The role of PD-1 in HIV Pathogenesis

When the body is infected with any pathogen, the immune system must respond with just the right amount of force - enough to overcome the invader but not so much as to cause damage. Failure to get this balance right can result either in death through disease or through inflammation and tissue damage. If the immune system manages to keep the invading pathogen in check but fails to clear it from the body, the consequence can be a persistent infection, as seen in infections with hepatitis B and C viruses and with human immunodeficiency virus, HIV-1.
Earlier this year, it was shown that exhausted killer T cells in mice persistently infected with lymphocytic choriomeningitis virus (LCMV) can be characterized by expression of an inhibitory molecule called programmed death-1 (PD-1). This cell-surface molecule is responsible for normal down-regulation of the immune response to virus infection, but in chronic infections, PD-1 expression on T cells seems to signal that the T cells are giving up the fight against the virus. Administration of an antibody which blocks PD-1 allows the exhausted T cells to regain the ability to secrete cytokines, to kill other cells and to proliferate, leading to control of the invading virus.
This week, a new paper has been published which shows that the same mechanism appears to be responsible for loss of immune function in HIV infection (Trautmann L, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006 Aug 20). One of the paradoxes of HIV infection is that the virus causes a massive cellular immune response, but that this fails to clear the virus from the body. early on in the course of HIV infection, as many as one in five circulating killer T cells are responding directly to HIV antigens. Many immunologists believe that virus-specific killer T cells are a key component of immunity to HIV-1, particularly in the early stages of infection. So where does the body go wrong with HIV infections? Well, if the new data published this week are confirmed, blocking PD-1 with antibodies might allow the immune system to continue fighting the virus, and possibly even win by eventually clearing the infection completely, so preventing the development of AIDS.