Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Japan.
AIDS. 2009 Nov 13;23(17):2265-75. doi: 10.1097/QAD.0b013e328332817c.
To determine whether HIV-1-specific CD4 T cells with proliferative capacity are eliminated or functionally defective because of HIV-1 reactivation.
The loss of proliferative capacity by HIV-1-specific CD4 T cells compromises the host's ability to maintain protective immunity against HIV-1 and is a hallmark of disease progression. We used a recombinant lentivirus encoding an HIV-specific short hairpin (sh)RNA (Lenti shNef366) with known HIV-inhibitory activity to analyze the functional state of HIV-1-specific CD4 T cells.
T lymphocytes from untreated chronically HIV-infected patients with documented high viral loads (above 10 000 HIV-RNA) were transduced with Lenti shNef366, and the proliferation, differentiation, and cytokine production of HIV-specific CD4 T cells were analyzed.
Lenti shNef366 restored the proliferation of HIV p24-specific CD4 T cells in eight of 12 patients tested, affecting primarily CD27 or CD28 CD4 T cells that were at an intermediate stage of differentiation. Although cytokine production by CD4 T cells remained poor after transduction with Lenti shNef366, improved proliferative capacity was associated with significantly higher levels of expression of CD107a.
In chronic stages of HIV-1 infection with high levels of HIV replication, proliferation-competent HIV-specific CD4 T cells in an intermediate stage of differentiation are present but are exquisitely and strongly impaired. Blocking HIV reactivation may restore a key functional property of memory T cells.
确定具有增殖能力的 HIV-1 特异性 CD4 T 细胞是因 HIV-1 再激活而被消除还是功能缺陷。
HIV-1 特异性 CD4 T 细胞增殖能力的丧失削弱了宿主维持针对 HIV-1 的保护性免疫的能力，是疾病进展的标志。我们使用编码具有已知 HIV 抑制活性的 HIV 特异性短发夹 (sh)RNA（Lenti shNef366）的重组慢病毒来分析 HIV-1 特异性 CD4 T 细胞的功能状态。
用 Lenti shNef366 转导未经治疗的慢性 HIV 感染患者的 T 淋巴细胞，这些患者的病毒载量（HIV-RNA 超过 10000）已被记录，分析 HIV 特异性 CD4 T 细胞的增殖、分化和细胞因子产生。
Lenti shNef366 恢复了 12 名患者中的 8 名患者的 HIV p24 特异性 CD4 T 细胞的增殖，主要影响处于中间分化阶段的 CD27 或 CD28 CD4 T 细胞。尽管 Lenti shNef366 转导后 CD4 T 细胞的细胞因子产生仍然较差，但增殖能力的提高与 CD107a 的表达水平显著升高相关。
在 HIV-1 复制水平较高的慢性 HIV-1 感染阶段，存在处于中间分化阶段的增殖能力正常的 HIV 特异性 CD4 T 细胞，但它们受到强烈和高度的损伤。阻断 HIV 再激活可能恢复记忆 T 细胞的一个关键功能特性。
