page 2717. Their results may help explain the failure of a recent HIV vaccine trial.
The HIV-1 vaccine used in Merck's STEP trial relied on a weakened form of a common cold virus, Adenovirus 5 (Ad5), to carry bits of HIV into the body. One worry about the Ad5 vector was that widespread immunity to adenoviruses might cause the vaccine to be ousted before an anti-HIV response could develop. Instead, there was a chance that vaccine recipients who had circulating antibodies against Ad5 were contracting the virus more often, one factor that forced termination of the trial.
Perreau et al. now show that HIV spread through T cell–dendritic cell (DC) co-cultures three times as fast when Ad5 and neutralizing antiserum—present in people with prior immunity—was added to the cultures. Ad5-antibody complexes triggered DC maturation in the presence of Fcγ receptors (FcγR) and Toll-like receptor (TLR)−9. The authors suspect that FcγR facilitated the uptake of Ad5-antibody complexes into the cell, where viral components could then activate TLR9 to trigger DC maturation and activation.
The mature DCs activated both CD4+ and CD8+ T cells, which may have assisted HIV infection in two ways. Activated CD4+ cells could provide HIV with more cells to infect. And activated Ad5-specific CD8+ T cells could attack infected DCs, thereby reducing the pool of DCs presenting HIV antigens. Indeed, weaker HIV-specific CD8 responses were seen in Ad5-seropositive individuals in response to vaccination.
Merck's vaccine may have made it to phase 2 trials because nonhuman primates don't naturally come in contact with human adenoviruses, and therefore the potential problem went unrecognized. AM