Toll-Like Receptor Agonists as Adjuvants for HIV Vaccines

Toll-like receptors (TLRs) are pattern-recognition receptors responsible for detecting invading pathogens. About 13 TLRs are currently known to be expressed (see Table 1). TLR2 detects lipotechoic acid and bacterial lipoproteins, TLR4 recognizes LPS, TLR5, flagellin and TLR3 detects double-stranded RNA. The unmethylated CPG DNA of bacteria and viruses is detected by TLR9. TLR7 recognizes single-stranded RNA of viruses. TLR 11 in mice recognizes profillin from Toxoplasma gondii. Binding to TLRs expressed on dendritic cells (DCs) can trigger adaptive immune responses and DCs thus serve as a bridge between innate and adaptive immunity. In HIV, it has been shown that polymorphism of the TLR9, 4, 7 and 8 plays a role in disease progression and viral load. In addition, several researchers began investigating using TLR agonists as adjuvants for HIV vaccine candidates. TLR3 has shown good results if used with vaccine proteins selectively delivered to DCs by antibodies to DEC-205/CD205, a receptor for antigen presentation. TLR7/8 and TLR9 agonists enhanced immune responses if conjugated to the vaccine protein. A triple combination of TLR2/6, -3, and -9 agonists and IL-15 synergistically up regulated immune responses to vaccine formulated as recombinant MVA viruses expressing SIVmac239 Gag, Pol, Env and Rev, Tat, Nef. These and other studies are just beginning to unravel the potential of TLRs agonists and much more and broader research is needed in order to revitalize the field of HIV vaccines.