Back in January, the blog covered a Nature paper from Rafi Ahmed's group regarding the receptor PD-1. The paper showed that expression of PD-1 by CD8 T cells is associated with a loss of function that immunologists call "exhaustion." Importantly, the paper also showed that - in a mouse model of infection with the virus LCMV - the function of virus-specific CD8 T cells could be restored (and, consequently, LCMV viral load reduced) by using an antibody to block interactions between PD-1 and its ligand PD-L1. The authors suggested that these findings may have implications for chronic viral infections in humans where the virus-specific T cell response shows signs of exhaustion, such as HIV and hepatitis C.
Now, two newly published papers report on the expression of PD-1 on the CD8 T cells of individuals with HIV infection. Both studies report similar results: In untreated HIV infection, levels of PD-1 were significantly higher on CD8 T cells compared to uninfected individuals. PD-1 expression also correlated with other surrogate markers of disease progression; there was an inverse correlation with CD4 T cell counts and a positive correlation with HIV viral load levels. PD-1 expression was analyzed just on HIV-specific CD8 T cells, and the same correlations emerged. PD-1 expression was also significantly higher on HIV-specific CD8 T cells compared to those specific for CMV (and, in most cases, EBV) in the same individuals. One paper also looked at expression of PD-1 on HIV-specific CD4 T cells and found a similar picture to that seen for CD8 T cells, including the significant correlations with CD4 T cell counts and viral load.
Both research groups also looked at the effects on HIV-specific T cells of blocking PD-1/PD-L1 interactions with a specific antibody in vitro (in a lab dish). They found that the antibody enhanced production of cytokines and also increased the ability of HIV-specific T cells (both CD4 and CD8) to proliferate (copy themselves) in response to stimulation with HIV antigens. It's important to stress that a variety of in vitro interventions have previously been shown to affect HIV-specific T cell function to some degree; the cytokine IL-12, for example. Blocking PD-1, however, appears to exert more dramatic restorative effects.
While these results (and those of the previous mouse studies with LCMV) suggest that blocking PD-1 may have therapeutic potential, it is also possible that it could cause immunological problems such as autoimmune disease (if blocking PD-1 "switched on" T cells specific for body tissues, for example). Additional studies will be required to explore these issues. There is already a company called Medarex that is making an anti-PD-1 antibody (dubbed MDX-1106) for human trials, they recently announced that the FDA had granted permission for a phase I trial in people with refractory cancers. The safety of the approach will need to be carefully evaluated, particularly given the recent shocking outcome of a trial that was also looking at an antibody targeting an immunological receptor (TGN1412 which targeted CD28).
A number of news stories about these PD-1 studies were published today, see MedPage Today, New Scientist, Xinhua and the Kaiser Daily News Report. A Wall Street Journal article by Mark Schoofs appears to give the most detailed accounting of the findings but requires a subscription, however it is likely to appear soon in the Wall Street Journal section of AEGIS. Howard Hughes Medical Institute also issued a press release, as did the University of Montreal (whose press office unfortunately got a bit carried away, entitling the release: Montreal researchers make a major strategic breakthrough in controling the AIDS virus - a little premature, to say the least). CBS has also just joined the fray, leaping toward hyperbole with only the strategic use of a question mark to cushion the fall: AIDS Epidemic Mystery Solved? A number of the stories make it sound like the overexpression of PD-1 is some neat trick accomplished by HIV; it's perhaps worth remembering that, at least so far, the data are suggesting that this is a hallmark of T cell exhaustion.
Study links & abstracts:
Nature advance online publication 20 August 2006 | doi:10.1038/nature05115
Cheryl L. Day, Daniel E. Kaufmann, Photini Kiepiela, Julia A. Brown, Eshia S. Moodley, Sharon Reddy, Elizabeth W. Mackey, Joseph D. Miller, Alasdair J. Leslie, Chantal DePierres, Zenele Mncube, Jaikumar Duraiswamy, Baogong Zhu, Quentin Eichbaum, Marcus Altfeld, E. John Wherry, Hoosen M. Coovadia, Philip J. R. Goulder, Paul Klenerman, Rafi Ahmed, Gordon J. Freeman & Bruce D. Walker
Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.
Nature Medicine Published online: 20 August 2006 | doi:10.1038/nm1482
Lydie Trautmann, Loury Janbazian, Nicolas Chomont, Elias A Said, Sylvain Gimmig, Benoit Bessette, Mohamed-Rachid Boulassel, Eric Delwart, Homero Sepulveda, Robert S Balderas, Jean-Pierre Routy, Elias K Haddad & Rafick-Pierre Sekaly
The engagement of programmed death 1 (PD-1) to its ligands, PD-L1 and PD-L2, inhibits proliferation and cytokine production mediated by antibodies to CD3. Blocking the PD-1–PD-L1 pathway in mice chronically infected with lymphocytic choriomeningitis virus restores the capacity of exhausted CD8+ T cells to undergo proliferation, cytokine production and cytotoxic activity and, consequently, results in reduced viral load. During chronic HIV infection, HIV-specific CD8+ T cells are functionally impaired, showing a reduced capacity to produce cytokines and effector molecules as well as an impaired capacity to proliferate. Here, we found that PD-1 was upregulated on HIV-specific CD8+ T cells; PD-1 expression levels were significantly correlated both with viral load and with the reduced capacity for cytokine production and proliferation of HIV-specific CD8+ T cells. Notably, cytomegalovirus (CMV)-specific CD8+ T cells from the same donors did not upregulate PD-1 and maintained the production of high levels of cytokines. Blocking PD-1 engagement to its ligand (PD-L1) enhanced the capacity of HIV-specific CD8+ T cells to survive and proliferate and led to an increased production of cytokines and cytotoxic molecules in response to cognate antigen. The accumulation of HIV-specific dysfunctional CD8+ T cells in the infected host could prevent the renewal of a functionally competent HIV-specific CD8+ repertoire.