Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice.
Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice.
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DOI：
10.1371/journal.ppat.1010183
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发表时间：
2022-01
期刊：
影响因子：
6.7
通讯作者：
Su L
中科院分区：
文献类型：
--
作者：
Hioe CE;Li G;Liu X;Tsahouridis O;He X;Funaki M;Klingler J;Tang AF;Feyznezhad R;Heindel DW;Wang XH;Spencer DA;Hu G;Satija N;Prévost J;Finzi A;Hessell AJ;Wang S;Lu S;Chen BK;Zolla-Pazner S;Upadhyay C;Alvarez R;Su L
抗体是疫苗激发的主要免疫成分，可诱导对微生物病原体的保护。在泰国RV144 HIV-1疫苗试验中，疫苗效力为31%，唯一降低风险的主要关联是针对HIV-1包膜V1V2区域的强有力的抗体反应。在接种疫苗的人群中，V3抗体与感染风险也呈负相关。然而，识别这些区域的抗体并不表现出强大的中和活性。因此，我们检测了针对免疫优势的V1V2和V3位点的中和能力差的单抗的抗病毒潜力，方法是被动地将人单抗接种给植入CD34+造血干细胞的人源化小鼠，然后用表达HIV-1二级耐药毒株外膜的HIV-1感染性分子克隆进行粘膜攻击。抗V1V2mAb2158或抗V3mAb2219不能预防感染，但V3mAb2219在降低病毒载量方面优于V1V2mAb2158。与V1V2 mAb2158相比，V3mAb2219具有更强的结合病毒和细胞相关的HIV-1包膜、介导抗体依赖的细胞吞噬作用(ADCP)和C1q补体结合的能力。2219基因Fc区的突变在体外降低了这些效应器的活性，并降低了人源化小鼠的病毒控制能力。这些结果证明了除ADCC以外的Fc功能对于没有有效中和活性的抗体的重要性。在过去的十年中，估计每年有150至200万人感染艾滋病毒-1，但控制这一大流行所需的疫苗是无法获得的。在人类功效试验中测试的疫苗中，RV144疫苗方案显示出适度的疗效，并显示针对病毒包膜糖蛋白的非中和抗体与病毒获取减少有关。为了设计更有效的HIV-1疫苗，需要更好地了解这些抗体的抗病毒机制。在这里，针对病毒包膜上两个免疫原点的非中和单抗被评估为被动给药给随后用HIV-1攻击的人源化小鼠。这些抗体没有阻止粘膜中的HIV-1感染，但降低了病毒载量。病毒减量水平与抗体结合力和通过其Fc片段介导的效应功能相关，包括抗体依赖的吞噬和补体激活，而不是通常研究的抗体依赖的细胞毒性。当引入突变以降低Fc活性时，病毒控制力的降低进一步证明了Fc功能的重要性。本研究为多种Fc依赖的抗体功能在HIV-1免疫控制中的重要贡献提供了新的证据。
Antibodies are principal immune components elicited by vaccines to induce protection from microbial pathogens. In the Thai RV144 HIV-1 vaccine trial, vaccine efficacy was 31% and the sole primary correlate of reduced risk was shown to be vigorous antibody response targeting the V1V2 region of HIV-1 envelope. Antibodies against V3 also were inversely correlated with infection risk in subsets of vaccinees. Antibodies recognizing these regions, however, do not exhibit potent neutralizing activity. Therefore, we examined the antiviral potential of poorly neutralizing monoclonal antibodies (mAbs) against immunodominant V1V2 and V3 sites by passive administration of human mAbs to humanized mice engrafted with CD34+ hematopoietic stem cells, followed by mucosal challenge with an HIV-1 infectious molecular clone expressing the envelope of a tier 2 resistant HIV-1 strain. Treatment with anti-V1V2 mAb 2158 or anti-V3 mAb 2219 did not prevent infection, but V3 mAb 2219 displayed a superior potency compared to V1V2 mAb 2158 in reducing virus burden. While these mAbs had no or weak neutralizing activity and elicited undetectable levels of antibody-dependent cellular cytotoxicity (ADCC), V3 mAb 2219 displayed a greater capacity to bind virus- and cell-associated HIV-1 envelope and to mediate antibody-dependent cellular phagocytosis (ADCP) and C1q complement binding as compared to V1V2 mAb 2158. Mutations in the Fc region of 2219 diminished these effector activities in vitro and lessened virus control in humanized mice. These results demonstrate the importance of Fc functions other than ADCC for antibodies without potent neutralizing activity. In the past decade, HIV-1 has infected an estimated 1.5 to 2 million people every year, but vaccines needed to control this pandemic are unavailable. Among vaccines tested in the human efficacy trials, the RV144 vaccine regimen showed a modest efficacy and revealed non-neutralizing antibodies against the virus envelope glycoproteins as a correlate of reduced virus acquisition. To design more efficacious HIV-1 vaccines, a better understanding about antiviral mechanisms of these antibodies is needed. Here non-neutralizing monoclonal antibodies against two immunogenic sites on the virus envelope were evaluated for passive administration to humanized mice that were subsequently challenged with HIV-1. The antibodies did not block mucosal HIV-1 infection but reduced virus burden. The level of virus reduction correlated with the antibody binding potency and the effector functions mediated through their Fc fragments, which included antibody-dependent phagocytosis and complement activation, but not the commonly studied antibody-dependent cellular cytotoxicity. The importance of the Fc functions was further demonstrated by reduced virus control when mutations were introduced to decrease Fc activities. This study provides new evidence for the important contribution of multiple Fc-dependent antibody functions in immune control against HIV-1.
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影响因子：
3.7
作者：
Gottardo R;Bailer RT;Korber BT;Gnanakaran S;Phillips J;Shen X;Tomaras GD;Turk E;Imholte G;Eckler L;Wenschuh H;Zerweck J;Greene K;Gao H;Berman PW;Francis D;Sinangil F;Lee C;Nitayaphan S;Rerks-Ngarm S;Kaewkungwal J;Pitisuttithum P;Tartaglia J;Robb ML;Michael NL;Kim JH;Zolla-Pazner S;Haynes BF;Mascola JR;Self S;Gilbert P;Montefiori DC
通讯作者：
Montefiori DC
影响因子：
5.4
作者：
Costa, Matthew R.;Pollara, Justin;Wang, Shixia
通讯作者：
Wang, Shixia
影响因子：
3.7
作者：
Gorny, Miroslaw K.;Pan, Ruimin;Zolla-Pazner, Susan
通讯作者：
Zolla-Pazner, Susan
HIV-1 疫苗功效试验的免疫相关分析。
DOI：
10.1056/nejmoa1113425
发表时间：
2012-04-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Haynes BF;Gilbert PB;McElrath MJ;Zolla-Pazner S;Tomaras GD;Alam SM;Evans DT;Montefiori DC;Karnasuta C;Sutthent R;Liao HX;DeVico AL;Lewis GK;Williams C;Pinter A;Fong Y;Janes H;DeCamp A;Huang Y;Rao M;Billings E;Karasavvas N;Robb ML;Ngauy V;de Souza MS;Paris R;Ferrari G;Bailer RT;Soderberg KA;Andrews C;Berman PW;Frahm N;De Rosa SC;Alpert MD;Yates NL;Shen X;Koup RA;Pitisuttithum P;Kaewkungwal J;Nitayaphan S;Rerks-Ngarm S;Michael NL;Kim JH
通讯作者：
Kim JH
影响因子：
64.5
作者：
Chung AW;Kumar MP;Arnold KB;Yu WH;Schoen MK;Dunphy LJ;Suscovich TJ;Frahm N;Linde C;Mahan AE;Hoffner M;Streeck H;Ackerman ME;McElrath MJ;Schuitemaker H;Pau MG;Baden LR;Kim JH;Michael NL;Barouch DH;Lauffenburger DA;Alter G
通讯作者：
Alter G