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. 2009 Sep;83(17):8353-63.
doi: 10.1128/JVI.00780-09. Epub 2009 Jun 24.

Virus entry via the alternative coreceptors CCR3 and FPRL1 differs by human immunodeficiency virus type 1 subtype

R Nedellec  1 , M Coetzer, N Shimizu, H Hoshino, V R Polonis, L Morris, U E A Mårtensson, J Binley, J Overbaugh, D E Mosier
Affiliations

Virus entry via the alternative coreceptors CCR3 and FPRL1 differs by human immunodeficiency virus type 1 subtype

R Nedellec et al. J Virol. 2009 Sep.

Abstract

Human immunodeficiency virus type 1 (HIV-1) infects target cells by binding to CD4 and a chemokine receptor, most commonly CCR5. CXCR4 is a frequent alternative coreceptor (CoR) in subtype B and D HIV-1 infection, but the importance of many other alternative CoRs remains elusive. We have analyzed HIV-1 envelope (Env) proteins from 66 individuals infected with the major subtypes of HIV-1 to determine if virus entry into highly permissive NP-2 cell lines expressing most known alternative CoRs differed by HIV-1 subtype. We also performed linear regression analysis to determine if virus entry via the major CoR CCR5 correlated with use of any alternative CoR and if this correlation differed by subtype. Virus pseudotyped with subtype B Env showed robust entry via CCR3 that was highly correlated with CCR5 entry efficiency. By contrast, viruses pseudotyped with subtype A and C Env proteins were able to use the recently described alternative CoR FPRL1 more efficiently than CCR3, and use of FPRL1 was correlated with CCR5 entry. Subtype D Env was unable to use either CCR3 or FPRL1 efficiently, a unique pattern of alternative CoR use. These results suggest that each subtype of circulating HIV-1 may be subject to somewhat different selective pressures for Env-mediated entry into target cells and suggest that CCR3 may be used as a surrogate CoR by subtype B while FPRL1 may be used as a surrogate CoR by subtypes A and C. These data may provide insight into development of resistance to CCR5-targeted entry inhibitors and alternative entry pathways for each HIV-1 subtype.

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Figures

FIG. 1.
FIG. 1.
(A) Entry mediated by eight, late-stage subtype C env clones determined on U87-CD4 or NP2/CD4 cell lines lacking any exogenous CoR. Two independent env clones from the same patient (4-1, triangle; 4-3, inverted triangle), and one env clone from a separate patient (11-1, filled diamond) were able to mediate virus entry into U87-CD4 cells well above the background of the assay, whereas no env clone could use endogenous coreceptors expressed on NP2-CD4 cells at levels that were scored positive (3.5 log RLU). (B) Entry mediated by two SIVmac239 env clones (one gp160 and a second gp140) and one SIVmac251 gp140 env clone on NP-2.CD4 cells expressing the indicated alternative CoR. The SIVmac239 results are shown in black or open symbols, while the SIVmac251 results are shown as gray-filled symbols.
FIG. 2.
FIG. 2.
(A) Entry mediated by 15 full-length env clones from different HIV-1 subtype A-infected patients via CCR5 or the alternative CoRs CCR3, CCR8, APJ, CMKLR1 (ChemR23), FPRL1, GPR1, or CXCR4. Data are expressed as log RLU, with the mean ± standard error shown by horizontal lines. Only data for positive use of CoR are shown, defined as RLU of >3.2 × 103 (log 3.5), with background of <500. env clones from chronic infection are shown in black or open symbols while env clones from recent transmission are shown in gray. (B) Linear regression analysis of entry via CCR5 (x axis) versus entry via alternative coreceptors. The bold line indicates significant correlation between the regression lines fitted by Prism, version 5.0, for CCR5 and FPRL1. Use of CCR5 and other CoRs (including CCR3; shown here for comparison with Fig. 3) did not show statistically significant correlation.
FIG. 3.
FIG. 3.
(A) Entry mediated by 18 subtype B env clones from different patients plotted as described in the legend of Fig. 2. (B) Linear regression analysis of entry via CCR5 versus via alternative CoR, analyzed as described in the legend of Fig. 2. The bold regression lines for CCR3 and APJ indicate significant correlation with CCR5-mediated entry, but entry via FPRL1 did not show significant correlation with CCR5.
FIG. 4.
FIG. 4.
(A) Entry mediated by 22 subtype C env clones from different patients at early stages of infection plotted as described in the legend of Fig. 2. (B) Linear regression analysis of entry via CCR5 versus three alternative CoRs showing significant correlation with CCR5: CCR3, CCR8, and FPRL1.
FIG. 5.
FIG. 5.
(A) Entry mediated by 11 subtype D env clones from different patients plotted as described in the legend of Fig. 2. One subtype D env clone (93/UG/065) is depicted in lighter fill because it was the only one capable of robust entry via CXCR4. (B) Linear regression analysis of entry via CCR5 versus via alternative CoRs. No significant correlations were observed.
FIG. 6.
FIG. 6.
Comparison of virus entry mediated by env clones from different subtypes (A, B, C, or D), with log RLU values depicted in box-and-whisker plots such that the vertical bars represent the range of observed values and the box represents the 25th to 75th percentile. Results for each subtype are color-coded with subtype A in blue, subtype B in magenta, subtype C in green, and subtype D in salmon. The difference in virus entry mediated by CCR3 for subtype B versus subtypes A, C, and D is highly significant (***, P < 0.0001; Mann-Whitney U test). The difference in virus entry mediated by FPRL1 for subtype B versus subtype A (**, P = 0.005) or versus subtype C (**, P = 0.0094) is significant, but there is no significant difference between subtype B and subtype D entry via FPRL1.
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