Rectal tissue and vaginal tissue from intravenous VRC01 recipients show protection against ex vivo HIV-1 challenge
Rectal tissue and vaginal tissue from intravenous VRC01 recipients show protection against ex vivo HIV-1 challenge
复制标题
静脉注射VRC01受体的直肠组织和阴道组织显示出对体外HIV-1攻击的保护作用
DOI：
10.1172/jci146975
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发表时间：
2021-08-16
影响因子：
15.9
通讯作者：
McElrath, M. Juliana
中科院分区：
文献类型：
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作者：
Astronomo, Rena D.;Lemos, Maria P.;McElrath, M. Juliana
背景资料。VRC01是一种有效的、广泛中和的单抗，在动物模型中抑制猴-HIV感染。HVTN 104研究评估了VRC01在人体内的安全性和药代动力学。我们扩大了临床评价以确定静脉输注VRC01在HIV-1入口粘膜部位的分布和保护功能。方法健康的未感染HIV-1的男性(n=7)和女性(n=5)每2个月接受VRC01一次，在输注后4-13天提供一次粘膜和血清样本。11名男性和8名女性HIV血清阴性志愿者提供了未经处理的对照样本。结果：VRC01在所有受者的血清(96.2微克/毫升或1.3pg/ng蛋白)、直肠组织(0.11pg/ng蛋白)、直肠分泌物(0.13pg/ng蛋白)、阴道组织(0.1pg/ng蛋白)和宫颈分泌物(0.44pg/ng蛋白)中均可定量。男性血清VRC01/Ig G比值与配对直肠组织(r=0.893，P=0.012)和直肠分泌物(r=0.9643，P=0.003)中VRC01/Ig G比值呈正相关。HIV1(Bal26)感染VRC01受体21个直肠组织中的4个(P=0.005)，对照组22个直肠组织中的20个(P=0.005)，感染VRC01受体21个直肠组织中的20个和对照组12个(P=0.639)。VRC01受体14个阴道外植体中有0个感染HIV1(Bal26)，而对照组28个中有23个感染HIV1(P=0.003)。结论：静脉注射VRC01分布于女性生殖器和男性直肠粘膜，并保留了抗HIV1的功能，抑制了粘膜组织中高度中和敏感但不具有高抵抗力的HIV1毒株。这些发现有助于深入了解VRC01的粘膜渗透，并为体内保护作用提供了前景。
BACKGROUND. VRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and pharmacokinetics of VRC01 in humans. We extend the clinical evaluation to determine intravenously infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry.METHODS. Healthy, HIV-1-uninfected men (n = 7) and women (n = 5) receiving VRC01 every 2 months provided mucosal and serum samples once, 4-13 days after infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions, and tissue, and HIV-1 inhibition was determined in tissue explants.RESULTS. Median VRC01 levels were quantifiable in serum (96.2 mu g/mL or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein), and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r = 0.893, P = 0.012) and rectal secretions (r = 0.9643, P = 0.003). Ex vivo HIV-1(Bal26) challenge infected 4 of 21 rectal explants from VRC01 recipients versus 20 of 22 from controls (P = 0.005); HIV-1(Du422.1) infected 20 of 21 rectal explants from VRC01 recipients and 12 of 12 from controls (P = 0.639). HIV-1(Bal26) infected 0 of 14 vaginal explants of VRC01 recipients compared with 23 of 28 control explants (P = 0.003).CONCLUSION. Intravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti-HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective on in vivo protective efficacy.