Studies of innate immune stimulation with CpG in HIV infection

Abstract: Two types of human immunodeficiency virus (HIV) may cause acquired immune deficiency syndrome (AIDS): HIV-1, the most pathogenic virus of the two and found worldwide, and HIV-2, which is mostly detected in West Africa and known to be less transmissible and which demonstrates slower progression towards immunodeficiency. How CD4+ T cells are lost during these two infections is not yet completely clear; however, a constant battle against the rapid viral turnover, resulting in chronic inflammation, is thought to exhaust several compartments of the immune system. The interaction between HIV and innate immunity remains relatively unexplored, although there are indications that innate immunity can affect HIV disease progression. The Toll-like receptors (TLRs) are pattern recognition receptors, expressed on/in antigen presenting cells (APCs) that recognize conserved molecular patterns of diverse microorganisms. Triggering TLRs induces activation of APC, leading to expression of innate effector molecules and signals that initiate adaptive immune responses. Recent research also revealed that the use of TLR agonists might offer novel approaches to the development of therapeutic and prophylactic measures. In this thesis, the influence of HIV infection on the responsiveness of immune cells to TLR9 agonist (unmethylated cystidine-phosphate-guanosine (CpG) oligodeoxynucleotides (ODN)) and TLR7/8 agonist (R-848), was examined. We also investigated whether the innate immune responses mediated by CpG ODN and CpG ODN conjugated to the non-toxic B subunit of cholera toxin (CTB) could suppress HIV replication in vitro. Both advanced HIV-1 and HIV-2 infections were found to result in defective IFN-a responses after TLR9 stimulation with CpG ODN. Moreover, HIV-1-infected individuals displayed defective TLR7/8 responsiveness, as measured by IL-12 secretion after R-848 stimulation. This indicates that, during the immunocompetent phase of the infection, these innate responses may contribute to the control of HIV infection, and the loss of TLR responsiveness during advanced disease phases may contribute to the pathogenesis of HIV and the severity of opportunistic infections. We also demonstrated that CpG ODN could suppress the replication of both HIV-1 and HIV-2 strains. Furthermore, conjugation of ODNs with PS backbone to CTB enhanced the anti-HIV activity. These results may have implications for the development of novel intervention strategies to prevent HIV infection.