INFLAMMATION IN HIV-1 INFECTION
HIV infection is characterized by CD4+ T cell immunodeficiency in the context of generalized immune activation and dysregulation with widespread explosive infection and massive depletion of memory CD4+ T cells in acute HIV infection [137-140] and gradual loss of remaining CD4+ T cells due to persistent immune hyperactivation and insufficient regeneration and replenishment of the lost cells in chronic HIV infection [141,142].
The idea that immune activation contributes significantly to HIV pathogenesis emerged only few years after the discovery of HIV. The first evidence came from clinical studies of chronically infected patients, demonstrating that soluble [143,144] and CD8+ T cell [145-148] markers of immune activation were strong independent predictors of disease progression and mortality. Many later studies have supported and extended these findings and also the pre-infection [149] and early p.i. [150] systemic level of immune activation strongly predict HIV disease progression rate. Studies of SIV infection have revealed that immune activation is the principal factor responsible for the immunopathology accompanying pathogenic SIV [151] and HIV infection [142,152,153]. The recent demonstration that induction of immune activation in non-pathogenic SIV infection increases viral replication and CD4+ T cell loss in GALT serves as a proof-of-concept of a causal relationship between immune activation, viral replication and CD4+ T cell depletion in HIV/SIV infection [154].
Thus, the prevailing view today is that - following the first “hit” by HIV - the immunopathologic rather than cytopathic properties of HIV account for the progressive immunodeficiency and ultimate immune collapse.
Although the critical role of immune activation is perceived - the mechanisms by which chronic immune activation translates into profound immunodeficiency and immune collapse are only beginning to emerge.
A prevailing view is that immune hyperactivation, in the context of pathogen (HIV) persistence and immunodeficiency, drives turnover of CD4+ Tem with downstream immune activation and upstream depletion of CD4+ Tcm and naive cells [155,156] ultimately leading to immune exhaustion [152,153] and immune collapse when the frequency of CD4+ Tem in lymphoid and extralymphoid tissues fall below the threshold required for effective resistance against pathogens [142].There is strong evidence that immune activation and high suPAR levels are intimately linked in HIV infection. In chronic antiretroviral-untreated HIV infection, suPAR is consistently positively associated with circulating TNF-α∕sTNFrII [12,93,116] and negatively associated with CD4-count [11,12,14,93,116] - whereas the negative correlation between suPAR and CD4-count is absent in less progressed [15] and HAART-treated HIV infection [93,116,157]. Also, the level of soluble immune activation markers are independent predictors of all circulating suPAR forms in HIV infection [12]. The observation that bulk- suPAR accumulates in ng levels per ml over several days in stimulated and non-stimulated whole-blood cultures [118] - similar in amount to circulating levels and reported release from cultures of mononuclear immune cells [61,70] - emphasizes that blood cells have a high constitutive and induced capacity to release uPAR. The lack of correlations between circulating suPAR forms and blood counts of immune cells in HIV infected patients [12] does not exclude that circulating immune cells contribute to high suPAR levels. In sepsis, the neutrophil count is negatively/not correlated with circulating suPAR [16,20] and in human endotoxemia the increase in circulating suPAR and uPAR-expressing monocytes coincides with low monocyte cell count [23], indicating that immune cell adhesion and/or emigration (and hence disappearance from blood) may enhance uPAR-release in vivo and thereby contribute to high suPAR levels.
This notion is supported by vitro studies in which adherence of PBMC or platelets to ECs enhances uPAR-release from PBMC and/or ECs [61] and co-clustering of TCR and β1 or β2-integrins increases uPAR-expression in T cells and promote their migration [56]. Finally, many pathogenic hallmarks of chronic HIV infection may, through different mechanisms, enhance uPAR-release from tissue/immune cells in vivo and thus contribute to high circulating suPAR levels. HIV itself [107,108], microbial translocation and high endotoxin levels [17,22,23,121], co-infections [13,26-30], bystander activation of immune cells [158] and bystander/antigen- driven extensive differentiation of naive T cells (low uPAR-expression) into effector/memory T cells (high uPAR-expression) [55,56,153], ongoing repopulation of GALT with extensive migration of CD4+ Tem may contribute to enhanced uPAR-release and lymphoid tissue/GALT remodelling and/or collagen deposition [159,160] probably involves enhanced local uPAR-expression and release, as uPAR is highly expressed in tissues undergoing repair and/or extensive remodelling due to the critical involvement of protease activity in this process [7,8,133,134].The potential association between suPAR and several hallmarks of chronic HIV infection, i.e. pathogen/bystander-induced activation, turnover, adhesion and migration of immune cells, EC activation and lymphoid tissue remodelling (and indirectly CD4+ T cell depletion in GALT), may explain both the strong predictive value of suPAR and support the notion that suPAR reflects multiple pathogenic events including HIV replication [35-38].