Biological and Genetic Characterization of a Human Immunodeficiency Virus Strain Resistant to CXCR4 Antagonist T134

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Abstract
The chemokine receptors CXCR4 and CCR5 are considered to be potential targets for the inhibition of HIV-1 replication. We have reported that T134 and T140 inhibited X4 HIV-1 infection specifically because they acted as CXCR4 antagonists. In the present study, we have generated a T134-resistant virus (trHIV-1NL4-3) in a cell culture with gradually increasing concentrations of the compound. The EC50 of T134 against trHIV-1NL4-3 recovered after 145 passages was 15 times greater than that against wild-type HIV-1NL4-3. This adapted virus was resistant to other CXCR4 antagonists, T140, AMD3100, and ALX40-4C, and SDF-1; from 10 to 145 times greater than that against wild-type HIV-1NL4-3. On the other hand, T134, T140, and ALX40-4C were still active against AMD3100-resistant viruses (arHIV-1018A). The trHIV-1NL4-3 contained the following mutations in the V3 loop of gp120: N269K, Q278T, R279K, A284V, F285L, V286Y, I288T, K290E, N293D, M294I, and Q296K; an insertion of T at 290; and Δ274-275 (SI). In addition, many other mutations were recognized in the V1, V2, and V4 domains. Thus, resistance to T134 may be the consequence of amino acid substitutions in the envelope glycoprotein of X4 HIV-1. The trHIV-1NL4-3 could not utilize CCR5 as an HIV infection coreceptor, although many amino acid substitutions were recognized. The trHIV-1NL4-3 acquired resistance to vMIP II, which could inhibit both X4 and R5 HIV-1 infection. However, neither the ligands of CCR5, RANTES, and MIP-1α, nor a CCR5 low molecular antagonist, TAK-779, were able to influence the infection of trHIV-1NL4-3. Those results indicated that alternation of coreceptor usage of trHIV-1NL4-3 was not induced.