The influence of mucosal inflammation on early events following SIV infection in rhesus macaques

Thesis (Ph.D.)--University of Washington, 2012Mucosal inflammation is associated with increased HIV infection. However, the virological and immunological mechanisms associated with mucosal inflammation are not well understood. The goal of the studies is to determine the impact of mucosal inflammation on virus acquisition and early events following infection using SIV infection of rhesus macaques. We introduced two forms of mucosal inflammation: induced gingival inflammation (chapter 3 and 4) and Haemophilus ducreyi-induced penile inflammation (chapter 5). After successful induction of mucosal inflammation, macaques were non-traumatically exposed to SIV through either the oral or penile route (corresponding to the site of inflammation). The goal of the study is to understand the ability of mucosal inflammation to influence SIV acquisition, virological and immunological changes associated with SIV infection in rhesus macaques. Following SIV challenges, the macaques were monitored for the frequency of SIV infection, number of founder viruses, plasma viral loads, immune changes at mucosal sites and systemic tissues. Although our results showed that overall SIV acquisition rates (through oral or penile challenge) were not significantly affected in the presence of mucosal inflammation (in the form of induced gingivitis or Haemophilus ducreyi related genital inflammation), we observed that mucosal inflammation was associated with an increased number of transmitted founder viruses, indicating that mucosal inflammation can alter host susceptibility to SIV, and by analogy HIV. The influence of mucosal inflammation on SIV pathogenesis in rhesus macaques was assessed. Following oral SIV infection, examination of the level of immune modulators in the oral cavity (gingival crevicular fluid and gingival biopsy) showed an increased production of IFN-alpha;, OAS and CXCL10 in SIV infected macaques with gingival inflammation, compared to SIV infected control macaques during acute infection. In addition, higher levels of plasma IFN-alpha; and IFN-gamma; in the peripheral blood were observed in SIV infected macaques with gingival inflammation during acute infection. Furthermore, these macaques were more likely to have OAS upregulation and myeloperoxidase production in the peripheral lymph nodes. These results indicate that mucosal inflammation can modulate early immunological events following SIV infection. Taken together, these studies demonstrate that mucosal inflammation has influences on not only host susceptibility to SIV but also early immunological changes following SIV infection. The effects between mucosal inflammation and SIV infection have the potential to impact the early stages of the SIV infection with potential implications for treatments or vaccines development