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Journal of Virology, August 2007, p. 8165-8179, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.02792-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Conserved Changes in Envelope Function during Human Immunodeficiency Virus Type 1 Coreceptor Switching{triangledown}

Cristina Pastore,1 Rebecca Nedellec,1 Alejandra Ramos,1 Oliver Hartley,2 John L. Miamidian,3 Jacqueline D. Reeves,3,{ddagger} and Donald E. Mosier1*

Department of Immunology, The Scripps Research Institute, La Jolla, California,1 Department of Structural Biology and Bioinformatics, University of Geneva, Geneva, Switzerland,2 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania3

Received 18 December 2006/ Accepted 5 May 2007

We studied the evolution of human immunodeficiency virus type 1 (HIV-1) envelope function during the process of coreceptor switching from CCR5 to CXCR4. Site-directed mutagenesis was used to introduce most of the possible intermediate mutations in the envelope for four distinct coreceptor switch mutants, each with a unique pattern of CCR5 and CXCR4 utilization that extended from highly efficient use of both coreceptors to sole use of CXCR4. Mutated envelopes with some preservation of entry function on either CCR5- or CXCR4-expressing target cells were further characterized for their sensitivity to CCR5 or CXCR4 inhibitors, soluble CD4, and the neutralizing antibodies b12-IgG and 4E10. A subset of mutated envelopes was also studied in direct CD4 or CCR5 binding assays and in envelope-mediated fusion reactions. Coreceptor switch intermediates displayed increased sensitivity to CCR5 inhibitors (except for a few envelopes with mutations in V2 or C2) that correlated with a loss in CCR5 binding. As use of CXCR4 improved, infection mediated by the mutated envelopes became more resistant to soluble CD4 inhibition and direct binding to CD4 increased. These changes were accompanied by increasing resistance to the CXCR4 inhibitor AMD3100. Sensitivity to neutralizing antibody was more variable, although infection of CXCR4-expressing targets was generally more sensitive to neutralization by both b12-IgG and 4E10 than infection of CCR5-expressing target cells. These changes in envelope function were uniform in all four series of envelope mutations and thus were independent of the final use of CCR5 and CXCR4. Decreased CCR5 and increased CD4 binding appear to be common features of coreceptor switch intermediates.

* Corresponding author. Mailing address: Department of Immunology—IMM7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-9121. Fax: (858) 784-9190. E-mail: dmosier{at}scripps.edu

{triangledown} Published ahead of print on 16 May 2007.

{ddagger} Present address: Monogram Biosciences, 345 Oyster Point Blvd., South San Francisco, CA 94080.

Journal of Virology, August 2007, p. 8165-8179, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.02792-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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