In vivo significance of T-reg cells during FIV infection

描述(申请人提供)：我们已经描述了猫体内的CD4 CD25 Treg细胞，并证明它们在猫免疫缺陷病毒(FIV)感染的动物中被长期激活。来自FIV感染猫的Treg细胞显著抑制了CD4 CD25-T细胞的增殖，并且由于慢性FIV感染，在体内明显被激活。由于激活的Treg细胞在抑制功能上是非抗原特异性的，这些细胞可能反过来抑制或激活对包括FIV抗原在内的各种抗原的CD4T辅助反应，从而导致这种感染的获得性免疫缺陷综合征(AIDS)。最近在HIV-1感染者中也有同样的观察结果，有趣的是，Treg功能水平的提高与良好的临床状态或对HAART的反应有关。正常情况下，Treg功能对于限制和下调免疫反应、防止过度炎症和自身免疫性疾病至关重要。目前尚不清楚Treg细胞在HIV感染中是有益的还是有害的，答案可能取决于疾病的阶段。在急性感染期间，HIV诱导的Treg活性可能限制了抗病毒反应的范围和有效性，而在无症状感染期间，Treg活性可能有助于控制慢性免疫激活，并限制激活的靶细胞的可用性。要解决Treg功能在HIV感染过程中的重要性，最确定的方法是在动物模型中去除Treg细胞。在这些研究中，我们将使用艾滋病毒的FIV/CAT模型来：1.确定在FIV感染之前或之后立即耗尽Treg细胞是否会产生更有效的抗病毒免疫反应，以及2.)确定在FIV感染的无症状阶段，Treg细胞的耗尽是否会导致抗病毒T细胞免疫的扩张和/或血浆病毒血症的改变。这些研究的结果将为临床了解Treg在HIV感染中的作用提供依据，并将指导未来调节Treg功能的方法。

DESCRIPTION (provided by applicant): We have described CD4+CD25+ Treg cells in the cat and demonstrated that they are chronically activated in feline immunodeficiency virus (FIV) infected animals. Treg cells from FIV-infected cats significantly inhibited proliferation of CD4+CD25- T cells, and are apparently activated in vivo as a result of the chronic FIV infection. As activated Treg cells are non-antigen specific in their suppressive function, it is possible that these cells could in turn suppress or anergize CD4+ T helper responses to a variety of antigens including FIV antigen and thereby contribute to the acquired immunodeficiency syndrome (AIDS) characteristic of this infection. The same observation has recently been reported in HIV-1 infected people and interestingly, increased levels of Treg function were associated with a favorable clinical status or respose to HAART. Normally, Treg function is critical to limit and down-regulate immune responses, preventing excessive inflammation and autoimmune disease. Whether Treg cells in HIV infection are beneficial or detrimental is unclear and the answer may depend on the stage of disease. It is possible that HIV-induced Treg activity during acute infection may limit the scope and efficacy of the anti-viral response, whereas Treg activity during asymptomatic infection may serve to control chronic immune activation and limit availability of activated target cells. The most definitive way to address the significance of Treg function during HIV infection is to deplete Treg cells in an animal model. In these studies we will employ the FIV/cat model of HIV to: 1.) Determine whether depletion of Treg cells before or immediately after FIV infection results in a more effective anti-viral immune response, and 2.) Determine whether depletion of Treg cells during the asymptomatic phase of FIV infection results in the expansion of antiviral T-cell immunity and/or change in plasma viremia. Results from these studies will provide a clinical understanding of Treg function in HIV infection and will guide future approaches to modulate Treg function.