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.
