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. IntroductionCD8 ϩ T cells play a critical role in clearing human immunodeficiency virus (HIV) infection in vivo. 1 In general, typical progressors (TPs) have insufficient CD8 ϩ T-cell responses to HIV and fail to maintain durable control of the HIV load, whereas long-term nonprogressors (LTNPs) preferentially maintain functional HIVspecific CD8 ϩ T cells that can persistently control viral replication. [2][3][4][5][6][7][8][9][10] During the CD8 ϩ T-cell response to HIV, there is a complex process of memory CD8 ϩ T-cell differentiation. 11 On the basis of CD45RA and CCR7 surface marker expression and relative function, 4 subpopulations of memory CD8 ϩ T cells are proposed to exist: naive CD45RA ϩ CCR7 ϩ T cells, central memory CD45RA Ϫ CCR7 ϩ T (T CM ) cells, effector memory CD45RA Ϫ CCR7 Ϫ T (T EM ) cells, and terminally differentiated effector CD45RA ϩ CCR7 Ϫ T (T EM RA) cells. [12][13][14][15] The T CM subpopulation readily differentiates into proliferating effector cells and homes to T-cell areas of the secondary lymphoid organs, but it has little or no effector function. The T EM subset has selectively lost constitutive CCR7 expression and produces high levels of perforin, IFN-␥, and IL-4 within hours of antigenic stimulation. The T EM RA subset, the T EM subpopulation that expresses CD45RA, can produce high levels of perforin. Thus, T EM cells are characterized by rapid effector function. Champagne et al 16 have demonstrated that chronic HIV-1 infection affects the differentiation pattern of different CD8 ϩ T-cell subsets; however, the molecular mechanisms of how this process occurs remain undefined.Memory T-cell responses are an important component of protective immunity against viral infection. However, memory T-cell responses generated during chronic viral infection often show defects in antiviral function and skewed differentiation of the memory T-cell subsets. [16][17][18] For example, the proportion ...

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