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Journal of Virology, December 1998, p. 10108-10117, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

CCR5- and CXCR4-Utilizing Strains of Human Immunodeficiency Virus Type 1 Exhibit Differential Tropism and Pathogenesis In Vivo

Robert D. Berkowitz,1 Sabina Alexander,1 Cris Bare,1 Valerie Linquist-Stepps,1 Mark Bogan,1 Mary E. Moreno,1 Lisa Gibson,1 Eric D. Wieder,1 Jon Kosek,2 Cheryl A. Stoddart,1 and Joseph M. McCune1,3,*

Gladstone Institute of Virology and Immunology1 and Departments of Microbiology & Immunology and Medicine, University of California, San Francisco,3 San Francisco, and Department of Pathology, Stanford University, Stanford, and Veterans Hospital, Palo Alto,2 California

Received 25 June 1998/Accepted 26 August 1998

CCR5-utilizing (R5) and CXCR4-utilizing (X4) strains of human immunodeficiency virus type 1 (HIV-1) have been studied intensively in vitro, but the pathologic correlates of such differential tropism in vivo remain incompletely defined. In this study, X4 and R5 strains of HIV-1 were compared for tropism and pathogenesis in SCID-hu Thy/Liv mice, an in vivo model of human thymopoiesis. The X4 strain NL4-3 replicates quickly and extensively in thymocytes in the cortex and medulla, causing significant depletion. In contrast, the R5 strain Ba-L initially infects stromal cells including macrophages in the thymic medulla, without any obvious pathologic consequence. After a period of 3 to 4 weeks, Ba-L infection slowly spreads through the thymocyte populations, occasionally culminating in thymocyte depletion after week 6 of infection. During the entire time of infection, Ba-L did not mutate into variants capable of utilizing CXCR4. Therefore, X4 strains are highly cytopathic after infection of the human thymus. In contrast, infection with R5 strains of HIV-1 can result in a two-phase process in vivo, involving apparently nonpathogenic replication in medullary stromal cells followed by cytopathic replication in thymocytes.

* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, CA 94141-9100. Phone: (415) 695-3828. Fax: (415) 826-8449. E-mail: mike_mccune.givi{at}quickmail.ucsf.edu.

Journal of Virology, December 1998, p. 10108-10117, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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