Coreceptor choice and T cell depletion by R5, X4, and R5X4 HIV-1 variants in CCR5-deficient (CCR5delta32) and normal human lymphoid tissue.
Coreceptor utilization by HIV-1 is an important determinant of pathogenesis. However, coreceptor selectivity is defined in vitro, while in vivo critical pathogenic events occur in lymphoid tissues. Using pharmacological inhibitors, we recently provided evidence that coreceptor selectivity by the R5X4 dual-tropic isolate 89.6 was more restricted in ex vivo infected lymphoid tissue than in vitro [S. Glushakova, Y. Yi, J. C. Grivel, A. Singh, D. Schols, E. De Clercq, R. G. Collman, and L. Margolis (1999). J. Clin. Invest. 104, R7-R11]. Here we extend those observations using CCR5-deficient (CCR5Delta32) lymphoid tissue as well as additional primary isolates. We definitively show that neither CCR5 nor secondary coreceptors used in vitro mediate 89.6 infection in lymphoid tissue. We also demonstrate that restricted coreceptor use in lymphoid tissue ex vivo compared with in vitro utilization occurs with other dual-tropic primary isolates and is not unique to 89.6. For all strains tested that are dual tropic in vitro, severe CD4 T cell depletion in lymphoid tissue correlated with preferential CXCR4 use in this ex vivo system.
Laboratory of Molecular and Cellular Biophysics, National Institutes of Health, Bethesda, Maryland 20892, USA.
N
N
Malkevitch
D H
DH
McDermott
Y
Y
Yi
J C
JC
Grivel
D
D
Schols
E
E
De Clercq
P M
PM
Murphy
S
S
Glushakova
R G
RG
Collman
L
L
Margolis
D018791:CD4 Lymphocyte Count; D003588:Cytopathogenic Effect, Viral; D005838:Genotype; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D066298:In Vitro Techniques; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology / Q000821:virology*; D010641:Phenotype; D019713:Receptors, CCR5 / Q000172:deficiency* / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology / Q000821:virology
D019713:Receptors, CCR5; D019718:Receptors, CXCR4