Inducing strong responses from T helper (TH) cells - long seen as a desirable goal for HIV vaccines - and using multiple antigens can hamper the effectiveness of vaccine candidates for HIV, according to an analysis of macaque experiments and a multicenter, phase 1 trial. The results from both studies highlight how investigators will need to carefully account for the effects of activated TH cells in their efforts to create a workable vaccine for HIV. Many vaccine candidates for HIV aim to induce strong and durable antibody responses, often by stimulating responses from CD4 TH cells. However, recent research has called this assumption into question: some studies indicate HIV-specific CD4 T cells are more easily infected by the virus, and a previous trial showed that a vaccine candidate actually increased the risk of acquiring HIV among some individuals. Venkateswarlu Chamcha and colleagues studied immunization data from four previous studies in macaques and discovered that a vaccine for SIV only granted strong protection to animals that had a lower frequency of vaccine-specific T helper type 1 (TH1) cells. Specifically, they observed that vaccine-induced CD4 T cells migrated to mucosal tissue in the colon and cervix, where they persisted and expressed a higher amount of CCR5, a coreceptor that HIV exploits to enter immune cells. The authors theorize that the stimulated cells could be abrogating vaccine protection by providing new targets for the virus to infect.