Friday, July 23, 2010

PD-1 Inhibitors, a Curish Therapy Ready for Clinical Trials

PD-1 (Programmed Death-1--very Star Wars) is a T-cell receptor. Technically, it is a signaling receptor that appears not only on T-cells, but on other immune system cells: B cells, natural killer T cells and macrophages.

For this discussion, though, let's focus just on T-cells. PD-1 signals to T-cells not to activate. T-cell activation is when a t-cell recognizes that cells coming at it are from a particular disease and the T-cells then present a custom package of disease-fighting strategies just for that disease. PD-1 signals to T-cells not to do this.

PD-1 seems to be a way to target latent, HIV-infected T-cells so that they can be killed. Dr. Sandrina Da Fonseca from the  Vaccine and Gene Therapy Institute, in Florida, presented test tube data at the International AIDS Society HIV Reservoirs Conference (remember, when you hear the term "HIV reservoirs," it usually means AIDS cure research). The data showed that T cells taken from people with AIDS that had a lot of PD-1 also had a lot of HIV-1 DNA in them and that contributed to bigger viral reservoirs. 

So: Lots of PD-1 in cells = lots of AIDS genetic material = a bigger viral reservoir.

Dr.  Da Fonseca showed that this may be due to the fact that PD-1 allows the HIV DNA in the infected cells to stay in a latent state. If it’s latent virus (not activated, just sitting there), it doesn’t die off and might live for years. Drugs can't reach latent virus, also.

In Dr. Da Fonseca’s experiment, disruption of this PD-1 effect through drugs or antibodies caused viral replication of the provirus (the HIV genetic material that has become integrated inside human T cells). And in this case, viral replication is good—scientists are trying to find and flush out latent, silent HIV virus that remains in viral reservoirs, even in patients with “undetectable” viral load. If cells are replicating, it's detectable to researchers. Also, AIDS drugs can kill replicating virus.

Can we try this In people with AIDS? There is also separate evidence from other studies that shows that PD-1 inhibitors can actually strengthen the immune system. They were originally developed to help revive exhausted T-cells. That would be helpful for people with AIDS.

SO—PD-1 inhibitors, which are already in clinical trials in people for other diseases, might be good things to try with people with AIDS, to see if they activate latent, HIV-infected T-cells—so they can potentially (we hope) die or be killed by regular AIDS drugs. 

Would PD-1 be a total cure? There are both anatomical (brain, genital tract) reservoirs and types of cells that are reservoirs. So whether this would be the end of the line for all HIV viral reservoirs remains to be seen. But it would be good to find out. Soon.

[Thanks to Richard Jeffreys for his thoughts on the types of cells that PD-1 appears on and its role in reviving T-cells.]

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