Kollmann T R, Pettoello-Mantovani M, Zhuang X, Kim A, Hachamovitch M, Smarnworawong P, Rubinstein A, Goldstein H
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.
J Exp Med. 1994 Feb 1;179(2):513-22. doi: 10.1084/jem.179.2.513.
A small animal model that could be infected with human immunodeficiency virus 1 (HIV-1) after peripheral inoculation would greatly facilitate the study of the pathophysiology of acute HIV-1 infection. The utility of SCID mice implanted with human fetal thymus and liver (SCID-hu mice) for studying peripheral HIV-1 infection in vivo has been hampered by the requirement for direct intraimplant injection of HIV-1 and the continued restriction of the resultant HIV-1 infection to the human thymus and liver (hu-thy/liv) implant. This may have been due to the very low numbers of human T cells present in the SCID-hu mouse peripheral lymphoid compartment. Since the degree of the peripheral reconstitution of SCID-hu mice with human T cells may be a function of the hu-thy/liv implant size, we increased the quantity of hu-thy/liv tissue implanted under the renal capsule and implanted hu-thy/liv tissue under the capsules of both kidneys. This resulted in SCID-hu mice in which significant numbers of human T cells were detected in the peripheral blood, spleens, and lymph nodes. After intraimplant injection of HIV-1 into these modified SCID-hu mice, significant HIV-1 infection was detected by quantitative coculture not only in the hu-thy/liv implant, but also in the spleen and peripheral blood. This indicated that HIV-1 infection can spread from the thymus to the peripheral lymphoid compartment. More importantly, a similar degree of infection of the hu-thy/liv implant and peripheral lymphoid compartment occurred after peripheral intraperitoneal inoculation with HIV-1. Active viral replication was indicated by the detection of HIV-1 gag DNA, HIV-1 gag RNA, and spliced tat/rev RNA in the hu-thy/liv implants, peripheral blood mononuclear cells (PBMC), spleens, and lymph nodes of these HIV-1-infected SCID-hu mice. As a first step in using our modified SCID-hu mouse model to investigate the pathophysiological consequences of HIV-1 infection, the effect of HIV-1 infection on the expression of human cytokines shown to enhance HIV-1 replication was examined. Significantly more of the HIV-1-infected SCID-hu mice expressed mRNA for human tumor necrosis factors alpha and beta, and interleukin 2 in their spleens, lymph nodes, and PBMC than did uninfected SCID-hu mice. This suggested that HIV-1 infection in vivo can stimulate the expression of cytokine mRNA by human T cells.(ABSTRACT TRUNCATED AT 400 WORDS)
一种能够在经外周接种后感染人类免疫缺陷病毒1型（HIV-1）的小动物模型，将极大地促进对急性HIV-1感染病理生理学的研究。植入人胎儿胸腺和肝脏的SCID小鼠（SCID-hu小鼠）在体内研究外周HIV-1感染的效用，一直受到直接向植入物内注射HIV-1的要求以及由此产生的HIV-1感染持续局限于人类胸腺和肝脏（人胸腺/肝脏）植入物的限制。这可能是由于SCID-hu小鼠外周淋巴区室中存在的人类T细胞数量非常少。由于用人类T细胞对外周重建的SCID-hu小鼠的程度可能是人类胸腺/肝脏植入物大小的函数，我们增加了植入肾包膜下的人类胸腺/肝脏组织的数量，并在双侧肾包膜下植入人类胸腺/肝脏组织。这产生了在其外周血、脾脏和淋巴结中检测到大量人类T细胞的SCID-hu小鼠。在向这些改良的SCID-hu小鼠的植入物内注射HIV-1后，通过定量共培养不仅在人类胸腺/肝脏植入物中，而且在脾脏和外周血中检测到了显著的HIV-1感染。这表明HIV-1感染可以从胸腺扩散到外周淋巴区室。更重要的是，在用HIV-1进行外周腹腔接种后，人类胸腺/肝脏植入物和外周淋巴区室出现了相似程度的感染。在这些感染HIV-1的SCID-hu小鼠的人类胸腺/肝脏植入物、外周血单核细胞（PBMC）、脾脏和淋巴结中检测到HIV-1 gag DNA、HIV-1 gag RNA和剪接的tat/rev RNA，表明存在活跃的病毒复制。作为使用我们改良的SCID-hu小鼠模型研究HIV-1感染病理生理后果的第一步，我们研究了HIV-1感染对已显示可增强HIV-1复制的人类细胞因子表达的影响。与未感染的SCID-hu小鼠相比，感染HIV-1的SCID-hu小鼠在其脾脏、淋巴结和PBMC中表达人类肿瘤坏死因子α和β以及白细胞介素2 mRNA的比例显著更高。这表明体内HIV-1感染可刺激人类T细胞表达细胞因子mRNA。（摘要截短为400字）
