Abstract
BackgroundSince there is still no protective HIV vaccine available, better insights into immune mechanism of persons effectively controlling HIV replication in the absence of any therapy should contribute to improve further vaccine designs. However, little is known about the mucosal immune response of this small unique group of patients. Using the SIV-macaque-model for AIDS, we had the rare opportunity to analyze 14 SIV-infected rhesus macaques durably controlling viral replication (controllers). We investigated the virological and immunological profile of blood and three different mucosal tissues and compared their data to those of uninfected and animals progressing to AIDS-like disease (progressors).ResultsLymphocytes from blood, bronchoalveolar lavage (BAL), and duodenal and colonic biopsies were phenotypically characterized by polychromatic flow cytometry. In controllers, we observed higher levels of CD4+, CD4+CCR5+ and Gag-specific CD8+ T-cells as well as lower immune activation in blood and all mucosal sites compared to progressors. However, we could also demonstrate that immunological changes are distinct between these three mucosal sites.Intracellular cytokine staining demonstrated a significantly higher systemic and mucosal CD8+ Gag-specific cellular immune response in controllers than in progressors. Most remarkable was the polyfunctional cytokine profile of CD8+ lymphocytes in BAL of controllers, which significantly dominated over their blood response. The overall suppression of viral replication in the controllers was confirmed by almost no detectable viral RNA in blood and all mucosal tissues investigated.ConclusionA strong and complex virus-specific CD8+ T-cell response in blood and especially in mucosal tissue of SIV-infected macaques was associated with low immune activation and an efficient suppression of viral replication. This likely afforded a repopulation of CD4+ T-cells in different mucosal compartments to almost normal levels. We conclude, that a robust SIV-specific mucosal immune response seems to be essential for establishing and maintaining the controller status and consequently for long-term survival.
Highlights
Since there is still no protective HIV vaccine available, better insights into immune mechanism of persons effectively controlling HIV replication in the absence of any therapy should contribute to improve further vaccine designs
We aimed to investigate if and how the mucosal immune system contributes to the control of viral replication, and we performed detailed analyses of three distinct mucosal sites ex vivo
When analyzing blood and three different mucosal sites from our controllers of Indian origin, we found in blood, bronchoalveolar lavage (BAL), duodenum and colon almost normal CD4+ T-cell levels, which significantly exceed those of progressors
Summary
Since there is still no protective HIV vaccine available, better insights into immune mechanism of persons effectively controlling HIV replication in the absence of any therapy should contribute to improve further vaccine designs. Using the SIV-macaque-model for AIDS, we had the rare opportunity to analyze 14 SIV-infected rhesus macaques durably controlling viral replication (controllers). Since there is currently no protective vaccine available, the understanding of viral-host interactions and immune responses in the small number of HIVinfected individuals demonstrating robust control of. The dramatic loss of CD4+ T-cells in all mucosal tissue is a hallmark of early HIV infection [9,10,11,12], which subsequently leads to several local opportunistic infections and contributes to AIDS [13,14,15]. The experimental infection of rhesus macaques (RM) with simian immunodeficiency virus (SIV) has been intensively utilized as a model to investigate the pathogenesis of human HIV infection. Larger cohorts of such animals have rarely been studied, and in particular their viral kinetics and virus-specific immune responses at different mucosal sites have not yet been comprehensively investigated
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