Several years ago scientists discovered a link between T-cell dysfunction and the expression of a receptor named PD-1 on the T-cell surface. The initial discovery related to T cells in
mice that had become functionally compromised due to battling a chronic viral
infection (LCMV); it turned out that these exhausted T cells expressed very high
levels of PD-1. Receptors like PD-1 can essentially be thought of as antennae on the outside of the cell that can interact with, and respond to, specific
signaling molecules in the cell’s environment. Depending on the signal, the
receptor may sink back inside the cell to convey a message to the command
center in the nucleus. This message in turn affects the behavior of the T
cell and may lead to greater or lesser expression of the receptor. The PD-1
receptor can interact with at least two molecules (described as ligands): PD-L1
and PD-L2. Because high levels of PD-1 expression were associated with reduced
T-cell function, researchers studied the effects of administering an antibody
that targets PD-1 and thereby blocks its ability to interact with its ligands.
The results of this experiment drew a lot of attention, because the strategy
successfully rejuvenated the exhausted T cells and improved their ability to
control LCMV replication. Similar laboratory findings were subsequently
reported with T cells targeting cancers, leading to the development of
anti-PD-1 antibodies as cancer therapies (an approach that has begun to show some success in human
trials). PD-1 has also since been found to be highly expressed on exhausted
HIV-specific T cells in humans, and a small study in macaques reported that
PD-1 blockade reduced SIV viral load.
In addition to blocking PD-1, investigators are looking at
the effects of an alternative strategy of targeting the ligand PD-L1. Brent
Palmer and colleagues recently reported the first in vivo results obtained with
this approach using the humanized mouse model of HIV infection. Encouragingly,
the researchers found that blocking PD-L1 led to significant reductions in HIV viral
load and preservation of CD4 T-cells counts without apparent adverse effects. Bristol
Myers-Squibb supplied the anti-PD-L1 antibody for the study; the company is manufacturing it under the name BMS-936559 primarily for clinical trials in people with cancers.
The AIDS Clinical Trials Group (ACTG) currently
has two research protocols in development that plan to investigate an anti-PD1 antibody (MK-3475, made by Merck) and the BMS-936559 anti-PD-L1 antibody in people with HIV infection. The
studies will look at both T-cell function and effects on the latent HIV
reservoir (due to evidence that latently infected CD4 T cells express high
levels of PD-1). Safety will be the primary concern for these trials because PD-1 is
also thought to be important in reducing the function of T cells that might
otherwise be harmful (e.g., T cells capable of reacting with self antigens and
causing autoimmunity).
The Journal of Immunology
January 1, 2013
vol. 190 no. 1 211-219
Brent E. Palmer*, C. Preston Neff†, Jonathan LeCureux†,
Angelica Ehler*, Michelle DSouza*, Leila Remling-Mulder†, Alan J. Korman‡,
Andrew P. Fontenot* and Ramesh Akkina†
*Division of Allergy and Clinical Immunology, University of
Colorado Anschutz Medical Campus, Aurora, CO 80045;
†Department of Microbiology, Immunology and Pathology,
Colorado State University, Fort Collins, CO 80523; and
‡Bristol-Myers Squibb, Biologics Discovery California,
Milpitas, CA 95035
ABSTRACT
The programmed death-1 (PD-1) pathway limits the function of
virus-specific T cells during chronic infection. We previously showed that
blockade of the PD-1 pathway increases HIV-1–associated T cell function in
vitro. However, the effect of PD-1 blockade on HIV-1 disease progression in
vivo has not been examined. As in humans, HIV-1–infected humanized
BALB/c-Rag2−/−γc−/− (Rag-hu) mice express elevated levels of PD-1 on T cells
during chronic infection. To examine the effect of PD-1 blockade on disease
progression, Rag-hu mice with chronic HIV-1 infection were treated with a
blocking mAb directed against programmed cell death-1 ligand-1, the ligand for
PD-1. Programmed cell death-1 ligand-1–treated Rag-hu mice exhibited a
progressive decrease in the HIV-1 plasma viral load, with a 7-fold decrease by
day 7, a 20-fold decrease by day 14, a 178-fold decrease by day 21, and a
269-fold decrease by day 28 postinitiation of treatment. By day 7, 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-d
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
infection. Furthermore, to our knowledge, these data demonstrate for the first
time that blockade of the PD-1 pathway reduces HIV-1 viral loads.
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