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Updated: Jul 9, 2026
Prediction of HIV-1 Coreceptor Usage (Tropism) by Sequence Analysis using a Genotypic Approach
Published on: December 1, 2011
HIV-1 escape to CCR5 coreceptor antagonism through selection of CXCR4-using variants in vitro
Gemma Moncunill1, Mercedes Armand-Ugón, Eduardo Pauls
1Retrovirology Laboratory IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Badalona, Spain.
Background:
HIV-1 coreceptor switch from CCR5 to CXCR4 is associated with disease progression and AIDS. Selection of resistant HIV-1 to CCR5 agents in cell culture has often occurred in the absence of coreceptor switch. With CCR5 antagonists currently in clinical trials, their impact on coreceptor use is still in doubt.
Methods:
Six R5 HIV-1 strains were passaged in lymphoid cells expressing high CXCR4 and low CCR5, in the absence or presence of CCR5 inhibitors (TAK-779, mAb 2D7 and CCL5). AMD3100, zidovudine and lamivudine were used as controls. Phenotype and genotype changes as well as virus coreceptor use were evaluated.
Results:
In the absence of drug pressure, three out of six strains expanded their coreceptor use to CXCR4 at different times, suggesting that not all virus strains had the capacity to do so. Lowering the replication rate with a suboptimal concentration of different anti-HIV agents (reverse transcriptase inhibitors or CCR5 agents) delayed coreceptor switch. However, virus breakthrough was observed earlier in the presence of CCR5-targeting agents than in presence of reverse transcriptase inhibitors and was associated with a change in sensitivity to TAK-779 or AMD3100, virus coreceptor expansion to CXCR4 and changes in the V3 loop region of gp120.
Conclusion:
Our results suggest that HIV-1 may escape CCR5 drug pressure through coreceptor switch. Experimental conditions strongly determine the outcome of CCR5 drug pressure in cell culture. A cell culture model of the evolution of HIV-1 coreceptor use may be relevant to assess the propensity of clinical isolates to develop resistance through coreceptor change.
Insights
HIV-1 can develop drug resistance by switching coreceptors from CCR5 to CXCR4, especially under CCR5 antagonist pressure. This study shows that experimental conditions significantly influence HIV-1 evolution and resistance mechanisms.
Area of Science:
- Virology
- Immunology
- Drug Resistance
Background:
- HIV-1 coreceptor switch from CCR5 to CXCR4 correlates with disease progression.
- CCR5 antagonist resistance in cell culture often occurs without coreceptor switch.
- The impact of CCR5 antagonists on HIV-1 coreceptor use remains uncertain.
Purpose of the Study:
- To investigate HIV-1 coreceptor switch under CCR5 antagonist pressure.
- To evaluate the influence of experimental conditions on HIV-1 resistance.
- To assess the relevance of cell culture models for predicting clinical resistance.
Main Methods:
- Passaging of R5 HIV-1 strains in lymphoid cells with varying CCR5 and CXCR4 expression.
- Exposure to CCR5 inhibitors (TAK-779, mAb 2D7, CCL5) or control drugs.
- Evaluation of phenotypic and genotypic changes, including coreceptor use and V3 loop mutations.
Main Results:
- Some HIV-1 strains naturally switched to CXCR4 use.
- Suboptimal anti-HIV agents delayed coreceptor switch.
- CCR5 antagonists led to earlier virus breakthrough, associated with CXCR4 switch and V3 loop changes.
Conclusions:
- HIV-1 may evade CCR5 drug pressure via coreceptor switch.
- Experimental conditions critically affect CCR5 drug pressure outcomes in vitro.
- Cell culture models can assess HIV-1 resistance evolution through coreceptor change.
