Sørensen Birger, Sommerfelt Maja A, Stjernholm Grete, Smith Peter Lawrence, Ökvist Mats, Hovden Arnt-Ove, Hoddevik Gunnar, Redfield Robert, Ustina Valentina, Jelmert Øyvind, Zeldis Jerome, Dalgleish Angus
1 Bionor Pharma AS , Oslo, Norway .
2 St. George's, University of London , Institute of Infection and Immunity, London, United Kingdom .
AIDS Res Hum Retroviruses. 2017 Jun;33(6):558-566. doi: 10.1089/AID.2016.0184. Epub 2017 Jan 31.
Antibodies to the carboxy-terminal constant (C5) region 5 of the HIV-1 envelope glycoprotein gp120 have previously been associated with slow disease progression. This is one of the regions on gp120 that interact with the transmembrane glycoprotein, gp41, anchoring it to the viral and infected cell membrane. This study analyzed humoral responses to a novel heterodimeric peptide construct comprising the C5 region and a compatible region on gp41. Antibody levels to C5/gp41 were associated with slow disease progression in a treatment naive historical longitudinal cohort from Norway (n = 32; p = .00001). Elevated anti-C5/gp41 antibody levels correlated with moderate viral load (VL) (50-10,000 copies/ml) in a cohort, including natural viral suppressors (NVS) in the Unites States (n = 58; p = .002). Analysis of HIV-positive sera from treatment naive patients in Estonia (n = 300) showed an inverse correlation between anti-C5/gp41 antibodies and VL when comparing VL 2,000-10,000 copies/ml with VL >10,000 (p = .050). Further mapping using peptide inhibition of antibody binding revealed that responses to the C5 subdomain correlated with preserved CD4 counts (n = 55; p = .0012) irrespective of VL in this cohort. The C5 region encompassing C5 shows sequence similarity to the shared epitope (SE) of certain HLA-DR associated with immune dysfunction. Partial antigenic cross-reactivity between SE and C5 is indicated by partial inhibition of NVS antibody binding using SE 15-mer peptide (median 65% inhibition), the C5 6-mer peptide (79% inhibition), and binding of rheumatoid arthritis patient sera to both SE and C5 peptide sequences. The potential influence of these observations on HIV-1 pathogenesis remains to be determined.
针对人类免疫缺陷病毒1型（HIV-1）包膜糖蛋白gp120羧基末端恒定（C5）区5的抗体先前已被证明与疾病进展缓慢有关。这是gp120上与跨膜糖蛋白gp41相互作用的区域之一，可将其锚定在病毒和受感染细胞膜上。本研究分析了对一种新型异二聚体肽构建体的体液反应，该构建体包含C5区和gp41上的一个相容区域。在挪威一个未经治疗的历史纵向队列（n = 32；p = 0.00001）中，针对C5/gp41的抗体水平与疾病进展缓慢相关。在一个队列中，包括美国的天然病毒抑制者（NVS）（n = 58；p = 0.002），抗C5/gp41抗体水平升高与中等病毒载量（VL）（50 - 10,000拷贝/毫升）相关。对爱沙尼亚未经治疗的HIV阳性患者血清（n = 300）的分析表明，当比较2,000 - 10,000拷贝/毫升的VL与>10,000的VL时，抗C5/gp41抗体与VL呈负相关（p = 0.050）。使用肽抑制抗体结合的进一步定位显示，在该队列中，无论VL如何，对C5亚结构域的反应与保存的CD4细胞计数相关（n = 55；p = 0.0012）。包含C5的C5区与某些与免疫功能障碍相关的HLA-DR共享表位（SE）具有序列相似性。使用SE 15聚体肽（中位抑制率65%）、C5 6聚体肽（79%抑制率）以及类风湿性关节炎患者血清与SE和C5肽序列的结合对NVS抗体结合的部分抑制表明SE和C5之间存在部分抗原交叉反应。这些观察结果对HIV-1发病机制的潜在影响仍有待确定。
