Li J T, Halloran M, Lord C I, Watson A, Ranchalis J, Fung M, Letvin N L, Sodroski J G
Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
J Virol. 1995 Nov;69(11):7061-7. doi: 10.1128/JVI.69.11.7061-7067.1995.
Chimeric simian-human immunodeficiency viruses (SHIV) containing the human immunodeficiency virus type 1 (HIV-1) tat, rev, env, and, in some cases, vpu genes were inoculated into eight cynomolgus monkeys. Viruses could be consistently recovered from the CD8-depleted peripheral blood lymphocytes of all eight animals for at least 2 months. After this time, virus isolation varied among the animals, with viruses continuing to be isolated from some animals beyond 600 days after inoculation. The level of viral RNA in plasma during acute infection and the frequency of virus isolation after the initial 2-month period were higher for the Vpu-positive viruses. All of the animals remained clinically healthy, and the absolute numbers of CD4-positive lymphocytes were stable. Antibodies capable of neutralizing HIV-1 were generated at high titers in animals exhibiting the greatest consistency of virus isolation. Strain-specific HIV-1-neutralizing antibodies were initially elicited, and then more broadly neutralizing antibodies were elicited. env sequences from two viruses isolated more than a year after infection were analyzed. In the Vpu-negative SHIV, for which virus loads were lower, a small amount of env variation, which did not correspond to that found in natural HIV-1 variants, was observed. By contrast, in the Vpu-positive virus, which was consistently isolated from the host animal, extensive variation of the envelope glycoproteins in the defined variable gp120 regions was observed. Escape from neutralization by CD4 binding site monoclonal antibodies was observed for the viruses with the latter envelope glycoproteins, and the mechanism of escape appears to involve decreased binding of the antibody to the monomeric gp120 glycoproteins. The consistency with which SHIV infection of cynomolgus monkeys is initiated and the similarities in the neutralizing antibody response to SHIV and HIV-1 support the utility of this model system for the study of HIV-1 prophylaxis.
将含有1型人类免疫缺陷病毒（HIV-1）的tat、rev、env基因，以及某些情况下的vpu基因的嵌合猿猴-人类免疫缺陷病毒（SHIV）接种到8只食蟹猴体内。在至少2个月的时间里，能持续从所有8只动物的CD8细胞耗竭的外周血淋巴细胞中分离出病毒。在此之后，不同动物的病毒分离情况各异，有些动物在接种后600天仍能分离出病毒。Vpu阳性病毒在急性感染期间血浆中的病毒RNA水平以及最初2个月后病毒分离的频率更高。所有动物临床均保持健康，CD4阳性淋巴细胞的绝对数量稳定。在病毒分离最稳定的动物中产生了高滴度的能够中和HIV-1的抗体。最初诱导产生了菌株特异性的HIV-1中和抗体，随后诱导产生了更具广谱中和作用的抗体。对感染一年多后分离出的两种病毒的env序列进行了分析。在病毒载量较低的Vpu阴性SHIV中，观察到少量env变异，这与天然HIV-1变异体中发现的情况不同。相比之下，在从宿主动物中持续分离出的Vpu阳性病毒中，在确定的可变gp120区域观察到包膜糖蛋白有广泛变异。对于具有后一种包膜糖蛋白的病毒，观察到其逃避了CD4结合位点单克隆抗体的中和作用，逃避机制似乎涉及抗体与单体gp120糖蛋白的结合减少。食蟹猴感染SHIV的一致性以及对SHIV和HIV-1的中和抗体反应的相似性，支持了该模型系统在HIV-1预防研究中的实用性。
