IrsiCaixa-HIVACAT, Institut de Recerca en Ciències de la Salut Germans Trias i Pujol (IGTP), Hospital Germans Trias, Universitat Autònoma de Barcelona, Badalona, Barcelona, Catalonia, Spain.
PLoS One. 2012;7(2):e30330. doi: 10.1371/journal.pone.0030330. Epub 2012 Feb 1.
CD4 T-cell decay is variable among HIV-infected individuals. In exceptional cases, CD4 T-cell counts remain stable despite high plasma viremia. HIV envelope glycoprotein (Env) properties, namely tropism, fusion or the ability to induce the NK ligand NKp44L, or host factors that modulate Env cytopathic mechanisms may be modified in such situation.
We identified untreated HIV-infected individuals showing non-cytopathic replication (VL>10,000 copies/mL and CD4 T-cell decay<50 cells/µL/year, Viremic Non Progressors, VNP) or rapid progression (CD4 T-cells<350 cells/µL within three years post-infection, RP). We isolated full-length Env clones and analyzed their functions (tropism, fusion activity and capacity to induce NKp44L expression on CD4 cells). Anti-Env humoral responses were also analyzed.
Env clones isolated from VNP or RP individuals showed no major phenotypic differences. The percentage of functional clones was similar in both groups. All clones tested were CCR5-tropic and showed comparable expression and fusogenic activity. Moreover, no differences were observed in their capacity to induce NKp44L expression on CD4 T cells from healthy donors through the 3S epitope of gp41. In contrast, anti- Env antibodies showed clear functional differences: plasma from VNPs had significantly higher capacity than RPs to block NKp44L induction by autologous viruses. Consistently, CD4 T-cells isolated from VNPs showed undetectable NKp44L expression and specific antibodies against a variable region flanking the highly conserved 3S epitope were identified in plasma samples from these patients. Conversely, despite continuous antigen stimulation, VNPs were unable to mount a broad neutralizing response against HIV.
Env functions (fusion and induction of NKp44L) were similar in viremic patients with slow or rapid progression to AIDS. However, differences in humoral responses against gp41 epitopes nearby 3S sequence may contribute to the lack of CD4 T cell decay in VNPs by blocking the induction of NKp44L by gp41.
CD4 细胞衰减在 HIV 感染者中各不相同。在特殊情况下，尽管血浆病毒载量很高，但 CD4 细胞计数仍保持稳定。HIV 包膜糖蛋白（Env）的特性，即嗜性、融合或诱导 NK 配体 NKp44L 的能力，或调节 Env 细胞病变机制的宿主因素，可能会在这种情况下发生改变。
我们鉴定了未经治疗的 HIV 感染者，他们表现出非细胞病变性复制（VL>10,000 拷贝/ml 和 CD4 T 细胞衰减<50 个细胞/μl/年，病毒血症非进展者，VNP）或快速进展（CD4 T 细胞<感染后三年内 350 个细胞/μl，RP）。我们分离了全长 Env 克隆，并分析了它们的功能（嗜性、融合活性和诱导 CD4 细胞表达 NKp44L 的能力）。还分析了抗 Env 抗体反应。
从 VNP 或 RP 个体中分离的 Env 克隆没有表现出明显的表型差异。两组的功能性克隆比例相似。所有测试的克隆均为 CCR5 嗜性，表达和融合活性相当。此外，在诱导健康供体 CD4 T 细胞表达 NKp44L 的能力方面，它们之间没有差异，通过 gp41 的 3S 表位。相比之下，抗 Env 抗体表现出明显的功能差异：VNP 患者的血浆阻断自身病毒诱导 NKp44L 表达的能力明显高于 RP。一致地，从 VNP 中分离的 CD4 T 细胞表现出无法检测到的 NKp44L 表达，并且在这些患者的血浆样本中鉴定出针对高度保守的 3S 表位侧翼的可变区的特异性抗体。相反，尽管持续存在抗原刺激，VNP 仍无法针对 HIV 产生广泛的中和反应。
在进展为艾滋病的病毒血症患者中，Env 功能（融合和诱导 NKp44L）相似。然而，针对 gp41 3S 序列附近表位的抗体反应差异可能通过阻断 gp41 诱导 NKp44L 的表达，导致 VNP 中 CD4 T 细胞衰减的缺乏。
