Mucosal immune responses in HIV-1 exposed uninfected individuals

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Medicine

Sammanfattning: The development of HIV vaccines and immunotherapeutics remains hampered by our lack of understanding correlates of immune protection to infection and disease. The major (perhaps only) piece of evidence indicating that long-term, solid resistance to HIV infection is indeed possible comes from HIV exposed yet uninfected individuals (EUI). In these cohorts of commercial sexworkers and discordant couples, frequent exposure to HIV infection occurs without productive infection taking place. These groups have attracted substantial attention since they may provide clues to the immune correlates of HIV protection. Mucosal and systemic HIV-specific. immune responses have been described in some, EUI groups; these include HIV-specific CD4+ and CD8+ T cells and HIV neutralizing IgA antibodies. However, the role of HIV specific IgA antibodies in mucosal protection must be further evaluated, especially in relation to innate immune factors. The potential value of protective mediators, including interferon alpha (IFN?), regulated upon activation, normal T-cell expressed and secreted (RANTES), secretory leukocyte protease inhibitor (SLPI), leukemia inhibitory factor (LIF) and defensins, still remains to be validated. The present thesis aims to evaluate mucosal immune responses in individuals who seem to resist HIV-1-infection despite repeated exposure to the virus. Mucosal and plasma samples were collected from EUI female sex workers (FSWs) from the slum areas Pumwani and Kibera of Nairobi, Kenya and ectocervical biopsies were collected from Nigerian EUI FSWs. HIV-1 positive and healthy low-risk HIV-1 negative individuals were included as controls. The mucosal and plasma samples were quantified for IgA1/IgA2 and innate immune factors. Also, the neutralizing capacity of fractions representing IgA and innate factors was evaluated in classical PBMC neutralization assays and dendritic cell (DC)/PBMC co-cultures. Cervical biopsies were stained for cellular markers, cytokines/chemokines and innate molecules at the single cell level by immunohistochemistry and quantified by computerized in situ imaging. We detected a clear association between HIV neutralizing IgA in the genital tract and subsequent protection against sexual HIV acquisition in a prospective, nested case-control study. Also, we detected an HIV-1 neutralizing activity in mucosal samples of EUI FSWs that was neither due to IgA1 nor correlated with high levels of SLPI. Furthermore, we have shown that mucosal and plasma samples from HIV-1 infected individuals inhibit the transfer of HIV-1 R5 primary isolates from DC to T cells, in contrast, EUI seem to lack this ability. Finally, we have described the expression of a number of innate immune molecules with proposed anti-HIV-1 activity at the single cell level in the cervical tissue of FSWs at risk of HIV-1 infection. We detected a higher expression of IFN? and RANTES in these women as compared to low-risk HIV-1 uninfected controls. The conclusions we draw from our studies are; i) HIV neutralizing IgA in the genital tract may indeed protect individuals from subsequent sexual HIV acquisition, ii) preexisting IFNa and RANTES in cervical mucosa may contribute to protection of sexual HIV transmission in subjects with higher risk-behaviors, iii) due to previous encounter with HIV, mucosal tissues of EUI may contain pre-existing and-carbohydrate antibodies and/or a triggered innate immunity, and iv) EUI may block HIV infection at an earlier phase of viral transmission through the genital mucosa, before DC-T cell interaction. Our studies on the lower female genital tract of groups with different HIV-1 encountering risk behaviors will hopefully elevate our knowledge about potential microbicide targeting sites and have clear implications for HIV vaccine development.

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