and cytopathicity in SCID-hu mice of R5 human immunodeficiency virus type 1 (HIV-1) biological clones from early and late stages of infection of three patients who never developed MT-2 cell syncytium-inducing (SI; R5X4 or X4) viruses. Several of the late-stage non-MT-2 cell syncytium-inducing (NSI; R5) viruses from these patients depleted human CD4(+) thymocytes from SCID-hu mice. Earlier clones from the same patients did not deplete CD4(+) thymocytes from SCID-hu mice as well as later clones. We studied three R5 HIV-1 clones from patient ACH142 in greater detail. Two of these clones were obtained prior to the onset of AIDS; the third was obtained following the AIDS diagnosis. In GHOST cell infection assays, all three ACH142 R5 HIV-1 clones could infect GHOST cells expressing CCR5 but not GHOST cells expressing any of nine other HIV coreceptors tested. Furthermore, these patient clones efficiently infected stimulated peripheral blood mononuclear cells from a normal donor but not those from a homozygous CCR5Delta32 individual. Statistical analyses of data obtained from infection of SCID-hu mice with patient ACH142 R5 clones revealed that only the AIDS-associated clone significantly depleted CD4(+) thymocytes from SCID-hu mice. This clone also replicated to higher levels in SCID-hu mice than the two earlier clones, and a significant correlation between viral replication and CD4(+) thymocyte depletion was observed. Our results indicate that an intrinsic property of AIDS-associated R5 patient clones causes their increased replication and cytopathic effects in SCID-hu mice and likely contributes to the development of AIDS in patients who harbor only R5 quasispecies of HIV-1.
Scoggins
R M
RM
Department of Microbiology and Myles H. Thaler Center for AIDS and Human Retrovirus Research, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia 22908, USA.
Taylor
J R
JR
Patrie
J
J
van't Wout
A B
AB
Schuitemaker
H
H
Camerini
D
D
D000818:Animals; D016516:CD4-CD8 Ratio; D003588:Cytopathogenic Effect, Viral / Q000235:genetics; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006720:Homozygote; D006801:Humans; D008099:Liver / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D019713:Receptors, CCR5 / Q000235:genetics; D013950:Thymus Gland / Q000821:virology; D014779:Virus Replication / Q000235:genetics
D019713:Receptors, CCR5