Innate immune responses among hiv-1 highly exposed seronegative (hesn) individuals to a liveattenuated influenza vaccine as a model for mucosal viral infection

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.