Polymorphism of HIV type 1 Gag p7/p1 and p1/p6 cleavage sites: Clinical significance and implications for resistance to protease inhibitors
Polymorphism of HIV type 1 Gag p7/p1 and p1/p6 cleavage sites: Clinical significance and implications for resistance to protease inhibitors
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DOI：
10.1089/08892220050116970
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发表时间：
2000-09-01
影响因子：
1.5
通讯作者：
Telenti, A
中科院分区：
文献类型：
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作者：
Bally, F;Martinez, R;Telenti, A
HIV-1 Gag p7/p1和p1/p6切割位点的氨基酸取代可以在抗逆转录病毒压力下选择或代表天然多态性。尚未研究这些变化是否与特定蛋白酶（PR）突变模式和不同的临床演变相关。通过回归分析比较110例HIV-1感染患者血清中p7/p1和p1/p6切割位点序列，使用临床、实验室和序列变量，以及CD 4（+）细胞计数和病毒载量随时间的演变。35例未接受PR抑制剂（PI）的患者中有16例（46%）和75例接受含PI方案的患者中有49例（65%）具有p7/p1和/或p1/p6切割位点多态性（p = 0.06）。A431 V和/或L449 F仅存在于PI治疗失败的个体中（分别为17/75 [23%]和3/75 [3%]）。A431 V与PR M46 I，L（OR 13.7; 95%CI 4.2-44.3）和V82 A，F，T（OR 8.8; 95%CI 2.7-27.8）之间存在显著相关性。自然多态性P453 L与PR I84 V的选择强相关（OR 49.5; 95%CI 12-212），并且针对V82突变进行选择（OR 0.15; 95%CI 0.02-1.2）。在中位随访15个月后，在治疗失败的个体中，没有多态性与疾病进展参数相关。在p7/p1和p1/p6切割位点处仅可容许有限的一组氨基酸取代。A431 V与特定的PR抑制剂突变相关。P453 L基因多态性可能通过I84 V而不是V82突变指导PR耐药途径。未记录切割位点置换的短期临床影响。
Amino acid substitutions at HIV-1 Gag p7/p1 and p1/p6 cleavage sites may be selected under antiretroviral pressure or represent natural polymorphisms. Whether changes are associated with specific protease (PR) mutation patterns and different clinical evolution has not been investigated. p7/p1 and p1/p6 cleavage site sequences from sera from 110 patients infected with HIV-1 were compared by regression analysis, using clinical, laboratory, and sequence variables, and the evolution of CD4(+) cell counts and viral load over time. Sixteen of 35 (46%) individuals naive to PR inhibitors (PIs), and 49 of 75 (65%) receiving PI-containing regimens had a p7/p1 and/or p1/p6 cleavage site polymorphism (p = 0.06). A431V and/or L449F were present exclusively among individuals failing PI treatment (17 of 75 [23%] and 3 of 75 [3%], respectively). There was a significant association between A431V and PR M46I,L (OR 13.7; 95% CI 4.2-44.3) and V82A, F, T (OR 8.8; 95% CI 2.7-27.8). Natural polymorphism P453L was strongly associated with the selection of PR I84V (OR 49.5; 95% CI 12-212) and selected against V82 mutation (OR 0.15; 95% CI 0.02-1.2). After a median followup of 15 months, no polymorphism was associated with parameters of disease progression among individuals failing treatment. Only a limited set of amino acid substitutions can be tolerated at p7/p1 and p1/p6 cleavage sites. A431V is selected in association with specific PR inhibitor mutations. Natural polymorphism P453L might direct the PR resistance pathway through I84V instead of V82 mutation. No short-term clinical impact of cleavage site substitutions was documented.