HIV-induced immune activation - pathogenesis and clinical relevance. Summary of a workshop organised by the German AIDs Society (DAIG e.v.) and the ICH Hamburg, Hamburg, Germany, November 22, 2008

An d t HE I 0 H HAMb u Rg 0 Ac k g Ro u n d 0 0 H. J. s tellbrink , s . b aldus, g . b ehrens, J. R. b ogner, t . Harrer, c . Hoffmann, J. van l unzen, J. Munch, P. Racz, c . s cheller, M. s toll, k . t enner-Racz, J. Rockstroh t his manuscript is communicated by the g erman AId s s ociety (d AIg ) (www.daignet.de). It summarizes a series of presentations and discussions during a workshop on immune activation due to HIV infection. t he workshop was held on n ovember 22nd 2008 in Hamburg, g ermany. It was organized by the Ic H Hamburg under the auspices of the g erman AId s s ociety (d AIg e.V.). - HIV infection is characterized by progressive c d 4+ t cell depletion and chronic immune activaton, resulting in polyclonal hypergammaglobulinaemia as well as increased turnover and apoptosis rates of t -cells [1-11]. Immune activation per se is a physiological response. t he question has to be raised, however, if the persistence of HIV-induced immune activation over many years actually overstretches regenerative and homeostatic mechanisms, which are driven by increased cell turnover, and thereby leads to immune exhaustion. Highly active antiretroviral therapy (HAARt ) reduces immune activation via a reduction of viral replication. It is as yet unclear, however, if it can be continued safely and effectively for decades in order to achieve a normal life expectancy. f urthermore, some patients retain elevated levels of immune activation despite successful HAARt . A detailed analysis of the mechanisms and its consequences could therefore reveal important novel complementary approaches to HIV therapy, which could help to overcome the limitations of current therapies. IMMu n E Ac t IVAt Io n An d IMMu n E f u n c t Io n (c . s cheller, Wrzburg) t he immune system is based on innate and adaptive immune responses. Innate responses are older in evolution and are characterized both by immune cells such as macrophages and natural killer cells recognizing conserved structures of microorganisms, and the release of cytokines. Adaptive immunity comprises b cell- and t -cell-mediated responses. Approximately 10 12 different binding specificities of cell surface receptors induce activation and differentiation to effector cells following antigen contact. A fraction of effector cells returns to a deactivated, resting memory state within a couple of days, from which they can be awakened very quickly upon reexposure to the same antigen (acquired immunity). t he other activated effector cells then proceed to fulfil their function and undergo apoptosis after 2-3 weeks. Apoptosis is the natural consequence of activation. t he absence of programmed cell death would lead to the accumulation of senescent, non-functional effector cells in the sense of a super-leukemia. - Chronic immune activation Most infectious agents are cleared by the immune system after days to weeks. s ome are not eradicated but controlled to the extent of a latent, clinically stable phase, and immune activation is reduced subsequently. In HIV infection, however, it persists. Recent studies suggest several reasons. c d 4+ t -cells are massively depleted from the gastrointestinal lymphatic tissue (g Al t ) during acute HIV infection, but also in later stages of the infection [12, 13]. t his affects mainly the effector site (lamina propria), less so the inductive site (Peyers plaques) [14]. It is estimated that half of the c d 4+ t cells of the body reside in the g Al t . t hey display the memory phenotype and express c c R5, the dominant coreceptor of HIV in the early phase of infection. t he conditions for the first peak of virus replication are ideal within the gastrointestinal tract. As early as several days following infection, most of the cells are infected and succumb to the early burst of replication, most likely due to the viral cytopathic effect. t his probably leads to an irreversible loss of a large proportion of the memory c d 4+ t -cell pool. s tudies in subjects on antiretroviral therapy show that the number of c d 4+ t -cells in the g Al t does not return to 1. Stellbrink Rev_Umbruchvorlage 20.01.10 14:57 Seite 2 Eu Ro PEAn Jo u Rn Al o f MEd Ic Al REs EARc H normal even after years of successful treatment [15]. t his feature of HIV infection, however, is also observed in non-pathogenic animal models, i.e. monkeys infected by s IV variants that do not cause disease in their natural host [16, 17] such as sooty mangabeys and African green monkeys. s evere gastrointestinal c d 4+ t -cell depletion is subsequently associated with the translocation of microbial antigens from the gut lumen into the host tissue, leading to activation of innate and adaptive immune responses. d epending on the stage of HIV infection, levels of lipopolysaccharides (l Ps ) in the serum are increased, which stem from gram-negative bacteria in the gut [4]. s ooty mangabeys and African green monkeys, however, exhibit no increase of l Ps translocation and immune activation. d uring antiretroviral therapy l Ps levels are reduced, but do not reach the levels of normal controls. Moreover, as a consequence of the development of HIV-specific t -cell responses, stimulation and expansion of c d 4+ t -cells continuously provides new target -cells for HIV replication. t he continuation of this state over many years apparently overstretches the regenerative capacities of the immune system, and AId s develops. - Immune senescence l ike all cells of the body, the immune system underlies ageing. In the process of t -cell receptor rearrangement during t -cell maturation in the thymus, excised t -cell receptor d n A persists in the cells (t -cell-receptor excision circles, or t REc s). As t REc s are not duplicated during mitosis, the content of t REc s in the blood is diluted with ongoing cell proliferation. t hus, t REc content reflects both thymic output and preceding rounds of t -cell proliferation with an accumulation of older t -cells. HIV infection leads to a shift in the average immunological age of peripheral blood t -cells: t REc content is markedly recuced in t cells during HIV infection, as compared with an uninfected person. t elomer shortening during cell division serves as another marker of cell senescence. b oth impaired thymic t -cell generation as well as chronic immune activation resulting in increased numbers of terminally differentiated t -cells probably contribute to this phenomenon and result in severe t -cell lymphopenia in the course of progressive AId s . In addition to immune senescence, HIV infection leads to release of inflammatory and pro-inflammatory cytokines that initiate mechanisms known from physiological ageing, such as osteoporosis, arteriosclerosis, and HIV dementia (inflamaging). t he AId s epidemic is clearly recognized as a viral zoonosis [18]. More than 30 primate species in Africa have been shown to be infected with simian immunodeficiency viruses (s IV). t he causative agent of AId s , HIV-1, arose by tran (...truncated)