Prophylactic and therapeutic benefits of short-term 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques following oral inoculation with simian immunodeficiency virus with reduced susceptibility to PMPA
Prophylactic and therapeutic benefits of short-term 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques following oral inoculation with simian immunodeficiency virus with reduced susceptibility to PMPA
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DOI：
10.1128/jvi.74.4.1767-1774.2000
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发表时间：
2000-02-01
影响因子：
5.4
通讯作者：
Pedersen, NC
中科院分区：
文献类型：
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作者：
Van Rompay, KKA;Miller, MD;Pedersen, NC
猴免疫缺陷病毒（SIV）感染的新生猕猴是一个有用的动物模型，人类儿科艾滋病的发病机制和发展干预策略，旨在防止感染或延缓疾病的进展。在先前的研究中，我们证明了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毒性野生型（即，药物敏感）SIVmac 251。在本研究中，我们确定了病毒接种物的药物敏感性降低如何影响化学预防的成功。SIVmac 055是一种毒性分离株，其对PMPA的体外敏感性降低了5倍，与逆转录酶（RT）中的K65 R突变和额外的氨基酸变化（N69 T，R82 K，A158 S，S211 N）相关。8只新生猕猴经口接种SIVmac 055。三只未处理的对照动物被SIVmac 055感染;这些动物具有持续的高病毒血症，并在3个月内发展出致命的免疫缺陷。从口服SIVmac 055接种前24小时开始，每天一次用PMPA（30 mg/kg体重）处理5只动物4周。5只PMPA处理的动物中有2只没有感染迹象。另外三只PMPA处理的幼年猕猴感染了艾滋病，但出现了延迟的病毒血症，增强了抗病毒抗体反应，并且病程较慢（艾滋病在5至15个月内发生）。在来自任何PMPA处理或未处理的SIVmac 055感染动物的病毒分离物中未检测到回复到野生型易感性或K65 R突变的丢失。RT中出现了几个额外的氨基酸变化，但它们并不完全与PMPA治疗相关。这项研究的结果表明，预防性管理PMPA的人类新生儿和成人暴露于人类免疫缺陷病毒后，仍然是有益的，即使在病毒变异体的存在下，降低易感性PMPA。
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)propyl] adenine (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.