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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4671-4678.
Prepublished online as a Blood First Edition Paper on February 1, 2007; DOI 10.1182/blood-2006-09-044826.
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CLINICAL TRIALS AND OBSERVATIONS
PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors
Ji-Yuan Zhang1,2,
Zheng Zhang2,
Xicheng Wang3,
Jun-Liang Fu2,
Jinxia Yao2,
Yanmei Jiao3,
Liangen Chen2,
Hui Zhang2,
Jianan Wei4,
Lei Jin2,
Ming Shi2,
George Fu Gao1,
Hao Wu3, and
Fu-Sheng Wang1,2
1 Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China;
2 Research Center of Biological Therapy, Beijing 302 Hospital, Beijing, China;
3 Department of Infectious Diseases, Beijing You-an Hospital Affiliated with Capital University of Medical Science, Beijing, China;
4 HIV/AIDS Research Center, Beijing Guang-An-Men Hospital, Beijing, China
The immunoreceptor PD-1 is significantly up-regulated on exhausted CD8+ T cells during chronic viral infections such as HIV-1. However, it remains unknown whether PD-1 expression on CD8+ T cells differs between typical progressors (TPs) and long-term nonprogressors (LTNPs). In this report, we examined PD-1 expression on HIV-specific CD8+ T cells from 63 adults with chronic HIV infection. We found that LTNPs exhibited functional HIV-specific memory CD8+ T cells with markedly lower PD-1 expression. TPs, 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 up-regulation was also associated with reduced perforin and IFN- production, as well as decreased HIV-specific effector memory CD8+ T-cell proliferation in TPs but not LTNPs. 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 up-regulation mediates HIV-specific CD8+ T-cell exhaustion. Blocking the PD-1/PD-L1 pathway may represent a new therapeutic option for this disease and provide more insight into immune pathogenesis in LTNPs.
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