|Home | About | Journals | Submit | Contact Us | Français|
The progressive loss of effector function in the setting of chronic viral infections has been associated with the upregulation of programmed death 1 (PD-1), a negative regulator of activated T cells. In HIV infection, increased levels of PD-1 expression correlate with CD8+ T cell exhaustion, which has been shown in vitro to be reversible with PD-1 blockade. Velu and colleagues recently reported the first in vivo study showing enhancement of a virus-specific immune response through PD-1 blockade using an anti-PD-1 antibody in an SIV-macaque model. Their results show an expansion of virus-specific, polyfunctional CD8+ T cells. Anti-PD1 antagonists show promise as a novel immunotherapy for HIV. However, several issues including development of autoimmunity, regulatory T cells and multiple inhibitory receptors associated with CD8+ T cell exhaustion should first be addressed to help ensure a successful response in chronic HIV infected patients.
The ability of the body to regulate the immune response is essential for the maintenance of self-tolerance. In the setting of chronic infections, this immune regulation function is also able to prevent the deleterious effects of unchecked immune activation caused by the body’s response to the persistent antigen. Our immune system has developed various mechanisms to perform this regulatory role, one of which is through the transmembrane immunoreceptor, PD-1 (programmed death 1).
Ishida et al.  first isolated the PD-1 gene in a T-cell hybridoma and reported that the activation of this gene was probably involved in programmed cell death. Subsequent murine studies revealed expression of PD-1 on the surface of activated T and B lymphocytes and its role in immune regulation by disruption of the gene resulting in autoimmune diseases [2,3,4]. More recently, the progressive loss of T cell effector function in chronic viral infections has been associated with PD-1 upregulation [5,6,7,8]. Indeed, findings from mice infected with a lymphocytic choriomeningitis virus strain causing persistent infection, showed an upregulation of mRNA encoding PD-1, and blocking of PD-1 receptor led to an increase in virus-specific CD8+ T cell proliferation and an increased fraction of cells producing interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα), with and without CD4+ T cell help . Chronic infections such as cytomegalovirus, Hepatitis C virus (HCV) and Hepatitis B virus result in similar inverse correlation between PD-1 expression and virus specific CD8+ T cell response [6,7,8]. Moreover, reversibility of the T cell exhaustion was observed after blocking the PD-1 receptor .
In HIV infection, the level of expression of PD-1 on T cells correlates with decreased HIV-specific T cell function . Moreover, PD-1 expression predicts disease progression in that it positively correlates with increases in HIV-specific CD8+ T cells and plasma viral load, while negatively correlating with CD4+ T cell counts . Similarly, a positive correlation was observed between plasma viremia and PD-1 expression on Gag-specific CD4+ T cells . Furthermore, PD-1 expression positively correlates with the sensitivity of CD8+ T cells to apoptosis . A possible mechanism for the impairment of T cell function is the presence of HIV derived Toll-like receptor 7/8 ligands that induce the upregulation of the PD-1 ligand (PD-L1) on antigen presenting cells . The increased interaction between PD-1 and its ligand in chronic viral infections such as in HIV is believed to be the cause for the functional exhaustion, hence the positive correlation with the viremia (Figure 1A).
PD-1 blockade using PD-1 antibodies led to an increase in HIV specific CD8+ T cell proliferation and cytokine production demonstrating that HIV-induced T cell exhaustion is reversible in vitro  (Figure 1B). Likewise, ART-induced decrease in plasma viremia led to decreased PD-1 expression. In clinical studies, however, the suppression of plasma viremia with effective ART results in limited reactivity to HIV antigens despite decreased PD-1 expression and increased CD4+ T cell reactivity to microbial pathogens [14, 22]. It is postulated that this is due to the decreased antigen stimulation as viremia is suppressed. Immunotherapeutic studies of HIV infection aim to increase this T cell reactivity leading to control of viral replication.
Velu and colleagues in their recent Nature article presented the first in vivo study to show enhancement of a virus-specific immune response through PD-1 blockade using a PD-1 antibody . Nine SIV-infected macaques, 5 in the early phase of infection and 4 in the chronic phase, received an anti-PD-1 antibody while another 5 SIV-infected macaques received an isotype control antibody. Their results showed an expansion of the Gag-CM9 tetramer-specific CD8+ T cells of approximately 2.5 to 11-fold in the treated group. Additionally, an enhancement of Gag-specific CD8+ T cell function was observed after the blockade as measured by the co-expression of IFNγ, interleukin 2 (IL-2), and TNFα. The enhanced immunologic response after anti-PD-1 treatment corresponded with significant reductions in plasma viremia and prolonged survival of the infected macaques. Serum anti-nuclear antibody (ANA) levels were unchanged after treatment suggesting no evidence of autoimmune disease which had been observed in murine studies of PD-1 gene disruption . The antigen-specific T cell proliferation was significantly elevated until about day 45. Similarly, enhancement of HIV-specific CD8+ T cell function peaked at around day 21 and then decreased. These changes reflected a significant reduction in plasma viremia initially, which went back to baseline by day 43 post-treatment. The transient response was associated with a decline in anti-PD-1 antibody between days 14 and 28.
The results of this study of PD-1 blockade in an SIV-macaque model show promise of anti-PD1 antagonists as a novel immunotherapy for HIV. Increasing the immune response to the virus, particularly the Gag-specific polyfunctional CD8+ T cells which are associated with control of viremia , through PD-1 blockade may allow patients to obtain well-spaced intermittent treatment without being on prolonged and continuous antiretroviral regimens. Administration of PD-1 did not result in toxic side effects or symptoms of autoimmunity. This is consistent with the clinical trial by Berger et al.  which showed that administration of 0.2 to 6.0 mg/kg of CT-011 (a humanized IgG1 monoclonal PD-1 antibody) was well tolerated in patients with hematologic malignancies.
Despite the promising results of the study, there are some issues that need to be further investigated. Although there was no significant increase in ANA levels post-administration, it will be important to know whether repeated treatments will increase the likelihood of autoimmune events. Another issue to consider is the effect of the blockade of regulatory T cells (Treg). Francheschini et al.  showed that PD-L1 negatively regulated Tregs in persons chronically infected with HCV. There have been a number of studies showing ability of Tregs to suppress the immune response to HIV [20,21]. We have shown that these cells can inhibit polyfunctionality in Gag-specific CD8+ T cells (Macatangay et al., unpublished results). Blocking PD-1 will not only increase the anti-viral function of the CD8+ T cells but may also enhance the function of the antigen-specific Tregs which may negate the antiviral response. Although this study has suggested that the transient immune response was secondary to declining titers of anti-PD-1 antibody, it is important to look into whether an increase in Treg frequency and function is responsible for this transient response or whether the possible increase was responsible for bystander immunosuppression that prevented autoimmune events from occurring. A third issue to consider is the presence of multiple inhibitory receptors that coregulate CD8+ T cell exhaustion in chronic viral infection as shown by Blackburn et al.  How important are the other inhibitory receptors, such as LAG3 and 2B4, in T cell exhaustion in HIV? Will blockade of PD-1 be enough to reverse the exhaustion or are these other inhibitory receptors playing a significant role that led to the transient immunologic and viral response? Exploring these issues may be necessary to help ensure a successful response of chronic HIV infected patients to anti-PD-1 therapy.