AIDS Research and Treatment of apoptosis in VC compared to progressors [90], both sup- porting the idea of a lower turnover as contributing to non- progression. However, low turnover could also simply reﬂect a lower IA. Contrary, another study found elevated levels of apoptotic cells in non-progressors compared to progressors [91], implying that a high turnover is beneﬁcial. This ﬁnding makes sense, if we assume that activated cells are eliminated by apoptosis. Then an increasing proportion of apoptotic cells eliminate the harmful IA, thereby diminishing disease progression. Either way, evidence is lacking, and whether a high turnover of cells is contributing to non-progression is still to be determined. Thus, it seems reasonable to assume that the level of IA is a determinant for how fast the turnover of T cells is, thereby relating IA to exhaustion (Table 2). Indeed, it has been proposed that IA leads to CD4+ cell depletion because it erodes the na¨ıve T-cell pool [92]. Still, the reason for the strong predictive value of IA in HIV infection is uncertain, but low IA found in controllers suggests that IA forms an important role in lack of progression. 6. Immune Regulation: Pro- and Anti-Inﬂammatory Cells The understanding of the immune system is constantly changing as a consequence of rapidly expanding knowledge. Recently, the discovery of T-cell subsets with pro- and anti- inﬂammatory properties has altered our view on immunol- ogy. Regulatory T cells (Tregs) are anti-inﬂammatory T cells, while Th17 cells have proinﬂammatory properties. Tregs are crucial in sustaining tolerance to self-antigens [93, 94] and suppressing T-cell activation resulting in down-regulation of immune activation, including reduction in anti-tumor immunity, graft rejection, and graft versus host disease ([95], reviewed in [96]). Finally, the role of Tregs in chronic viral infections, including HIV, has gained considerable interest due to their immunosuppressive capabilities. Thus, in theory, Tregs can downregulate the chronic IA seen in HIV infection making Tregs a key element in the understanding of the interaction between the host immune system and HIV (reviewed in [97]). For this reason, Tregs have been suggested as downregulators of the unbeneﬁcial unspeciﬁc IA in HIV-infection, expecting high levels of Tregs as being an advantage. However, levels of Tregs in HIV-infected, untreated, progressing patients have been shown to be elevated compared to healthy controls in a number of studies ([98–100] reviewed in [101]). This suggests that high levels of Tregs are actually harmful, possibly because they downregulate beneﬁcial HIV-speciﬁc responses. In support of this, the level of Tregs in controllers has been reported to be lower compared to progressors, and closer to healthy controls, although conﬂicting results have been reported as well [70, 77, 102–106]. Furthermore, it has been shown that the suppressive activity of Tregs in EC is preserved, while it was found to be disrupted in progressors [105]. Finally, Tregs have been suggested to increase with age (reviewed in [107]), possibly contributing to the reported loss of non-progression in some individuals. All together this is supportive of a signiﬁcant inﬂuence of Tregs on non-progression. 5 However, like most other pieces in the puzzle of under- standing the interaction of HIV and the immune system the Treg element has proven to be more complex than expected. Thus, Tregs are closely related to IL-17-producing Th17 cells. Tregs and Th17 cells share a reciprocal maturation pathway and function together in opposing ways to control the inﬂammatory response upon infection. While Tregs inhibit autoimmunity, Th17 cells have been shown to play a critical role in the induction of autoimmune tissue injury and immune responses [108]. Th17 cells have been shown to be rapidly depleted during acute SIV infection cells, and a disturbed balance of Th17 cells and Tregs has been suggested to be associated with subsequent high IA and disease pro- gression ([109, 110], reviewed in [101, 111]). In controllers, a maintained balance between Tregs and Th17 cells is reported [102] (reviewed in [112]), highlighting the signiﬁcance of a well-regulated balance between Tregs and Th17 cells. Th17 cells and Tregs have primarily been examined in controllers. However, one study of a group of non-progressors, where most participants met the LTNP criteria, have found elevated levels of Th17 cells compared to progressors [113]. Thus, a high level of Th17 cells may contribute to lack of progression in controllers as well as in LTNP. However, HIV leads to redistribution of CD4+ cells between blood and lymphatic tissue (LT). Thus, it has been demonstrated that HIV binds to resting CD4+ cells and upregulates L-selectin causing the cells to home from the blood into lymph nodes (LNs) at enhanced rates [114, 115]. This has led to the homing theory, oﬀering an explanation for the loss of CD4+ cells due to cells leaving the blood and entering the LT (reviewed in [116]). Indeed, accumulation of Tregs has been found in secondary lymphatic tissue (SLT) compared to peripheral blood in untreated HIV-infected patients [117, 118], indicating that the conclusion drawn from the reported ﬁndings of Tregs in peripheral blood is to be considered with caution. 7. Secondary Lymphatic Tissue and Microbial Translocation CD4+ cell depletion occurs in the blood as well as in the SLT of LN and gut-associated lymphatic tissue (GALT) where the majority of the CD4+ cells reside. During primary HIV infection a vast number of cells are depleted, reaching a loss of more than 50% in LN as chronic infection is established [119, 120]. It has been proposed that HIV damages the struc- tures in the LT, that help sustain the normal CD4+ cell popu- lation replacing the functional space with collagen. Thus, the greater the amount of the collagen deposition, the lower the CD4+ cell count and the smaller the number of naive CD4+ cells [121]. Also, LN biopsies from HIV- and SIV-infected individuals show breakdown of the lymph node architecture and evidence of apoptosis [122]. In contrast, a preserved lymph-node architecture was reported in the history of HIV in non-progressors compared to progressors, indicating that progressors host a preserved SLT [123]. GALT is the main defence against infectious microorganisms in the gastroin- testinal (GI) tract and consists largely of T cells. Importantly, the main part of Th17 cells reside in the GALT [124]. Th17 cells are important for the integrity of the gut mucosal