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Journal of Virology, September 2001, p. 8498-8506, Vol. 75, No. 18
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.18.8498-8506.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Human Immunodeficiency Virus Type 1 IIIB Selected for Replication In Vivo Exhibits Increased Envelope Glycoproteins in Virions without Alteration in Coreceptor Usage: Separation of In Vivo Replication from Macrophage Tropism†

Eric D. Miller,1 Karen M. Duus,1 Michael Townsend,1 Yanjie Yi,2 Ronald Collman,2 Marvin Reitz,3 and Lishan Su1,*

The Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-72951; Institute of Human Virology, University of Maryland at Baltimore, Baltimore, Maryland 212012; and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-60613

Received 30 March 2001/Accepted 14 June 2001

Analysis of viral replication and pathogenicity after in vivo selection of human immunodeficiency virus type 1 (HIV-1) attenuated in vitro will help to define the functions involved in replication and pathogenesis in vivo. Using the SCID-hu Thy/Liv mouse and human fetal thymus organ culture as in vivo models, we previously defined HIV-1 env determinants (HXB2/LW) which were reverted for replication in vivo (L. Su et al., Virology 227:46-52, 1997). In this study, we examined the replication of four highly related HIV-1 clones directly derived from Lai/IIIB or after selection in vivo to investigate the envelope gp120 determinants associated with replication in macrophages and in the thymus models in vivo. The LW/C clone derived from the IIIB-infected laboratory worker and HXB2/LW both efficiently infected monocyte-derived macrophages (MDM) and the human thymus. Although the laboratory worker (LW) isolates showed altered tropism from IIIB, they still predominantly used CXCR4 as coreceptors for infecting peripheral blood mononuclear cells, macrophages, and the thymus. Interestingly, a single amino acid mutation in the V3 loop associated with resistance to neutralizing antibodies was also essential for the replication activity of the LW virus in the thymus models but not for its activity in infecting MDM. The LW virions were equally sensitive to a CXCR4 antagonist. We further demonstrated that the LW HIV-1 isolate selected in vivo produced more infectious viral particles that contained higher levels of the Env protein gp120. Thus, selection of the laboratory-attenuated Lai/IIIB isolate in vivo leads to altered tropism but not coreceptor usage of the virus. The acquired replication activity in vivo is correlated with an early A-to-T mutation in the V3 loop and increased virion association of HIV-1 Env gp120, but it is genetically separable from the acquired replication activity in macrophages.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7295. Phone: (919) 966-6654. Fax: (919) 966-8212. E-mail: lsu{at}med.unc.edu.

dagger Dedicated to the memory of Eric D. Miller.

Journal of Virology, September 2001, p. 8498-8506, Vol. 75, No. 18
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.18.8498-8506.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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