Oral pre-exposure prophylaxis by anti-retrovirals raltegravir and maraviroc protects against HIV-1 vaginal transmission in a humanized mouse model.
Oral pre-exposure prophylaxis by anti-retrovirals raltegravir and maraviroc protects against HIV-1 vaginal transmission in a humanized mouse model.
复制标题
DOI：
10.1371/journal.pone.0015257
复制
发表时间：
2010-12-21
期刊：
影响因子：
3.7
通讯作者：
Akkina R
中科院分区：
文献类型：
--
作者：
Neff CP;Ndolo T;Tandon A;Habu Y;Akkina R
通过阴道经性途径传播HIV-1是最主要的病毒传播方式，每年导致数百万新感染。在缺乏有效疫苗的情况下，迫切需要开发暴露前预防(PrEP)的其他替代方法。目前被批准用于临床的许多新药在系统给药时也显示出防止病毒性传播的巨大潜力。一个小动物模型，允许对其全身性PrEP疗效的潜在候选进行快速临床前评估，将极大地促进这一研究领域的进展。我们之前已经证明RAG-HU人源化小鼠模型允许HIV-1通过阴道和直肠途径传播，并表现出与人类典型的CD4T细胞丢失。到目前为止，系统的PrEP研究主要局限于以替诺福韦和恩曲他滨为代表的RT抑制剂。在这些概念验证研究中，我们评估了两类临床批准的新药，它们具有不同的作用模式，即整合酶抑制剂Raltegravir和CCR5抑制剂马拉韦罗，作为潜在的全身化疗预防药物。我们的结果表明，在RAG-HU小鼠模型中，口服这两种药物中的任何一种都能完全保护小鼠免受阴道HIV-1的攻击。基于这些结果，这两种药物都显示出作为口服预备剂的进一步发展的巨大前景。
Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP). Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs.
登录
查看更多内容
影响因子：
3.7
作者：
Abbas, Ume L.;Anderson, Roy M.;Mellors, John W.
通讯作者：
Mellors, John W.
HIV-1 疫苗开发中的挑战。
影响因子：
64.8
作者：
Barouch, Dan H.
通讯作者：
Barouch, Dan H.
影响因子：
--
作者：
An, Dong Sung;Poon, Betty;Uittenbogaart, Christel H.
通讯作者：
Uittenbogaart, Christel H.
影响因子：
30.3
作者：
Legrand N;Ploss A;Balling R;Becker PD;Borsotti C;Brezillon N;Debarry J;de Jong Y;Deng H;Di Santo JP;Eisenbarth S;Eynon E;Flavell RA;Guzman CA;Huntington ND;Kremsdorf D;Manns MP;Manz MG;Mention JJ;Ott M;Rathinam C;Rice CM;Rongvaux A;Stevens S;Spits H;Strick-Marchand H;Takizawa H;van Lent AU;Wang C;Weijer K;Willinger T;Ziegler P
通讯作者：
Ziegler P
影响因子：
3.7
作者：
Berges, Bradford K.;Akkina, Sarah R.;Akkina, Ramesh
通讯作者：
Akkina, Ramesh