Furthermore, blockade of the PD-1 pathway increased SIV-specific T cell function, decreased SIV viral loads and opportunistic infections and increased the life span of SIV infected macaques (9). the percentage of CD4+ T cells was statistically higher in the treated compared with the untreated group and this trend was sustained throughout the 28 day treatment period. Moreover, there was a strong inverse correlation between plasma viral load and the percentage of both CD4+ (r= ?0.66; P<0.0001) and CD8+ (r=?0.64; P<0.0001) T cells in the treated mice but not the untreated mice. This study provides proof of concept that humanized mice can be used to examine the effects of immunotherapeutic interventions on HIV-1 contamination. Furthermore, these data demonstrate for the first time that blockade of the PD-1 pathway reduces HIV-1 MF498 viral loads. Introduction Virus-specific T cells are functionally compromised during chronic infections. Although these T cells retain some functional attributes, their ability to proliferate and produce multiple cytokines (1) (2), both of which have been correlated with control of viral replication, are severely affected (3C5). It is now widely accepted that receptor-based inhibitory pathways limit the function of virus-specific T cells during chronic viral contamination. Inhibitory receptors such as PD-1 are expressed at elevated levels on both CD4+ and CD8+ T cells in subjects with chronic HIV-1 contamination and diminished function of these cells may contribute to ineffective control of HIV-1 replication (6C8). Disruption of the PD-1 pathway using monoclonal antibodies (mabs) that block PD-1/PD-L1 interaction increases the proliferative and cytokine producing capacity of HIV-1-specific T cells (6). Furthermore, blockade of the PD-1 pathway increased SIV-specific T cell function, decreased SIV viral loads and opportunistic infections and increased the life span of SIV infected macaques (9). These findings suggest that monoclonal antibodies that block the PD-1 pathway may have therapeutic benefit in HIV-1 infected subjects. However, experimental studies designed to test the MF498 efficacy of PD-1 blocking reagents on HIV-1 disease progression, as defined by persistent HIV-1 viral loads and declining CD4+ T cell count, have been difficult to conduct due to the lack of suitable animal models. In this regard, recent advances in the development of new generation humanized mouse models for HIV-1 contamination now make these studies MF498 possible (10). These new mouse models are constructed by injecting human CD34 hematopoietic stem cells into either Rag2 common gamma chain knockout or NOD scid gamma(NOD.Cg-are continuously generated and infected humanized mice exhibit many of the clinical manifestations such as plasma viremia and decreasing CD4+ T cell counts akin to that seen in HIV-1 infected humans (14, 15). In addition to acute contamination we have shown that Rag-hu mice can also sustain chronic HIV-1 contamination lasting more than a year. HIV can be experimentally transmitted to these mice via multiple routes including natural mucosal Rabbit Polyclonal to IKK-gamma (phospho-Ser376) routes (16, 17). These important attributes of next generation humanized mice have paved the way to dramatically expedite novel immunotherapeutic and immune reconstitution efficacy studies and decreases SIV and LCMV replication evidence that interfering with the PD-1 pathway responsible for T cell exhaustion during chronic HIV-1 contamination reduces viral loads and improves CD4+ T cell levels. The highlight of our present study is that the potential benefits of PD-1 blockade during HIV-1 contamination are tested and verified in a physiologically relevant setting using a next generation humanized mouse model that mimics key aspects of chronic HIV-1 MF498 contamination. Until recently experimental studies centered on immune reconstitution and immuno-augmentation against HIV-1 have only been possible and carried out using non-human primate models infected with related viruses such as SIV/SHIV or in human clinical trials which are often expensive and time consuming. The recent advent of new mouse models that sustain continuous de novo multilineage human hematopoiesis have opened.