Phenotypic susceptibility of HIV-2 to raltegravir: integrase mutations Q148R and N155H confer raltegravir resistance

被引:21
|
作者
Smith, Robert A. [1 ]
Raugi, Dana N. [2 ]
Kiviat, Nancy B. [1 ]
Hawes, Stephen E. [3 ]
Mullins, James I. [2 ,4 ]
Sow, Papa S. [5 ]
Gottlieb, Geoffrey S. [2 ]
机构
[1] Univ Washington, Dept Pathol, Seattle, WA 98109 USA
[2] Univ Washington, Dept Med, Seattle, WA 98109 USA
[3] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98109 USA
[4] Univ Washington, Dept Microbiol, Seattle, WA 98109 USA
[5] Univ Cheikh Anta Diop Dakar, Ctr Hosp Univ Fann, Clin Malad Infect Ibrahima DIOP Mar, Dakar, Senegal
基金
美国国家卫生研究院;
关键词
HIV-1; HIV-2; integrase; N155H; Q148R; raltegravir; resistance; Y143C; RANDOMIZED CONTROLLED-TRIAL; IMMUNOLOGICAL RESPONSE; INHIBITOR RESISTANCE; PROTEASE INHIBITORS; DRUG-RESISTANCE; TREATMENT-NAIVE; VIRUS; INFECTION; EFFICACY; THERAPY;
D O I
10.1097/QAD.0b013e32834d8e52
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Objectives: Raltegravir is the first integrase strand transfer inhibitor approved for treating HIV-1 infection. Although emerging data suggest that raltegravir may also be useful for HIV-2 treatment, studies addressing the in-vitro susceptibility of HIV-2 to raltegravir are scarce, and the genetic pathways leading to raltegravir resistance in HIV-2 have not been adequately characterized. Our objectives were to directly compare the susceptibilities of HIV-1 and HIV-2 to raltegravir and to examine the role of mutations in HIV-2 integrase in emergent raltegravir resistance. Materials and methods: Single-cycle and spreading infection assays were used to quantify the sensitivities of wild-type HIV-1 and HIV-2 strains to raltegravir. HIV-2 integrase mutants were constructed by site-directed mutagenesis, and the replication capacities and raltegravir susceptibilities of the resultant variants were analyzed in single-cycle assays. Results: Raltegravir showed comparable activity againstwild-type HIV-1 andHIV-2 in both single-cycle and spreading infections, with EC50 values in the low nanomolar range. Amino acid changes Q148R and N155H individually conferred resistance to raltegravir (14-fold and seven-fold, respectively), whereas the Y143C replacement had no statistically significant effect on raltegravir sensitivity. The combination of Q148R with N155H resulted in high-level raltegravir resistance (> 1000-fold). In addition, all HIV-2 integrase variants tested showed impairments in replication capacity. Conclusion: Our data support clinical studies of raltegravir for treating HIV-2 infection and show that the Q148R and N155H changes alone are sufficient for raltegravir resistance in HIV-2. Further efforts are needed to improve access to HIV-2-active antiretrovirals, including raltegravir, in resource-limited areas where HIV-2 is endemic. (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
引用
收藏
页码:2235 / 2241
页数:7
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