Toll-like receptors (TLRs) are pattern recognition receptors, expressed by antigen presenting
cells (APCs) that recognize conserved molecular patterns of diverse microorganisms. TLR
triggering activates APCs, leading to expression of innate effector molecules and signals that
initiate adaptive immune responses. Studies have revealed that the use of TLR agonists might
offer novel approaches for the development of therapeutic and prophylactic measures. Two
types of human immunodeficiency virus (HIV) can cause acquired immune deficiency syndrome
(AIDS): HIV-1, which is found worldwide and HIV-2, which is mostly detected in West Africa
and known to be less transmissible and less pathogenic. During HIV infection, the constant
battle between the virus and the immune system because of rapid viral turnover results in
chronic immune activation that is thought to exhaust several compartments of the immune
system. The interactions between HIV and the innate immune system remain, however,
relatively unexplored.
Studies in this thesis show that the replication of both HIV-1 and HIV-2 strains can be
suppressed in vitro by the TLR9 agonist, CpG oligodeoxynucleotide (ODN). Additionally,
conjugation of ODNs with a phosphorothioate backbone to cholera toxin B subunit enhanced
the anti-HIV activity. These results indicate that the use of TLR agonists might have
implications for the development of new HIV intervention strategies. Furthermore, studies on
the impact of HIV on TLR stimuli responsiveness reveal that both advanced HIV-1 and HIV-2
infections were associated with defective IFN-α responses after in vitro TLR9 stimulation. In
addition, defective IL-12 expression after TLR7/8 stimulation was observed in HIV-1-infected
individuals. Moreover, levels of microbial translocation, measured as concentrations of
lipopolysaccharide (LPS) in plasma, were elevated in both HIV-1- and HIV-2-infected
individuals with AIDS. The plasma LPS levels correlated with CD4+ T cell count and viral load,
in addition to TLR responsiveness. These results suggest that alterations in innate immune
responses and microbial translocation are associated with the pathogenesis of both HIV-1 and
HIV-2 infections. Studies on the immunological consequences of treatment interruption- (TI)
associated viremia in HIV-1-infected individuals, showed that circulating dendritic cells were
reduced and that TLR stimuli responsiveness was dysregulated. Moreover, analyses of immune
activation markers showed that the frequency of HLA-DR+ T cells and spontaneously released
IL-12 increased during TI, whereas microbial translocation remained unaffected. Hence, innate
immunity and T cell markers of immune activation are affected during HIV-1 infection even
after short-term viremia, but prolonged viremia appears to be required for the detection of
microbial translocation.
This thesis adds knowledge on the potential use of TLR agonists for the development of novel
approaches to prevent HIV infection, but also emphasizes the need for better understanding of
the role of TLR responsiveness during the pathogenesis of HIV-1 and HIV-2 infections
