Infant transmitted/founder HIV-1 viruses from peripartum transmission are neutralization resistant to paired maternal plasma.
Infant transmitted/founder HIV-1 viruses from peripartum transmission are neutralization resistant to paired maternal plasma.
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DOI：
10.1371/journal.ppat.1006944
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发表时间：
2018-04
期刊：
影响因子：
6.7
通讯作者：
Permar SR
中科院分区：
文献类型：
--
作者：
Kumar A;Smith CEP;Giorgi EE;Eudailey J;Martinez DR;Yusim K;Douglas AO;Stamper L;McGuire E;LaBranche CC;Montefiori DC;Fouda GG;Gao F;Permar SR
尽管HIV-1在慢性感染中具有广泛的遗传多样性，但一个或几个母体病毒变异株会成为婴儿感染的根源。这些传播的/创始人(T/F)变种特别令人感兴趣，因为母体或婴儿艾滋病毒疫苗应能产生能够阻止这组病毒的包膜(Env)特异性免疫球蛋白G反应。然而，影响婴儿T/F病毒选择的母婴因素还不是很清楚。在这项研究中，我们通过单基因组扩增从16对来自美国抗逆转录病毒时代妇女婴儿传播研究(WITS)的母婴传播对中扩增出HIV-1 env基因。从血浆中鉴定婴儿T/F和具有代表性的母体非传播环境病毒变异株，并用于产生假病毒用于配对母体血浆中和敏感性分析。在21例婴儿T/F环境伪病毒中，有18例(85%)对配对母血具有中和抗性。然而，所有婴儿T/F病毒对一组HIV-1广谱中和抗体都是中和敏感的，对异源血浆中和抗体的敏感性也不同。此外，与来自母体非传播变种的伪病毒相比，这些婴儿T/F伪病毒对配对母体血浆的中和抵抗力总体更强(p=0.012)。总之，我们的发现表明，母体血浆抗体对循环病毒的自体中和选择了启动围产期传播的中和耐药病毒，这增加了人们的猜测，即在怀孕结束时增强这种反应可能会进一步降低婴儿感染HIV-1的风险。艾滋病毒-1的母婴传播可发生在怀孕期间(宫内)、分娩时(围产期)或母乳喂养(产后)。随着抗逆转录病毒治疗(ART)的出现，HIV-1的MTCT率显著降低。然而，在资源匮乏的地区，执行工作仍然面临重大挑战，因此很难消灭儿科艾滋病毒。更好地了解在传播时导致婴儿感染的病毒群体(从自体中和抗体中逃脱的变种)，将有助于设计免疫干预措施，以减少围产期艾滋病毒-1的传播。在这里，我们从WITS队列中选择了16对感染HIV-1的母婴(来自抗逆转录病毒之前的时代)，其中婴儿在围产期感染。用单基因组扩增(SGA)方法获得HIV-1 env基因序列。分析了这些婴儿环境伪病毒对母体血浆和一组广谱中和单抗的敏感性。我们证明，婴儿T/F病毒对母体血浆的抵抗力比非传播母体变异体更强，但对大多数(BNAbs)敏感。对婴儿T/F和非传播母体变异的信号序列分析揭示了V3和MPER区域对于抵抗配对母体血浆的潜在重要性。这些发现为母体免疫策略的设计提供了启示，以增强针对自体病毒群体V3区的中和抗体，这可能与母体ARV协同作用，进一步降低围产期HIV-1的传播率。
Despite extensive genetic diversity of HIV-1 in chronic infection, a single or few maternal virus variants become the founders of an infant’s infection. These transmitted/founder (T/F) variants are of particular interest, as a maternal or infant HIV vaccine should raise envelope (Env) specific IgG responses capable of blocking this group of viruses. However, the maternal or infant factors that contribute to selection of infant T/F viruses are not well understood. In this study, we amplified HIV-1 env genes by single genome amplification from 16 mother-infant transmitting pairs from the U.S. pre-antiretroviral era Women Infant Transmission Study (WITS). Infant T/F and representative maternal non-transmitted Env variants from plasma were identified and used to generate pseudoviruses for paired maternal plasma neutralization sensitivity analysis. Eighteen out of 21 (85%) infant T/F Env pseudoviruses were neutralization resistant to paired maternal plasma. Yet, all infant T/F viruses were neutralization sensitive to a panel of HIV-1 broadly neutralizing antibodies and variably sensitive to heterologous plasma neutralizing antibodies. Also, these infant T/F pseudoviruses were overall more neutralization resistant to paired maternal plasma in comparison to pseudoviruses from maternal non-transmitted variants (p = 0.012). Altogether, our findings suggest that autologous neutralization of circulating viruses by maternal plasma antibodies select for neutralization-resistant viruses that initiate peripartum transmission, raising the speculation that enhancement of this response at the end of pregnancy could further reduce infant HIV-1 infection risk. Mother to child transmission (MTCT) of HIV-1 can occur during pregnancy (in utero), at the time of delivery (peripartum) or by breastfeeding (postpartum). With the availability of anti-retroviral therapy (ART), rate of MTCT of HIV-1 have been significantly lowered. However, significant implementation challenges remain in resource-poor areas, making it difficult to eliminate pediatric HIV. An improved understanding of the viral population (escape variants from autologous neutralizing antibodies) that lead to infection of infants at time of transmission will help in designing immune interventions to reduce perinatal HIV-1 transmission. Here, we selected 16 HIV-1-infected mother-infant pairs from WITS cohort (from pre anti-retroviral era), where infants became infected peripartum. HIV-1 env gene sequences were obtained by the single genome amplification (SGA) method. The sensitivity of these infant Env pseudoviruses against paired maternal plasma and a panel of broadly neutralizing monoclonal antibodies (bNAbs) was analyzed. We demonstrated that the infant T/F viruses were more resistant against maternal plasma than non-transmitted maternal variants, but sensitive to most (bNAbs). Signature sequence analysis of infant T/F and non-transmitted maternal variants revealed the potential importance of V3 and MPER region for resistance against paired maternal plasma. These findings provide insights for the design of maternal immunization strategies to enhance neutralizing antibodies that target V3 region of autologous virus populations, which could work synergistically with maternal ARVs to further reduce the rate of peripartum HIV-1 transmission.
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DOI：
10.1056/nejmoa0911486
发表时间：
2010-06-17
期刊：
The New England journal of medicine
影响因子：
--
作者：
Chasela CS;Hudgens MG;Jamieson DJ;Kayira D;Hosseinipour MC;Kourtis AP;Martinson F;Tegha G;Knight RJ;Ahmed YI;Kamwendo DD;Hoffman IF;Ellington SR;Kacheche Z;Soko A;Wiener JB;Fiscus SA;Kazembe P;Mofolo IA;Chigwenembe M;Sichali DS;van der Horst CM;BAN Study Group
通讯作者：
BAN Study Group
影响因子：
82.9
作者：
Hessell AJ;Jaworski JP;Epson E;Matsuda K;Pandey S;Kahl C;Reed J;Sutton WF;Hammond KB;Cheever TA;Barnette PT;Legasse AW;Planer S;Stanton JJ;Pegu A;Chen X;Wang K;Siess D;Burke D;Park BS;Axthelm MK;Lewis A;Hirsch VM;Graham BS;Mascola JR;Sacha JB;Haigwood NL
通讯作者：
Haigwood NL
影响因子：
6.4
作者：
Grobler, J;Gray, CM;Williamson, C
通讯作者：
Williamson, C
影响因子：
2.1
作者：
Bulterys, Philip L.;Dalai, Sudeb C.;Katzenstein, David A.
通讯作者：
Katzenstein, David A.
影响因子：
3.3
作者：
Braibant M;Barin F
通讯作者：
Barin F