In the present study of chronic infection lasting more than a year, our data showed that there is an initial drop in peripheral blood CD4 T cell counts which occurs around 6 weeks for X4 virus-infected and at 9 weeks for R5 virus-infected animals (Fig

In the present study of chronic infection lasting more than a year, our data showed that there is an initial drop in peripheral blood CD4 T cell counts which occurs around 6 weeks for X4 virus-infected and at 9 weeks for R5 virus-infected animals (Fig. and if the CD4 T cell loss persists throughout the life of the infected humanized mice. In the present study we followed the HIV-1 infected RAG-hu mice to determine the long-term viral persistence and CD4 Picroside III T cell levels. Our results showed that viremia persists life-long lasting for more than a year, and that CD4 T cell levels display a continuous declining trend as seen in the human. These studies provide a chronic HIV-1 infection humanized mouse model that can be used to dissect viral latency, long-term drug evaluation and immune-based therapies. Introduction Since HIV-1 causes disease only in the human, a number of humanized mouse models have been developed through the years to study the viral pathogenesis in human cells in vivo. In this regard, two conventional human-mouse chimeric models, namely the hu-PBL-SCID mouse with transplanted adult human PBLs (Mosier et al., 1988), and the SCID-hu mouse model with transplanted human thymus and liver tissues (McCune et al., 1988) played an important role in HIV-1 pathogenesis studies using a human hemato-lymphoid system. However, despite many notable successes, some limitations exist. They lack multi-lineage human hematopoiesis and a functional human immune system. Also, these models primarily mimic an acute HIV infection with rapid CD4 T cell loss thus restricting pathogenesis studies to a short-term period lasting only a few weeks (Jamieson, Aldrovandi, and Zack, 1996; Mosier, 1996). Improved humanized mouse models have recently been developed that can rectify the above limitations (Manz, 2007; Shultz, Ishikawa, and Greiner, 2007). These new models include the NOD/SCIDc?/? and Rag2?/?c?/? strains reconstituted with human CD34 cells (RAG-hu and hNOG mice). Transplantation of human Picroside III CD34 hematopoietic stem cells into conditioned neonatal mice leads to de novo multi-lineage human hematopoiesis with the production of T cells, B cells and dendritic cells. Furthermore, an improvement of the standard SCID-hu mouse model involved transplantation of thymic and liver tissues Picroside III under the kidney capsule of NOD-SCID mice followed by reconstitution with autologous human CD34 cells (BLT mice) (Melkus et al., 2006). Multilineage hematopoiesis with the generation of HIV-susceptible CD4 T cells, macrophages, monocytes, and dendritic cells in addition to B cells with a capacity for primary human immune responses distinguish these newer humanized mouse models from that of previous conventional models (An et al., 2007; Baenziger et al., 2006; Brainard et al., 2009; Gorantla et al., 2006; Kuruvilla et al., 2007; Melkus et al., 2006; Tonomura et al., 2008; Traggiai et al., 2004; Watanabe et Rabbit polyclonal to ACSS3 al., 2007). A number of groups including ours have demonstrated the utility of these humanized mice as improved models for HIV-1 infection by showing chronic viremia lasting several weeks by both R5 and X4 tropic viral strains, virus replication in a variety of lymphoid and non-lymphoid organs including thymus, lymph nodes, spleen, lung, gut-associated lymphoid tissue, and male and female reproductive tracts. Viral infection leads to gradual CD4 T cell depletion (An et al., 2007; Baenziger et al., 2006; Berges et al., 2008; Berges et al., 2006; Brainard et al., 2009; Choudhary et al., 2009; Denton et al., 2008; Gorantla et al., 2006; Jiang et al., 2008; Kumar et al., 2008; Sun et al., 2007; Van Duyne et al., 2008; Watanabe et al., 2007; Zhang, Kovalev, and Su, 2006). Furthermore, although not robust enough to be protective, humoral and cellular immune responses against HIV-1 could also be seen to some extent (Baenziger et al., 2006; Brainard et al., 2009; Watanabe et al., 2007). Since human cells populate mucosal tissues such as the gut and vaginal tracts in both RAG-hu mice (Berges et al., 2008; Choudhary et al., 2009; Kwant-Mitchell, Ashkar, and Rosenthal, 2009) and BLT mice (Denton et al., 2008; Sun et al., 2007), another innovation with these new humanized mouse models has been the successful mucosal transmission of HIV-1 through both vaginal and rectal routes (Berges et al., 2008; Denton et al., 2008; Sun et al., 2007). In a recent report, RAG-hu mice were also shown to be capable of giving rise to protective human mucosal immune responses when infected by HSV-2 by the vaginal route (Kwant-Mitchell, Ashkar, and Rosenthal, 2009). HIV-1 infection in the human is life-long and the virus.