Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection.
Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection.
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DOI：
10.1097/qad.0000000000001575
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发表时间：
2017-09-10
期刊：
影响因子：
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通讯作者：
International HIV Adaptation Collaborative
中科院分区：
文献类型：
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作者：
Gatanaga H;Brumme ZL;Adland E;Reyes-Terán G;Avila-Rios S;Mejía-Villatoro CR;Hayashida T;Chikata T;Van Tran G;Van Nguyen K;Meza RI;Palou EY;Valenzuela-Ponce H;Pascale JM;Porras-Cortés G;Manzanero M;Lee GQ;Martin JN;Carrington MN;John M;Mallal S;Poon AFY;Goulder P;Takiguchi M;Oka S;International HIV Adaptation Collaborative
长效利匹韦林是预防HIV-1感染的暴露前预防（PrEP）的候选药物。然而，在少数HIV-1感染者中，逆转录酶密码子138（E138 X）处的利匹韦林耐药突变自然发生;特别是表达人白细胞抗原（HLA）-B*18的患者，其中逆转录酶-E138 X作为免疫逃逸突变出现。我们调查了逆转录酶-E138 X的全球患病率、B*18连锁和复制成本及其对利匹韦林PrEP的区域影响。我们分析了来自五大洲和五种HIV-1亚型的16个队列的7772例抗逆转录病毒初治患者的连锁逆转录酶-E138 X/HLA数据，以及来自公共数据库的非连锁全球逆转录酶-E138 X和HLA频率。评估了含E138 X的HIV-1变体的体外复制，作为传播后突变稳定性的替代。逆转录酶E138 X变异体（其中最常见的是利匹韦林耐药相关突变E138 A/G/K）在全球HLA-B*18阳性个体（P= 3.5 10−20）和除A型以外的所有HIV-1亚型中显著富集。逆转录酶E138 X和B*18频率在16个HIV/HLA基因型连锁的队列中（斯皮尔曼R= 0.75; P= 7.6 10−4）和来自43个国家的非连锁HIV/HLA数据中（斯皮尔曼R= 0.34，P= 0.02）呈正相关。值得注意的是，在B*18更常见的关键流行地区（例如撒哈拉以南非洲、东南欧），逆转录酶-E138 X频率接近（或超过）10%。这沿着逆转录酶-E138 X变体不赋予体外复制成本的观察，支持它们的持久性，以及随时间在循环中的持续积累。结果表明，天然免疫驱动的HIV-1多态性可能会损害基于抗逆转录病毒的预防，特别是在主要流行地区。在使用利匹韦林PrEP前应进行区域逆转录酶E138 X监测。
Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B*18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B*18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP. We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission. Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B*18-positive individuals globally (P= 3.5 10−20) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B*18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman’s R= 0.75; P= 7.6 10−4) and in unlinked HIV/HLA data from 43 countries (Spearman’s R= 0.34, P= 0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub-Saharan Africa, Southeastern Europe) where B*18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time. Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP.