Pathological Role of Anti-CD4 Antibodies in HIV-Infected Immunologic Nonresponders Receiving Virus-Suppressive Antiretroviral Therapy
Pathological Role of Anti-CD4 Antibodies in HIV-Infected Immunologic Nonresponders Receiving Virus-Suppressive Antiretroviral Therapy
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DOI：
10.1093/infdis/jix223
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发表时间：
2017-07-01
影响因子：
6.4
通讯作者：
Jiang, Wei
中科院分区：
文献类型：
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作者：
Luo, Zhenwu;Li, Zhen;Jiang, Wei
尽管使用抗逆转录病毒治疗（ART）抑制病毒，但CD 4（+）T细胞计数不增加的人类免疫缺陷病毒（HIV）感染患者的死亡率和发病率增加。在这里，我们发现了一个潜在的机制。与HIV阳性免疫应答者（即，CD 4（+）T细胞计数500个细胞/μ L的HIV阳性个体）和健康对照组的水平相比，HIV阳性免疫无应答者（即，CD 4（+）T细胞计数350个细胞/μ L的HIV阳性个体）的抗CD 4免疫球蛋白G（IgG）血浆水平显著升高。较高的血浆抗CD 4 IgG水平与钝化的CD 4（+）T细胞恢复相关。此外，从HIV阳性免疫无应答者中纯化的抗CD 4 IgG通过抗体依赖性细胞介导的细胞毒性（ADCC）在体外诱导自然杀伤（NK）细胞依赖性CD 4（+）T细胞的细胞溶解和凋亡。我们还发现，相对于记忆性CD 4（+）T细胞，抗CD 4 IgG介导的ADCC对初始CD 4（+）T细胞产生更大的凋亡。一致地，与应答者和健康对照相比，在免疫无应答者中观察到CD 107 a（+）NK细胞频率增加和初始CD 4（+）T细胞显著减少。这些数据表明，尽管ART有效，但自身反应性抗CD 4 IgG可能在钝化的CD 4（+）T细胞重建中发挥重要作用。
Increased mortality and morbidity occur among human immunodeficiency virus (HIV)-infected patients in whom CD4(+) T-cell counts do not increase despite viral suppression with antiretroviral therapy (ART). Here we identified an underlying mechanism. Significantly elevated plasma levels of anti-CD4 immunoglobulin G (IgG) were found in HIV-positive immunologic nonresponders (ie, HIV-positive individuals with CD4(+) T-cell counts of 350 cells/mu L), compared with levels in HIV-positive immunologic responders (ie, HIV-positive individuals with CD4(+) T-cell counts of 500 cells/mu L) and healthy controls. Higher plasma level of anti-CD4 IgG correlated with blunted CD4(+) T-cell recovery. Furthermore, purified anti-CD4 IgG from HIV-positive immunologic nonresponders induced natural killer (NK) cell-dependent CD4(+) T-cell cytolysis and apoptosis through antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. We also found that anti-CD4 IgG-mediated ADCC exerts greater apoptosis of naive CD4(+) T cells relative to memory CD4(+) T cells. Consistently, increased frequencies of CD107a(+) NK cells and profound decreases of naive CD4(+) T cells were observed in immunologic nonresponders as compared to responders and healthy controls ex vivo. These data indicate that autoreactive anti-CD4 IgG may play an important role in blunted CD4(+) T-cell reconstitution despite effective ART.