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. 2007 Aug;81(15):7885-93.
doi: 10.1128/JVI.00218-07. Epub 2007 May 16.

Coreceptor tropism in human immunodeficiency virus type 1 subtype D: high prevalence of CXCR4 tropism and heterogeneous composition of viral populations

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

Coreceptor tropism in human immunodeficiency virus type 1 subtype D: high prevalence of CXCR4 tropism and heterogeneous composition of viral populations

Wei Huang et al. J Virol. 2007 Aug.

Abstract

In human immunodeficiency virus type 1 (HIV-1) subtype B, CXCR4 coreceptor use ranges from approximately 20% in early infection to approximately 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.

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Figures

FIG. 1.
FIG. 1.
Coreceptor use of viral env populations. Infection of CCR5-and CXCR4-expressing cells is indicated by open circles and crosses, respectively. Infection was measured by luciferase activity (in RLU) produced in cell culture. Samples are grouped by subtype (A, D, and A/D recombinant; n = 33, 25, and 10, respectively). The horizontal dotted line indicates 200 RLU, the threshold for defining CXCR4 use in this study. The median RLU of each group is indicated by horizontal bars.
FIG. 2.
FIG. 2.
Phylogenetic analysis of env clones (gp16D) from DM-tropic subtype D samples. A 1,000-replicate bootstrap resampling of the data revealed >99% support for all patient-nodes.
FIG. 3.
FIG. 3.
Topologies of clones (gp160) from DM-tropic subtype D env populations. Different colors are used to indicate the tropism of individual env clones: red, R5-tropic clones; light blue with asterisk, dual-R-tropic clones (V3 region is R5-tropic-like [see the text]); purple, dual-X-tropic clones (V3 region is divergent or X4-tropic-like [see the text]); green, X4-tropic clones. (A) Samples with pure R5-tropic and pure X4-tropic viruses (no dual-X/dual-R-tropic clones); (B) samples with pure R5-tropic, pure X4-tropic, and dual-X/dual-R-tropic viruses; (C) samples with pure R5-tropic and dual-X/dual-R-tropic clones (no X4-tropic clones).
FIG. 4.
FIG. 4.
Net V3 charge of env clones. R5-tropic clones are indicated by open circles (median net V3 charge +3), dual-R clones are indicated by open triangles (median +4), dual-X clones are indicated by filled triangles (median +6), and X4-tropic clones are indicated by crosses (median +5).
FIG. 5.
FIG. 5.
Infectivity of X4-, R5-, dual-X- and dual-R-tropic env clones. Infectivity was measured by luciferase activity (in RLU) produced in cell culture. (A) Infectivity in CCR5-expressing cells; (B) infectivity in CXCR4-expressing cells. Dual-R-tropic clones (V3 loop is R5-tropic-like) and dual-X-tropic clones (V3 loop is divergent or X4-tropic-like) are graphed separately. The horizontal dotted line indicates 200 RLU, the threshold for defining CCR5 or CXCR4 use in the present study. In CCR5-expressing cells (A), the median RLU were as follows: X4-tropic, 66; dual-X-tropic, 12,868; dual-R-tropic, 1,514,000; and R5-tropic, 775,516. In CXCR4-expressing cells (B), the median RLU were as follows: X4-tropic, 745,039; dual-X-tropic, 740,747; dual-R-tropic, 415; and R5-tropic, 69.
FIG. 6.
FIG. 6.
Model for evolution of coreceptor tropism. R5-tropic viruses are represented in white, dual-R viruses in light gray, and dual-X/X4 viruses in dark gray. The top panel shows the introduction of mutations associated with CXCR4 tropism in the V3 loop of an R5 virus results in X4-tropic or dual-X progeny that have a large fitness disadvantage relative to the parental strain (indicated by an X). The bottom panel shows how the acquisition of non-V3 env mutations which confer low-level CXCR4 use, while maintaining efficient CCR5 use (dual-R viruses), leads to strains that may have a fitness advantage and correspond to precursors of dual-X or X4 viruses. See the Discussion for details.
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