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Journal of Virology, July 2004, p. 7565-7574, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7565-7574.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Intrinsic Obstacles to Human Immunodeficiency Virus Type 1 Coreceptor Switching{dagger}

Cristina Pastore, Alejandra Ramos, and Donald E. Mosier*

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

Received 13 February 2004/ Accepted 18 February 2004

The natural evolution of human immunodeficiency virus type 1 infection often includes a switch in coreceptor preference late in infection from CCR5 to CXCR4, a change associated with expanded target cell range and worsened clinical prognosis. Why coreceptor switching takes so long is puzzling, since it requires as few as one to two mutations. Here we report three obstacles that impede the CCR5-to-CXCR4 switch. Coreceptor switch variants were selected by target cell replacement in vitro. Most switch variants showed diminished replication compared to their parental R5 isolate. Transitional intermediates were more sensitive to both CCR5 and CXCR4 inhibitors than either the parental R5 virus or the final R5X4 (or rare X4) variant. The small number of mutations in viruses selected for CXCR4 use were distinctly nonrandom, with a dominance of charged amino acid substitutions encoded by G-to-A transitions, changes in N-linked glycosylation sites, and isolate-specific mutation patterns. Diminished replication fitness, less-efficient coreceptor use, and unique mutational pathways may explain the long delay from primary infection until the emergence of CXCR4-using viruses.

* Corresponding author. Mailing address: IMM-7, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9121. Fax: (858) 784-9190. E-mail: dmosier{at}scripps.edu.

{dagger} Publication 16057-IMM from The Scripps Research Institute.

Journal of Virology, July 2004, p. 7565-7574, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7565-7574.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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