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© The Rockefeller University Press, 0022-1007/1999/6/1953/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 12, June 21, 1999 1953-1960

Articles

Human Herpesvirus 6 (HHV-6) Causes Severe Thymocyte Depletion in SCID-hu Thy/Liv Mice

Alberto Gobbi*, Cheryl A. Stoddart{ddagger}, Mauro S. Malnati*, Giuseppe Locatelli*, Fabio Santoro*, Nancy W. Abbey§, Christopher Bare{ddagger}, Valerie Linquist-Stepps{ddagger}, Mary Beth Moreno{ddagger}, Brian G. Herndier§, Paolo Lusso*, and Joseph M. McCune{ddagger}

From the * Unit of Human Virology, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan 20132, Italy; the {ddagger} Gladstone Institute of Virology and Immunology, San Francisco, California 94110-9100; and the § Department of Pathology, University of California, San Francisco, California 94110

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that may act as a cofactor in the progression of AIDS. Here, we describe the first small animal model of HHV-6 infection. HHV-6 subgroup A, strain GS, efficiently infected the human thymic tissue implanted in SCID-hu Thy/Liv mice, leading to the destruction of the graft. Viral DNA was detected in Thy/Liv implants by quantitative polymerase chain reaction (PCR) as early as 4 d after inoculation and peaked at day 14. The productive nature of the infection was confirmed by electron microscopy and immunohistochemical staining. Atypical thymocytes with prominent nuclear inclusions were detected by histopathology. HHV-6 replication was associated with severe, progressive thymocyte depletion involving all major cellular subsets. However, intrathymic T progenitor cells (ITTPs) appeared to be more severely depleted than the other subpopulations, and a preferred tropism of HHV-6 for ITTPs was demonstrated by quantitative PCR on purified thymocyte subsets. These findings suggest that thymocyte depletion by HHV-6 may be due to infection and destruction of these immature T cell precursors. Similar results were obtained with strain PL-1, a primary isolate belonging to subgroup B. The severity of the lesions observed in this animal model underscores the possibility that HHV-6 may indeed be immunosuppressive in humans.

Key Words: thymus gland • acquired immunodeficiency syndrome • T lymphocyte subsets • flow cytometry • polymerase chain reaction

Address correspondence to Joseph M. McCune, Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, CA 94110-9100. Phone: 415-695-3828; Fax: 415-826-8449; E-mail: mmccune @gladstone.ucsf.edu

Some of the results in this manuscript were presented at the Annual Meeting of the Institute of Human Virology, Baltimore, MD, August 1998.

Abbreviations used: DAB, diaminobenzidine; DP, CD3– CD4+CD8+ and CD3+CD4+CD8+ double-positive; H&E, hematoxylin and eosin; HHV-6, human herpesvirus 6; ITTP, intrathymic T progenitor cell; SCID, severe combined immunodeficiency; SP4, mature CD3+ CD4+CD8– single-positive 4; SP8, mature CD3+CD4–CD8+ single-positive 8; TCID50, 50% tissue culture infectious dose.


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