| dc.description.abstract | It is now well established that Toll-like receptors (TLRs) are a key component of the
innate immune system which constitute a first line of host defense against invading
microorganisms. This response occurs within minutes or hours of pathogen entry or
vaccination which then initiates a cascade of events that elicit rapid acting defence
mechanisms and hence regulate the adaptive arm of immunity. It thus points to the
importance of not only understanding the early events in human immunodeficiency virus
(HIV) infection but also how natural immunity limits the early events in HIV-1 infection.
Especially why some individuals who are highly exposed to HIV remain uninfected after
repeated exposure. Since the initial site of exposure to HIV-1 during heterosexual
transmission occurs in the genital tract, also mucosal immune system is equipped with
unique innate defense mechanisms which provide a first line of protection against
invading pathogens
To better understand the correlates of mucosal protection against HIV, a viral challenge
system to model the virus was used. The model consists of a live attenuated influenza
vaccine administered intranasally to stimulate the mucosal system. In order to determine
how the immune system responds to a mucosal infectious insult and what role the innate
immune system plays in the development of these responses. The study participants were
two groups of HIV exposed uninfected women: Long term HIV exposed, seronegative
(HESN) or the (HIV resistant or HIV-R) and short term HIV exposed but uninfected,
susceptible individuals (HIV-S). In this study plasma, peripheral blood mononuclear cells
(PBMCs) and cervico-vaginal lavage (CVL) samples were collected from study
participants prior to and following vaccination at baseline (day 0) and day 1, 7 and 30
TLR7/8 (ssRNA40) or Brisbane Influenza virus strain. TLRs 3, 7, 8, 9 have been
implicated in viral defense. Cytokine and chemokine production in supernatants from
stimulated cells was measured using the multiplex assay on Luminex while in plasma and
CVL they were quantified using Cytometric bead array (CBA) kit by flow cytometry
(LSR II). Following stimulation with TLR 3, 4 ligands, comparison of the two groups
showed that HIV-R had significantly higher IL-6 levels at baseline compared to HIV-S
(p=0.0317). Also, significant higher levels of IL-2 in HIV-R at baseline (p=0.0317) and
30 days after vaccination (p=0.0079), as well as high Interferon-γ (IFN-γ) responses at
baseline (p=0.0079) and 7 days after vaccination (p=0.0317). Stimulation of PBMCs with
TLR 7, 8, 9 ligands also led to a significant increase in IL-2 production at baseline in
HIV-R as compared with HIV-S women (p=0.0159), a decrease of IL-2 was observed
after vaccination in both HIV-R and HIV-S. PBMCs stimulation with TLR 7, 8, 9 ligands
led to a significant increase in the chemokine IFN-γ -induced Protein-10 (IP-10) 7 days
after vaccination (p=0.00952) and 30 days after vaccination (p=0.0317) in HIV-R as
compared to HIV-S. The data obtained from this study suggests that stimulation of
PBMCS with TLR ligands in HIV-R individuals resulted in a more robust release of
immunologic factors which can influence the induction of stronger adaptive antiviral
immune responses. This may represent a virus-exposure–induced innate immune
protective response against HIV-1 infection. Therefore, a greater understanding of th
facilitate the development of new mucosal vaccines or prophylactic agents to prevent and
control infectious diseases. | en |
