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Journal of Virology, July 2002, p. 6966-6973, Vol. 76, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.14.6966-6973.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Coreceptor Phenotype of Natural Human Immunodeficiency Virus with Nef Deleted Evolves In Vivo, Leading to Increased Virulence

Andreas Jekle,1 Birgit Schramm,1,{dagger} Prerana Jayakumar,1,2 Verena Trautner,1,{ddagger} Dominique Schols,3 Erik De Clercq,3 John Mills,4 Suzanne M. Crowe,4 and Mark A. Goldsmith1,5*

Gladstone Institute of Virology and Immunology,1 School of Medicine,2 Department of Medicine, University of California— San Francisco, San Francisco, California 94141-9100,5 Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium,3 Macfarlane Burnet Institute for Medical Research and Public Health, Fairfield, Victoria, Australia 30784

Received 25 October 2001/ Accepted 5 April 2002

The Sydney Blood Bank Cohort is a group of patients with slowly progressive infection by a human immunodeficiency virus strain containing spontaneous deletions within the nef long terminal repeat region. In 1999, 18 years after the initial infection, one of the members (D36) developed AIDS. In this work, we used an ex vivo human lymphoid cell culture system to analyze two viral isolates obtained from this patient, one prior to the onset of AIDS in 1995 and one after disease progression in 1999. Both D36 isolates were less potent in depleting CD4+ T cells than a reference dualtropic, nef-bearing viral isolate. However, the 1999 isolate was measurably more cytotoxic to CD4+ T cells than the 1995 isolate. Interestingly, although both isolates were nearly equally potent in depleting CCR5+ CD4+ T cells, the cytotoxic effect of the 1999 isolate toward CCR5- CD4+ T cells was significantly higher. Furthermore, GHOST cell infection assays and blocking experiments with the CXCR4 inhibitor AMD3100 showed that the later D36 1999 isolate could infect both CCR5+ and CCR5- CXCR4+ cells efficiently, while infection by the 1995 isolate was nearly completely restricted to CCR5+ cells. Sequence analysis of the V1/V2 and V3 regions of the viral envelope protein gp120 revealed that the more efficient CXCR4 usage of the later isolate might be caused by an additional potential N-glycosylation site in the V1/V2 loop. In conclusion, these data show that an in vivo evolution of the tropism of this nef-deleted strain toward an X4 phenotype was associated with a higher cytopathic potential and progression to AIDS.

* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, CA 94141-9100. Phone: (415) 695-3775. Fax: (415) 695-1364. E-mail: mgoldsmith{at}gladstone.ucsf.edu.

{dagger} Present address: European Molecular Biology Laboratory, 69117 Heidelberg, Germany.

{ddagger} Present address: Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.

Journal of Virology, July 2002, p. 6966-6973, Vol. 76, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.14.6966-6973.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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