Inhibition of Type 1 Interferon During SIV Infection

我们假设，对SIV的早期先天免疫反应最初起到限制病毒产生的作用，但矛盾的是，通过将CD4+T细胞招募到感染部位，它可能还提供了足够多的细胞燃料，使病毒成为一种自我传播的感染。一旦建立了最初的创建者群体，并扩大了当地的病毒生产，病毒就会首先迅速传播到女性生殖道的引流淋巴结，如腹股沟淋巴结。它最终从引流结节进入血流、远端外周淋巴组织，在接种SIV后10-14天，SIV病毒载量在血浆和全身组织中达到峰值。病毒载量高峰后的下降与急性期适应性免疫反应的发展和扩大是一致的，这种反应可能在将病毒复制降低到设定点水平方面发挥作用。然而，随着时间的推移，免疫反应的持续刺激可能(类似于早期的先天反应)为病毒提供靶细胞，最终导致宿主死亡。宿主对HIV/SIV的免疫应答诱导了一种广泛的免疫激活状态。慢性全身性免疫激活水平已被证明是疾病进展的良好预测指标。我们将直接测试进入粘膜入口的早期先天干扰素反应对SIV感染在RMS中的建立、播散率和最终结果的贡献。为了做到这一点，我们将抑制干扰素的生物活性，通过在SIV感染之前和早期阶段用抗干扰素受体抗体(a干扰素-61537；R)治疗恒河猴。这项研究将分两个阶段进行；第一阶段将评估用干扰素-R抗体阻断干扰素反应对SIV传播的建立和传播速度的影响。第二阶段将评估干扰素受体对病毒动力学、MALT CD4+T细胞耗尽、SIV特异性免疫反应和疾病进展的影响。

We hypothesize that the early innate immune response to SIV initially serves to limit virus production but paradoxically, by recruiting CD4+ T cells to the site of infection, it likely also provides the cellular fuel in sufficiently high numbers enabling the virus to become a self-propagating infection. Once the initial founder populations have been established and local production of virus amplified, the virus quickly disseminates first to the draining lymph nodes of the female reproductive tract such as the inguinal lymph nodes. From the draining nodes it ultimately gains access to the blood stream, distal peripheral lymphatic tissues and by 10-14 days post inoculation SIV viral loads peak in the plasma and tissues throughout the body. The post peak decline in viral load is coincident with the development and expansion of an adaptive immune response, during the acute phase and this response may play a role in lowering viral replication to set-point levels. However, over time the constant stimulation of an immune response, which is not of sufficient quality or quantity to eliminate the virus, may (similar to the early innate response), provide target cells for the virus and ultimately contribute to the hosts demise. The hosts immune response to HIV/SIV induces a state of generalized immune activation. The level of chronic generalized immune activation has been shown to be a good predictor of disease progression. We will directly test the contribution of the early innate IFN response at the mucosal portal of entry to the establishment, rate of dissemination and ultimately the outcome of SIV infection in RMs. To do this we will inhibit the biological activity of IFN &  by treating rhesus macaques with an anti-IFN receptor antibody (aIFN-R) prior to and during the early stages of SIV infection. The study will be performed in 2 phases; Phase 1 will assess the effects of blocking INF responses with an antibody to IFN-R on the establishment and rate of SIV dissemination. Phase 2 will assess the effect of aIFN-R on viral dynamics, MALT CD4+ T cell depletion, SIV-specific immune responses and disease progression.