Armand-Ugón Mercedes, Quiñones-Mateu Miguel E, Gutiérez Arantxa, Barretina Jordi, Blanco Julià, Schols Dominique, De Clercq Erik, Clotet Bonaventura, Esté José A
Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
Antivir Ther. 2003 Feb;8(1):1-8.
HIV-1 strains with a syncytium-inducing phenotype that use CXCR4 (X4 strains) have been associated with faster disease progression and AIDS. Antiviral agents designed to block CXCR4 may prevent the emergence of X4 HIV strains but resistant strains that maintain the X4 phenotype can be raised by sequential passage in cell cultures. We have demonstrated that a laboratory adapted strain (NL4-3) and a cloned clinical isolate (CI-1) of HIV-1 cultured in the presence of the CXCR4 antagonist, AMD3100, became resistant to the compound without a change in co-receptor use. These strains became resistant through divergence with respect to the wild-type virus. Conversely, a clinical isolate made resistant to AMD3100 switched co-receptor use from X4 to R5 through a change in diversity from the original virus population. When dual infection competition/heteroduplex tracking assays were performed, all AMD3100-resistant strains, regardless of co-receptor use showed a significantly diminished fitness compared with the wild-type virus. Single virus infections, at a similar multiplicity of infection, also indicated that the wild-type strains possess better replicative ability than their corresponding resistant strains. Thus, viral resistance development to a CXCR4 antagonist such as AMD3100 is associated with reduced viral fitness.
具有合胞体诱导表型且使用CXCR4的HIV-1毒株（X4毒株）与疾病进展加快和艾滋病相关。旨在阻断CXCR4的抗病毒药物可能会阻止X4 HIV毒株的出现，但通过在细胞培养中连续传代可产生维持X4表型的耐药毒株。我们已经证明，在CXCR4拮抗剂AMD3100存在下培养的HIV-1实验室适应株（NL4-3）和克隆临床分离株（CI-1）对该化合物产生耐药性，且共受体使用情况未发生改变。这些毒株通过与野生型病毒的差异而产生耐药性。相反，一株对AMD3100产生耐药性的临床分离株通过与原始病毒群体多样性的改变，将共受体使用从X4转变为R5。当进行双重感染竞争/异源双链追踪分析时，所有对AMD3100耐药的毒株，无论共受体使用情况如何，与野生型病毒相比，其适应性均显著降低。在相似感染复数下的单病毒感染也表明，野生型毒株比其相应的耐药毒株具有更好的复制能力。因此，对CXCR4拮抗剂如AMD3100产生病毒耐药性与病毒适应性降低有关。
