Andersson J, Fehniger T E, Patterson B K, Pottage J, Agnoli M, Jones P, Behbahani H, Landay A
Division of Infectious Diseases, Karolinska Institute, Stockholm, Sweden.
AIDS. 1998 Jul 30;12(11):F123-9. doi: 10.1097/00002030-199811000-00004.
To evaluate immune reconstitution within HIV-infected lymphoid tissue during highly active antiretroviral therapy (HAART).
In situ cellular responses were studied in sequential tonsillar biopsies in three asymptomatic HIV-infected (CD4 cells greater than 400 x 10(6)/l) antiretroviral treatment-naive volunteers enrolled in a clinical trial to determine the early effect of HAART. Computerized image analysis was used to study immunohistochemically stained sequential tonsil sections for the patterns of local cytokine production, chemokine receptor expression and cellular distribution. Replicate quantitative assessments of samples before and after 4 weeks of therapy were used for the evaluation of drug effects and compared with four uninfected controls. Tonsillar HIV proviral-DNA was determined by fluorescent in situ 5'-nuclease assay.
HIV-infected tonsil tissue was characterized by extensive pro-inflammatory and type 1 cytokine expression. A five- to 15-fold elevation of interleukin (IL)-1 alpha, IL-12, IL-2 and interferon (IFN)-gamma protein expression was found compared with controls, and each encompassed a mean of at least 4.5% of the tissue compartment. This was reduced by 20-90% in all individuals after 4 weeks of HAART. In contrast, type 2 cytokine expression (IL-4, IL-10), plus tumour necrosis factor (TNF)-alpha, remained low throughout the study. HAART reduced, by 40%, the expression of HIV co-receptors, CCR5 and CXCR4, which initially were elevated four to six times over the control values. In addition, the myelomonocytic inflammatory proteins, CD68 and calprotectin, diminished by 26-83% after therapy. The HIV RNA was reduced to undetectable levels in plasma by HAART. However, a large pool of tonsil cells (2-7%), remained HIV DNA positive after 4 weeks of therapy.
Although immune activation may be the direct consequence of HIV replication, HAART-associated reconstitution begins with a reduction in inflammatory cytokine production which precedes the elimination of local proviral reservoirs.
评估高效抗逆转录病毒疗法（HAART）期间HIV感染的淋巴组织内的免疫重建情况。
在一项确定HAART早期疗效的临床试验中，对三名无症状HIV感染（CD4细胞大于400×10⁶/l）且未接受过抗逆转录病毒治疗的志愿者进行了连续的扁桃体活检，研究原位细胞反应。使用计算机图像分析技术，对免疫组化染色的连续扁桃体切片进行研究，以观察局部细胞因子产生模式、趋化因子受体表达和细胞分布情况。对治疗4周前后的样本进行重复定量评估，以评估药物疗效，并与四名未感染的对照进行比较。通过荧光原位5'-核酸酶测定法测定扁桃体HIV前病毒DNA。
HIV感染的扁桃体组织以广泛的促炎和1型细胞因子表达为特征。与对照组相比，白细胞介素（IL）-1α、IL-12、IL-2和干扰素（IFN）-γ蛋白表达升高了5至15倍，且每种细胞因子在组织区室中的平均占比至少为4.5%。在HAART治疗4周后，所有个体的这些细胞因子表达均降低了20%至90%。相比之下，在整个研究过程中，2型细胞因子表达（IL-4、IL-10）以及肿瘤坏死因子（TNF）-α一直保持在较低水平。HAART使HIV共受体CCR5和CXCR4的表达降低了40%，其最初比对照值升高了4至6倍。此外，治疗后骨髓单核细胞炎性蛋白CD68和钙卫蛋白减少了26%至83%。HAART使血浆中的HIV RNA降至无法检测的水平。然而，在治疗4周后，仍有大量扁桃体细胞（2%至7%）的HIV DNA呈阳性。
虽然免疫激活可能是HIV复制的直接后果，但HAART相关的免疫重建始于炎性细胞因子产生的减少，这先于局部前病毒储存库的清除。
