免疫驱动的病毒多态性有可能破坏基于抗逆转录病毒的暴露前预防，从而影响 HIV-1 感染的预防。
Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection.
机构信息
aAIDS Clinical Center, National Center for Global Health and Medicine, Tokyo bCenter for AIDS Research, Kumamoto University, Kumamoto, Japan cFaculty of Health Sciences, Simon Fraser University, Burnaby dBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada eDepartment of Paediatrics, University of Oxford, Oxford, UK fCentre for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico gInfectious Diseases Clinic, Roosevelt Hospital, Guatemala City, Guatemala hNational Hospital of Tropical Diseases, Dong Da District, Hanoi, Vietnam iHIV National Laboratory, Honduran Ministry of Health jHospital Escuela Universitario, Tegucigalpa, Honduras kGorgas Memorial Institute for Health Studies, Panama City, Panama lHospital Metropolitano Vivian Pellas, Managua, Nicaragua mMinistry of Health, Belmopan, Belize nUniversity of California San Francisco, San Francisco, California oCancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland pRagon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA qMurdoch University, Perth, Australia rVanderbilt University, Nashville, Tennessee, USA sDepartment of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
出版信息
AIDS. 2017 Sep 10;31(14):1935-1943. doi: 10.1097/QAD.0000000000001575.
OBJECTIVE
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)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP.
METHODS
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.
RESULTS
Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (P = 3.5 × 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10) 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 B18 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.
CONCLUSIONS
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.
目的
长效利匹韦林是预防 HIV-1 感染的暴露前预防（PrEP）候选药物。然而，逆转录酶密码子 138（E138X）处的利匹韦林耐药突变在少数 HIV-1 感染者中自然发生；特别是在表达人类白细胞抗原（HLA）-B18 的人群中，逆转录酶-E138X 是一种免疫逃逸突变。我们研究了全球范围内逆转录酶-E138X 和 B18 关联性及其对利匹韦林 PrEP 的区域影响的流行率、关联性和复制成本。
方法
我们分析了来自五个大陆和五个 HIV-1 亚型的 16 个队列中 7772 名抗逆转录病毒初治患者的相关逆转录酶-E138X/HLA 数据，以及来自公共数据库的不相关全球逆转录酶-E138X 和 HLA 频率。通过体外复制评估含有 E138X 的 HIV-1 变异体，作为传播后突变稳定性的替代指标。
结果
全球范围内（P=3.5×10），包括最常见的利匹韦林耐药相关突变 E138A/G/K 的逆转录酶-E138X 变体在 HLA-B18 阳性个体中明显富集，除 A 型外，在所有 HIV-1 亚型中均如此。在包含 HIV/HLA 基因型的 16 个队列中（Spearman's R=0.75，P=7.6×10）以及在来自 43 个国家的不相关 HIV/HLA 数据中（Spearman's R=0.34，P=0.02），逆转录酶-E138X 和 B18 的频率呈正相关。值得注意的是，在关键流行地区（例如撒哈拉以南非洲、东南欧），逆转录酶-E138X 的频率接近（或超过）10%，而 B18 在这些地区更为常见。这一点，加上观察到逆转录酶-E138X 变异体没有赋予体外复制成本，支持了它们在循环中随着时间的推移持续存在和积累。
结论
研究结果表明，自然发生的免疫驱动 HIV-1 多态性有可能破坏基于抗逆转录病毒的预防，特别是在关键流行地区。在使用利匹韦林 PrEP 之前，应进行区域内逆转录酶-E138X 监测。
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