Targeting the PD-1 Pathway for HIV Eradication?
The blockade of PD-1/PD-L1 interaction represents a promising therapeutic strategy for reactivation of virus-specific effector T cells to exert pathogen eradication in chronic viral infections like HIV. The first clinical trials are waiting the green light to start.
Programmed Death-1 (PD-1) is a negative regulator of T cell activation and proliferation that mediates suppressive action by binding to its ligands PD-L1 and PD-L2.
T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer.
Over the last few years, it has been established that PD-1 plays an active and reversible role in T cell exhaustion.
Under physiological conditions, PD-1 is induced after T cell activation and serves as an inhibitory feedback to dampen the TCR signalling cascade and prevent excessive T cell activation. PD-1 plays also an important role in the tolerance to self antigens.
Expression of PD-1 ligands is elevated in HIV infection in an effort to reduce ongoing inflammation.
HIV can also directly up-regulate the expression of PD-1 ligands on antigen presenting cells leading to an impairment of these cells’ function and, as a consequence, of HIV specific immune responses.
Increased PD-1 expression has also been correlated with worse immune reconstitution during ART.
PD-1, on the other hand, may also contribute to the maintenance of latent HIV in memory CD4 T cells.
PD-1 expressing memory CD4 cells contain more proviral DNA than PD-1 low cells, and PD-1 blockade triggers HIV expression in CD4 cells in vitro.
Immunotherapy based on the blockade of PD-1/PD-L1 interaction represents a promising therapeutic strategy for reactivation of virus-specific effector T cells to exert pathogen eradication in chronic HIV infection and also further purge the remaining viral reservoir.
The first clinical trial using anti PD-1 antibodies is under approval and ready to start.
This trial will have to answer a couple of questions:
-Is PD-1 blockade safe in HIV-infected patients?
-Does PD-1 blockade enhance HIV specific immune responses?
-Does PD-1 blockade allows a better immune reconstitution than what is obtained with ART alone?
-Does PD-1 blockade decreases residual inflammation found in HIV infection?
-Does PD-1 blockade reduces the level of HIV reservoirs
-Porichis F et al. Role of PD-1 in HIV Pathogenesis and as Target for Therapy. Curr HIV/AIDS Rep 2011; Dec 24. [Epub ahead of print]
-Eichbaum Q. PD-1 signaling in HIV and chronic viral infection potential for therapeutic intervention? Curr Med Chem. 2011; 18(26):3971-80.
- Grabmeier-Pfistershammer K et al. Identification of PD-1 as a unique marker for failing immune reconstitution in HIV-1-infected patients on treatment. J Acquir Immune Defic Syndr. 2011;56(2):118-24.
Key words: PD-1 HIV, PD-1 antibodies HIV