Chinnadurai Raghavan, Münch Jan, Kirchhoff Frank
Department of Virology, Universitätsklinikum, Ulm, Germany.
AIDS. 2005 Sep 2;19(13):1401-5. doi: 10.1097/01.aids.0000180785.25800.de.
Sequence variations in the gp41 heptad repeat 1 (HR1) region have been identified in some treatment-naive HIV-1-infected patients but it remained elusive whether they confer resistance to fusion inhibitors.
To evaluate whether naturally occurring sequence variations in the HIV-1 group M gp41 HR1 region affect the sensitivity to inhibition by T-20 and T-1249.
Site-directed mutagenesis was used to generate HIV-1 NL4-3 mutants containing changes in the gp41 HR1 domain which have been previously identified in treatment-naive patients infected with various HIV-1 group M subtypes. HIV-1 variants were produced by transient transfection of 293T cells and used to determine viral infectivity and sensitivity to the fusion inhibitors T-20 and T-1249.
Most naturally occurring sequence variations in the HR1 domain did not reduce viral infectivity. Three of the 10 HIV-1 variants analysed containing a single substitution of L33V, which is frequently present in subtype D isolates, or combined changes of L54M/Q56K or L34M/L54M/Q56R showed about fivefold reduced sensitivity to inhibition by T-20. In comparison, none of these HR1 sequence variations conferred resistance to T-1249.
Some naturally occurring sequence variations in the gp41 HR1 region reduce sensitivity of HIV-1 to inhibition by T-20 but not T-1249.
在一些未经治疗的HIV-1感染患者中已发现gp41七肽重复序列1（HR1）区域存在序列变异，但这些变异是否赋予对融合抑制剂的耐药性仍不明确。
评估HIV-1 M组gp41 HR1区域自然发生的序列变异是否会影响对T-20和T-1249抑制的敏感性。
采用定点诱变技术构建HIV-1 NL4-3突变体，其gp41 HR1结构域发生了先前在感染各种HIV-1 M组亚型的未经治疗患者中鉴定出的变化。通过瞬时转染293T细胞产生HIV-1变体，并用于测定病毒感染性以及对融合抑制剂T-20和T-1249的敏感性。
HR1结构域中大多数自然发生的序列变异并未降低病毒感染性。分析的10个HIV-1变体中有3个含有L33V单一位点替换（常见于D亚型分离株），或L54M/Q56K或L34M/L54M/Q56R的联合变化，这些变体对T-20抑制的敏感性降低了约5倍。相比之下，这些HR1序列变异均未赋予对T-1249的耐药性。
gp41 HR1区域中一些自然发生的序列变异会降低HIV-1对T-20抑制的敏感性，但不会降低对T-1249抑制的敏感性。
