Van Rompay K K, Miller M D, Marthas M L, Margot N A, Dailey P J, Canfield D R, Tarara R P, Cherrington J M, Aguirre N L, Bischofberger N, Pedersen N C
California Regional Primate Research Center, University of California, Davis, California 95616, USA.
J Virol. 2000 Feb;74(4):1767-74. doi: 10.1128/jvi.74.4.1767-1774.2000.
Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study pathogenesis and to develop intervention strategies aimed at preventing infection or delaying disease progression. In previous studies, we demonstrated that 9-¿2-(R)-(phosphonomethoxy)propylădenine (PMPA; tenofovir) was highly effective in protecting newborn macaques against infection with virulent wild-type (i.e., drug-susceptible) SIVmac251. In the present study, we determined how reduced drug susceptibility of the virus inoculum affects the chemoprophylactic success. SIVmac055 is a virulent isolate that has a fivefold-reduced in vitro susceptibility to PMPA, associated with a K65R mutation and additional amino acid changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight newborn macaques were inoculated orally with SIVmac055. The three untreated control animals became SIVmac055 infected; these animals had persistently high viremia and developed fatal immunodeficiency within 3 months. Five animals were treated once daily with PMPA (at 30 mg/kg of body weight) for 4 weeks, starting 24 h prior to oral SIVmac055 inoculation. Two of the five PMPA-treated animals had no evidence of infection. The other three PMPA-treated infant macaques became infected but had a delayed viremia, enhanced antiviral antibody responses, and a slower disease course (AIDS in 5 to 15 months). No reversion to wild-type susceptibility or loss of the K65R mutation was detected in virus isolates from any of the PMPA-treated or untreated SIVmac055-infected animals. Several additional amino acid changes developed in RT, but they were not exclusively associated with PMPA therapy. The results of this study suggest that prophylactic administration of PMPA to human newborns and to adults following exposure to human immunodeficiency virus will still be beneficial even in the presence of viral variants with reduced susceptibility to PMPA.
新生猕猴感染猿猴免疫缺陷病毒（SIV）是一种用于研究人类儿童艾滋病发病机制以及制定旨在预防感染或延缓疾病进展的干预策略的有用动物模型。在先前的研究中，我们证明9-[(2)-(R)-(膦酰甲氧基)丙基]腺嘌呤（PMPA；替诺福韦）在保护新生猕猴免受强毒野生型（即对药物敏感的）SIVmac251感染方面非常有效。在本研究中，我们确定病毒接种物的药物敏感性降低如何影响化学预防的效果。SIVmac055是一种强毒株，其对PMPA的体外敏感性降低了五倍，这与逆转录酶（RT）中的K65R突变以及其他氨基酸变化（N69T、R82K、A158S、S211N）有关。八只新生猕猴经口接种SIVmac055。三只未治疗的对照动物感染了SIVmac055；这些动物病毒血症持续居高不下，并在3个月内发展为致命的免疫缺陷。五只动物在经口接种SIVmac055前24小时开始，每天一次用PMPA（30mg/kg体重）治疗4周。五只接受PMPA治疗的动物中有两只没有感染迹象。另外三只接受PMPA治疗的幼猴感染了，但病毒血症出现延迟，抗病毒抗体反应增强，病程较慢（5至15个月出现艾滋病）。在任何接受PMPA治疗或未治疗的SIVmac055感染动物的病毒分离株中均未检测到向野生型敏感性的逆转或K65R突变的丢失。RT中出现了一些额外的氨基酸变化，但它们并非仅与PMPA治疗相关。本研究结果表明，即使存在对PMPA敏感性降低的病毒变体，对人类新生儿和暴露于人类免疫缺陷病毒后的成年人预防性给予PMPA仍然有益。
