Most people infected with HIV are able to mount a considerable immune response against the virus. Yet somehow, HIV eludes detection and eventually begins to kill immune cells. Scientists now have a new clue to how HIV stages its guerrilla warfare: An HIV gene called nef may help lower a molecular flag on infected cells that would normally signal the immune system to destroy them. The finding, reported in tomorrow's issue of Nature, may give researchers a target for designing new therapies.
Most cells infected with viruses or bacteria display small fragments of the microbe on their surfaces. This red flag--usually consisting of peptides bound to a group of molecules called the major histocompatibility complex (MHC)--are recognized and destroyed by immune cells such as cytotoxic T lymphocytes (CTLs). Earlier work has shown that HIV's nef gene influences the virus's ability to destroy the immune system.
To probe nef's effects, a team led by biochemist David Baltimore at the Massachusetts Institute of Technology in Cambridge, Massachusetts, examined how CTLs recognize and kill HIV-infected CD4 T lymphocytes, the virus's primary target. Baltimore's team infected cultured CD4 T lymphocytes with an HIV strain lacking a working nef gene. CTLs, they found, easily destroyed these cells, while other CD4 T lymphocytes infected by HIV with functional nef--which had up to 34 times less MHC on their surface--were much less susceptible to attack. This ability to evade destruction, Baltimore says, shows "that the nef gene plays a more centralized role than previously imagined in HIV's ability to persist in the body."
"The implications are pretty important if it turns out to be a real mechanism" for how HIV thwarts the immune system, says immunologist Quentin Sattentau of the Center for Immunology in Marseilles, France. The Nef protein--or possibly another molecule regulated by Nef--may allow HIV to get a better foothold in the body, Sattentau says, by decreasing MHC levels and thus protecting infected cells long enough for the virus to replicate and infect new cells.
Therapies that block Nef "might then shift the balance in favor of the host's CTLs," the authors say, and therefore improve the prognosis for HIV-infected people. But Baltimore cautions that any therapeutic implications for now are "highly speculative."