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Journal of Virology, April 2000, p. 3196-3204, Vol. 74, No. 7
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Human Immunodeficiency Virus Type 1 Pathogenesis in SCID-hu Mice Correlates with Syncytium-Inducing Phenotype and Viral Replication

David Camerini,1,* Hua-Poo Su,1 Graciela Gamez-Torre,1 Michael L. Johnson,2 Jerome A. Zack,3 and Irvin S. Y. Chen3

Department of Microbiology and Myles H. Thaler Center for AIDS and Human Retrovirus Research1 and Department of Pharmacology,2 University of Virginia, Charlottesville, Virginia 22908, and Department of Microbiology, Immunology and Molecular Genetics, Department of Medicine, and AIDS Institute, UCLA School of Medicine, Los Angeles, California 900953

Received 12 July 1999/Accepted 22 December 1999

Human immunodeficiency virus type 1 (HIV-1) patient isolates and molecular clones were used to analyze the determinants responsible for human CD4+ thymocyte depletion in SCID-hu mice. Non-syncytium-inducing, R5 or R3R5 HIV-1 isolates from asymptomatic infected people showed little or no human CD4+ thymocyte depletion in SCID-hu mice, while syncytium-inducing (SI), R5X4 or R3R5X4 HIV-1 isolates from the same individuals, isolated just prior to the onset of AIDS, rapidly and efficiently eliminated CD4-bearing human thymocytes. We have mapped the ability of one SI HIV-1 isolate to eliminate CD4+ human cells in SCID-hu mice to a region of the env gene including the three most amino-terminal variable regions (V1 to V3). We find that for all of the HIV-1 isolates that we studied, a nonlinear relationship exists between viral replication and the depletion of CD4+ cells. This relationship can best be described mathematically with a Hill-type plot indicating that a threshold level of viral replication, at which cytopathic effects begin to be seen, exists for HIV-1 infection of thymus/liver grafts in SCID-hu mice. This threshold level is 1 copy of viral DNA for every 11 cells (95% confidence interval = 1 copy of HIV-1 per 67 cells to 1 copy per 4 cells). Furthermore, while SI viruses more frequently achieve this level of replication, replication above this threshold level correlates best with cytopathic effects in this model system. We used GHOST cells to map the coreceptor specificity and relative entry efficiency of these early- and late-stage patient isolates of HIV-1. Our studies show that coreceptor specificity and entry efficiency are critical determinants of HIV-1 pathogenesis in vivo.

* Corresponding author. Mailing address: Thaler Center for AIDS Research, HSC Box 441, University of Virginia, Charlottesville, VA 22908. Phone: (804) 243-6119. Fax: (804) 982-1590. E-mail: dc9b{at}virginia.edu.

Journal of Virology, April 2000, p. 3196-3204, Vol. 74, No. 7
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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