Audigé Annette, Schlaepfer Erika, Bonanomi Athos, Joller Helene, Knuchel Marlyse C, Weber Markus, Nadal David, Speck Roberto F
Division of Infectious Diseases and Hospital Epidemiology, Institute of Clinical Immunology, and Clinic of Visceral and Transplantation Surgery, University Hospital of Zurich, Switzerland.
J Immunol. 2004 Feb 15;172(4):2687-96. doi: 10.4049/jimmunol.172.4.2687.
The cytokine response to invading microorganisms is critical for priming the adaptive immune response. During acute HIV infection, the response is disrupted, but the mechanism is poorly understood. We examined the cytokine response in human lymphoid tissue, acutely infected ex vivo with HIV. Lymphoid tissue was cultured either as blocks or as human lymphocyte aggregate cultures (HLAC) of tonsils and lymph nodes. This approach allowed us to examine the effects of HIV on cytokines using distinct culture techniques. In contrast to HLAC, mock-infected tissue blocks displayed a 50- to 100-fold up-regulation of mRNAs for IL-1beta, -6, and -8 in the first 6 days of culture. Parallel increases were also noted at the protein level in the supernatants. Although IL-1beta, -6, and -8 are known to synergistically enhance HIV replication, peak HIV replication (measured as p24 Ag) was similar in tissue blocks and HLAC. Surprisingly, vigorous HIV replication of CXCR4- and CCR5-tropic HIV strains did not result in characteristic mRNA profiles for IL-1beta, -2, -4, -6, -8, -10, -12, -15, IFN-gamma, TNF-alpha, TGF-beta, and beta-chemokines in tissue blocks or HLAC. The increased expression of IL-1beta, -6, and -8 in tissue blocks may approximate clinical situations with heightened immune activation; neutralization of these cytokines resulted in inhibition of HIV replication, suggesting that these cytokines may contribute to HIV replication in certain clinical settings. These results also indicate that different molecular mechanisms govern HIV replication in tissue blocks and HLAC. Prevention of effective cytokine responses may be an important mechanism that HIV uses during acute infection.
细胞因子对入侵微生物的反应对于启动适应性免疫反应至关重要。在急性HIV感染期间，这种反应受到破坏，但其机制尚不清楚。我们检测了体外急性感染HIV的人淋巴组织中的细胞因子反应。淋巴组织以组织块形式或作为扁桃体和淋巴结的人淋巴细胞聚集培养物（HLAC）进行培养。这种方法使我们能够使用不同的培养技术检测HIV对细胞因子的影响。与HLAC相反， mock感染的组织块在培养的前6天显示IL-1β、-6和-8的mRNA上调50至100倍。上清液中的蛋白质水平也有平行增加。虽然已知IL-1β、-6和-8可协同增强HIV复制，但组织块和HLAC中的HIV复制峰值（以p24抗原测量）相似。令人惊讶的是，CXCR4和CCR5嗜性HIV毒株的强烈HIV复制并未导致组织块或HLAC中IL-1β、-2、-4、-6、-8、-10、-12、-15、IFN-γ、TNF-α、TGF-β和β趋化因子的特征性mRNA谱。组织块中IL-1β、-6和-8表达的增加可能类似于免疫激活增强的临床情况；这些细胞因子的中和导致HIV复制受到抑制，表明这些细胞因子可能在某些临床环境中促进HIV复制。这些结果还表明，不同的分子机制控制着组织块和HLAC中的HIV复制。预防有效的细胞因子反应可能是HIV在急性感染期间使用的一种重要机制。
