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Journal of Virology, August 2007, p. 7885-7893, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.00218-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Coreceptor Tropism in Human Immunodeficiency Virus Type 1 Subtype D: High Prevalence of CXCR4 Tropism and Heterogeneous Composition of Viral Populations{triangledown}

Wei Huang,1* Susan H. Eshleman,2 Jonathan Toma,1 Signe Fransen,1 Eric Stawiski,1 Ellen E. Paxinos,1 Jeannette M. Whitcomb,1 Alicia M. Young,3 Deborah Donnell,3 Francis Mmiro,4 Philippa Musoke,4 Laura A. Guay,2 J. Brooks Jackson,2 Neil T. Parkin,1 and Christos J. Petropoulos1

Monogram Biosciences, South San Francisco, California,1 Johns Hopkins University School of Medicine, Baltimore, Maryland,2 Fred Hutchinson Cancer Research Center, Seattle, Washington,3 Makerere University, Kampala, Uganda4

Received 31 January 2007/ Accepted 5 May 2007

In human immunodeficiency virus type 1 (HIV-1) subtype B, CXCR4 coreceptor use ranges from ~20% in early infection to ~50% in advanced disease. Coreceptor use by non-subtype B HIV is less well characterized. We studied coreceptor tropism of subtype A and D HIV-1 collected from 68 pregnant, antiretroviral drug-naive Ugandan women (HIVNET 012 trial). None of 33 subtype A or 10 A/D-recombinant viruses used the CXCR4 coreceptor. In contrast, nine (36%) of 25 subtype D viruses used both CXCR4 and CCR5 coreceptors. Clonal analyses of the nine subtype D samples with dual or mixed tropism revealed heterogeneous viral populations comprised of X4-, R5-, and dual-tropic HIV-1 variants. In five of the six samples with dual-tropic strains, V3 loop sequences of dual-tropic clones were identical to those of cocirculating R5-tropic clones, indicating the presence of CXCR4 tropism determinants outside of the V3 loop. These dual-tropic variants with R5-tropic-like V3 loops, which we designated "dual-R," use CCR5 much more efficiently than CXCR4, in contrast to dual-tropic clones with X4-tropic-like V3 loops ("dual-X"). These observations have implications for pathogenesis and treatment of subtype D-infected individuals, for the association between V3 sequence and coreceptor tropism phenotype, and for understanding potential mechanisms of evolution from exclusive CCR5 use to efficient CXCR4 use by subtype D HIV-1.

* Corresponding author. Mailing address: Monogram Biosciences, 345 Oyster Point Blvd., South San Francisco, CA 94080. Phone: (650) 866-7429. Fax: (650) 624-4132. E-mail: whuang{at}monogrambio.com

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

Journal of Virology, August 2007, p. 7885-7893, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.00218-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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