the recently halted HIV type 1 (HIV-1) vaccine STEP trial

the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. The authors propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells. To test this hypothesis, Ad5 and Ad11 antibody titres were measured in 20 healthy volunteers. Dendritic cells (DCs) from these individuals were pulsed with replication defective Ad5 or Ad11 and co-cultured with autologous lymphocytes. Cytokine profiles, proliferative capacity, mucosal migration potential, and susceptibility to HIV infection of the adenovirus-stimulated memory CD4 T cells were measured. Stimulation of T cells from healthy Ad5-seropositive but Ad11-seronegative individuals with Ad5, or serologically distinct Ad11 vectors induced preferential expansion of adenovirus memory CD4 T cells expressing alpha(4)beta(7) integrins and CCR9, indicating a mucosal-homing phenotype. CD4 T-cell proliferation and IFN-gamma production in response to Ad stimulation correlated with Ad5 antibody titres. However, Ad5 serostatus did not correlate with total cytokine production upon challenge with Ad5 or Ad11. Expanded Ad5 and Ad11 memory CD4 T cells showed an increase in CCR5 expression and higher susceptibility to infection by R5 tropic HIV-1. This suggests that adenoviral-based vaccination against HIV-1 in individuals with pre-existing immunity against Ad5 results in preferential expansion of HIV-susceptible activated CD4 T cells that home to mucosal tissues, increases the number of virus targets, and leads to a higher susceptibility to HIV acquisition.

After the STEP vaccine trial was halted in 2007 for futility when the vaccine was declared ineffective, subgroup analyses revealed that people with high levels of antibodies to the vaccine delivery system (Adenovirus serotype 5 or Ad5) were more vulnerable to acquiring HIV infection if they received the vaccine rather than the placebo. This study of their immune responses found that the vaccine vector increased the number of CD4 T cells homing to mucosa to mount defences. Once there, they were sitting ducks for HIV to infect and replicate. Whether adenovirus vectors can be used in HIV vaccine trials remains in dispute and the current HVTN 505 trial is recruiting only individuals with low Ad5 titres to avoid increasing subjects’ susceptibility to HIV.