Abstract
Gut immune components are severely compromised among persons with AIDS, which allows increased translocation of bacterial lipopolysaccharides (LPS) into the systemic circulation. These microbial LPS are reportedly increased in chronically HIV-infected individuals and findings have correlated convincingly with measures of immune activation. Immune reconstitution inflammatory syndrome (IRIS) is an adverse consequence of the restoration of pathogen-specific immune responses in a subset of HIV-infected subjects with underlying latent infections during the initial months of highly active antiretroviral treatment (HAART). Whether IRIS is the result of a response to a high antigen burden, an excessive response by the recovering immune system, exacerbated production of pro-inflammatory cytokines or a lack of immune regulation due to inability to produce regulatory cytokines remains to be determined. We theorize that those who develop IRIS have a high burden of proinflammatory cytokines produced also in response to systemic bacterial LPS that nonspecifically act on latent mycobacterial antigens. We also hypothesize that subjects that do not develop IRIS could have developed either tolerance (anergy) to persistent LPS/tubercle antigens or could have normal FOXP3+ gene and that those with defective FOXP3+ gene or those with enormous plasma LPS could be vulnerable to IRIS. The measure of microbial LPS, anti-LPS antibodies and nonspecific plasma cytokines in subjects on HAART shall predict the role of these components in IRIS.
Highlights
Immune reconstitution inflammatory syndrome (IRIS): An existing lacuna in HIV immunology? IRIS is an adverse consequence of the restoration of pathogen-specific immune responses in HIV-infected patients during the initial months of highly active antiretroviral treatment (HAART) [1]
advanced clinical HIV disease (AIDS) Research and Therapy 2007, 4:29 http://www.aidsrestherapy.com/content/4/1/29 morbidity associated with HIV/tuberculosis (TB) is more important [1,11] as the crisis seem to be alarming in thirdworld nations, where the proportion of HIV/TB IRIS is reportedly high, ranging from 11% to 43% [12,13,14,15]
In spite of initiation of HAART, some experience a 'discordant response', whereby the HIV-1 RNA plasma level is below the limit of detection but the CD4+ cell count response is blunted. We propose that these individuals with HIV/TB coinfection might not progress to clinical IRIS owing to poor immune reconstitution despite considerable virological recovery
Summary
Immune reconstitution inflammatory syndrome (IRIS): An existing lacuna in HIV immunology? IRIS is an adverse consequence of the restoration of pathogen-specific immune responses in HIV-infected patients during the initial months of highly active antiretroviral treatment (HAART) [1]. Studies performed with human alveolar macrophages exposed to IL-10 in vitro show increased intracellular bacterial replication of Legionella pneumophila, [72] and decreased production of proinflammatory cytokines [73] These suggest that macrophages and monocytes in septic patients may develop a phenotype similar to that observed in endotoxin-tolerance, which could result in an impaired response to lung pathogens. The development of tolerance does not correlate with down-regulation of LPS-binding sites [77], suggesting the possible role of other mechanisms including the disruption of CD14/TLR signaling pathways [78] and the macrophage exposure to http://www.aidsrestherapy.com/content/4/1/29. It is hypothesized that subjects that do not progress to develop IRIS (IRIS tolerant) despite HAART initiation could develop tolerance (anergy) to persistent LPS/tubercle antigens
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