Tompkins Mary B, Tompkins Wayne A
Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, United States.
Vet Immunol Immunopathol. 2008 May 15;123(1-2):45-55. doi: 10.1016/j.vetimm.2008.01.011. Epub 2008 Jan 19.
FIV/HIV infections are associated with an early robust humoral and cellular anti-viral immune response followed by a progressive immune suppression that eventually results in AIDS. Several mechanisms responsible for this immune dysfunction have been proposed including cytokine dysregulation, immunologic anergy and apoptosis, and inappropriate activation of immune regulatory cells. Studies on FIV infection provide evidence for all three. Cytokine alterations include decreases in IL2 and IL12 production and increases in IFNgamma and IL10 in FIV(+) cats compared to normal cats. The elevated IL10:IL12 ratio is associated with the inability of FIV(+) cats to mount a successful immune response to secondary pathogens. Additionally, chronic antigenic (FIV) stimulation results in an increase in the percent of activated T cells expressing B7 and CTLA4 co-stimulatory molecules in infected cats. The expression of these molecules is associated with T cells that are undergoing apoptosis in the lymph nodes. As ligation of CTLA4 by B7 transduces a signal for induction of anergy, one can speculate that the activated T cells are capable of T cell-T cell interactions resulting in anergy and apoptosis. The inability of CD4(+) cells from FIV(+) cats to produce IL2 in response to recall antigens and the gradual loss of CD4(+) cell numbers could be due to B7-CTLA4 interactions. The chronic antigenemia may also lead to activation of CD4(+)CD25(+) T regulatory cells. Treg cells from FIV(+) cats are chronically activated and inhibit the mitogen-induced proliferative response of CD4(+)CD25(-) by down-regulating IL2 production. Although Treg cell activation can be antigen-specific, the suppressor function is not, and thus activated Treg cells would suppress responses to secondary pathogens as well as to FIV. Concomitant with the well-known virus-induced immune suppression is a progressive immune hyper-activation. Evidence for immune hyper-activation includes polyclonal B cell responses, gradual replacement of naïve CD4(+) and CD8(+) T cell phenotypes with activation phenotypes (CD62L(-), B7(+), CTLA4(+)), and the chronic activation of CD4(+)CD25(+) Treg cells. Thus lentivirus infections lead to severe immune dysregulation manifested as both chronic immune suppression and chronic immune activation. FIV infection of cats provides a number of advantages over other lentivirus infections as a model to study this immune dysregulation. It is a natural infection that has existed in balance with the cat's immune system for thousands of years. As such, the natural history and pathogenesis provides an excellent model to study the long-term relationships between AIDS lentivirus and host immune system function/dysregulation.
猫免疫缺陷病毒（FIV）/人类免疫缺陷病毒（HIV）感染与早期强烈的体液和细胞抗病毒免疫反应相关，随后是进行性免疫抑制，最终导致获得性免疫缺陷综合征（AIDS）。已提出几种导致这种免疫功能障碍的机制，包括细胞因子失调、免疫无反应性和细胞凋亡，以及免疫调节细胞的不适当激活。对FIV感染的研究为所有这三种机制提供了证据。与正常猫相比，FIV（+）猫的细胞因子改变包括白细胞介素2（IL2）和白细胞介素12（IL12）产生减少，以及干扰素γ（IFNγ）和白细胞介素10（IL10）增加。升高的IL10:IL12比值与FIV（+）猫无法对继发病原体产生成功的免疫反应有关。此外，慢性抗原（FIV）刺激导致感染猫中表达B7和细胞毒性T淋巴细胞相关抗原4（CTLA4）共刺激分子的活化T细胞百分比增加。这些分子的表达与淋巴结中正在经历细胞凋亡的T细胞有关。由于B7与CTLA4的结合转导了诱导无反应性的信号，人们可以推测活化的T细胞能够进行T细胞 - T细胞相互作用，从而导致无反应性和细胞凋亡。FIV（+）猫的CD4（+）细胞在对回忆抗原作出反应时无法产生IL2以及CD4（+）细胞数量的逐渐减少可能是由于B7 - CTLA4相互作用。慢性抗原血症也可能导致CD4（+）CD25（+）调节性T细胞的活化。FIV（+）猫的调节性T细胞被慢性活化，并通过下调IL2产生来抑制有丝分裂原诱导的CD4（+）CD25（ - ）细胞的增殖反应。虽然调节性T细胞的活化可以是抗原特异性的，但其抑制功能并非如此，因此活化的调节性T细胞会抑制对继发病原体以及FIV的反应。与众所周知的病毒诱导的免疫抑制同时存在的是进行性免疫过度激活。免疫过度激活的证据包括多克隆B细胞反应、幼稚CD4（+）和CD8（+）T细胞表型逐渐被活化表型（CD62L（ - ）、B7（+）、CTLA4（+））取代，以及CD4（+）CD25（+）调节性T细胞的慢性活化。因此，慢病毒感染导致严重的免疫失调，表现为慢性免疫抑制和慢性免疫激活。与其他慢病毒感染相比，猫的FIV感染作为研究这种免疫失调的模型具有许多优势。它是一种自然感染，已经与猫的免疫系统平衡存在了数千年。因此，其自然史和发病机制为研究艾滋病慢病毒与宿主免疫系统功能/失调之间的长期关系提供了一个极好的模型。
