In the advance online section of the journal Blood, a group of researchers based in Beijing, China present results confirming that expression of the molecule PD-1 is a useful marker for HIV-specific CD8 T cell exhaustion. The investigators compared expression of the molecule on HIV-specific CD8 T cells from people with progressing infection versus long-term non-progressors and found significant differences between the two groups. Similar to previously reported results, the authors also found that blocking PD-1/PD-L1 interactions in vitro appeared to restore potentially important CD8 T cell functions, such as the ability to proliferate in response to HIV. While the authors note that these findings may have therapeutic implications, there is increasing concern among researchers that non-specific attempts to block PD-1/PD-L1 interactions in vivo could provoke catastrophic autoimmunity. For example, unpublished research from Rafi Ahmed's group has shown that blocking PD-L1 during acute LCMV infection leads to fatal immunopathology in mice. Currently, several groups of researchers are planning to carefully evaluate the effects of anti-PD-1 strategies in animal models, including SIV-infected macaques and HCV-infected chimpanzees. Murine researchers are also investigating the effects of blocking interactions between PD-1 and it's second ligand, PD-L2, which is expressed on a far more limited range of cells than PD-L1 (primarily dendritic cells and macrophages), in the hopes that this approach may offer a safer means to enhance the function of exhausted T cells.
Blood First Edition Paper, prepublished online February 1, 2007; DOI 10.1182/blood-2006-09-044826.
Ji-Yuan Zhang, Zheng Zhang, Xicheng Wang, Jun-Liang Fu, Jinxia Yao, Yanmei Jiao, Liangen Chen, Hui Zhang, Jianan Wei, Lei Jin, Ming Shi, George Fu Gao, Hao Wu, and Fu-Sheng Wang*
Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
Research Center of Biological Therapy, Beijing, China
Department of Infectious Diseases, Beijing You-An Hospital Affiliated to Capital University of Medical Science, Beijing, China
HIV/AIDS Research Center, Beijing Guang-An-Men Hospital, Beijing, China
The immunoreceptor PD-1 is significantly upregulated on exhausted CD8+ T cells during chronic viral infections like HIV-1. However, it remains unknown whether PD-1 expression on CD8+ T cells differs between typical progressors (TP) and long-term non-progressors (LTNP). In this report, we examined PD-1 expression on HIV-specific CD8+ T cells from 63 adults with chronic HIV infection. We found that LTNP exhibited functional HIV-specific memory CD8+ T cells with markedly lower PD-1 expression. TP, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 upregulation was also associated with reduced perforin and IFN-{gamma} production, as well as decreased HIV-specific effector memory CD8+ T-cell proliferation in TP but not LTNP individuals. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8+ T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 upregulation mediates HIV-specific CD8+ T-cell exhaustion. Blocking PD-1/PD-L1 pathway may represent a new therapeutic option for this disease, and provide more insight into immune pathogenesis in LTNP individuals.
Comments