Impact of Mucosal Inflammation on Oral Simian Immunodeficiency Virus Transmission

Abstract

dMucosal tissues are the primary route of transmission for most respiratory and sexually transmitted diseases, including human immunodeficiency virus (HIV). There is epidemiological evidence that genital mucosal inflammation leads to enhanced HIV type 1 (HIV-1) transmission. The objective of this study was to assess the influence of periodontal inflammation on oral HIV transmission using a nonhuman primate model of teeth ligature-induced periodontitis. Simian immunodeficiency virus (SIV) was nontraumatically applied to the gingiva after moderate gingivitis was identified through clinical and immunologic analyses (presence of inflammatory cytokines). Overall oral SIV infection rates were similar in the gingivitis-induced and control groups (5 infections following 12 SIV administrations for each), although more macaques were infected with multiple viral variants in the gingivitis group. SIV infection also affected the levels of antiviral and inflammatory cytokines in the gingival crevicular fluid, and a synergistic effect was observed, with alpha interferon and interferon-inducible protein 10 undergoing significant elevations following SIV infection in macaques with gingivitis compared to controls. These increases in antiviral and inflammatory immune modulators in the SIV-infected gingivitis macaques could also be observed in blood plasma, although the effects at both compartments were generally restricted to the acute phase of the infection. In conclusion, while moderate gingivitis was not associated with increased susceptibility to oral SIV infection, it resulted in elevated levels of cytokines in the oral mucosa and plasma of the SIV-infected macaques. These findings suggest a synergy between mucosal inflammation and SIV infection, creating an immune milieu that impacts the early stages of the SIV infection with potential implications for long-term pathogenesis.

The well-tempered SIV infection: Pathogenesis of SIV infection in natural hosts in the wild, with emphasis on virus transmission and early events post-infection that may contribute to protection from disease progression

“…This approximates what was seen in the vaginal transmission studies, with establishment of viral replication at mucosal sites and virus dissemination into the draining lymphatics (Wood et al, 2013). Additionally, a pro-inflammatory response at the mucosa has been reported during oral SIVmac transmission in RMs, which may facilitate target cell recruitment to the site of infection to support early virus replication (Giavedoni et al, 2013). …”

The oral mucosa immune environment and oral transmission of HIV/SIV

“…These investigators identified an increased risk in SHIV infection in treated macaques, which likely resulted in both increased access to underlying target cells, recruitment of additional target cells to the site of inflammation as well as an activation of the target cells themselves (87). In contrast, a study from our laboratory experimentally induced gingival inflammation in adult rhesus macaques that mimicked the mild to moderate gingivitis common in humans (238). This was accomplished by tying silk ligatures around the base of the teeth and softening the macaque’s food with water.…”

“…This treatment induced strong upregulation of multiple inflammatory markers in the oral tissue, including IL6, IL8, and IL18. Macaques were then orally exposed to repeated low dose challenge of SIVmac251 and, surprisingly, the rate of SIV transmission was similar in the gingivitis and control macaque groups, although an increase in the number of viral variants that establish the SIV infection was observed (238). One interesting distinction that may explain the different findings in these two studies is that while gingivitis does result in inflamed mucosa it does not necessarily compromised the mucosal barrier, which likely occurred with acetic acid treatment, potentially explaining the increased susceptibility in the acetic acid treated animals but not in the gingivitis animals.…”

Using nonhuman primates to model HIV transmission

“…Depending on the exact site of viral transmission, there are various barriers to infection and target cell availability. Currently, there are limited NHP models dedicated to oral transmission [49,50]. Additional studies will be needed to expand our understanding of oral transmission.…”