4 not reach statistical signiﬁcance [51]. Likewise, a study of children with LTNP status displayed higher levels of na¨ıve cells compared to progressors and controls [52]. Thymic output is dramatically reduced with age, and the na¨ıve cells are increasingly generated from peripheral proliferation (reviewed in [53]). Proliferation of cells leads to a lower TREC count, and therefore na¨ıve cells in older indi- viduals have lower TREC counts [54, 55]. Thus, the reported loss of the non-progressor status in some individuals may be due to increasing age and thereby decreased thymic output, because the thymus is no longer able to meet the demands of a high production of cells. This is supported by the ﬁndings of an immune system in HIV-infected patients which is comparable to much older healthy individuals [39]. Also, high age is a predictor of poor immune reconstitution after initiation of cART [56]. 4.3. IL7. Production of CD4+cells is inﬂuenced by Inter- leukin 7 (IL-7). IL-7 is crucial in the T-cell homeostasis, and the IL-7 responsiveness is determined largely by the presence or absence of the IL-7 receptor (IL-7R), which is present on most mature T cells [57]. A negative correlation between IL-7 and CD4+ cell count is described. Consequently, HIV- infected progressors have high levels of IL-7 and reduced lev- els of IL-7R compared to healthy controls [58, 59], consistent with the need for increased production of CD4+ cells and a down-regulation of the receptor due to high plasma levels. Thus, controllers would be expected to display a pattern of IL-7/IL-7R closer to healthy controls than to progressors. This is supported by ﬁndings of lower levels of IL7 in controllers compared to controllers who lost their controller status [60] and by ﬁndings of lower levels of IL-7R in progressors compared to non-progressors [47]. In contrast, it would make sense that LTNPs display a pattern of IL-7/IL-7R more like progressors than controllers, because the need for CD4+ cell replenishment would be expected to depend on the level of viral replication—infection and cell—turnover, which is supported by ﬁndings from our own lab (unpub- lished data) These results are compatible with a hypothesis of low viral replication leading to a reduced number of new CD4+ cells becoming infected. Thereby, the level of IL-7 does not increase, and the IL-7R expression stays high. However, further studies are warranted to clarify this. 5. Destruction of Cells 5.1. Immune Activation, Senescence, and Apoptosis. Immune activation (IA) is a necessary and normal acute response upon infection with any pathogen, as an eﬀort to avoid infec- tion. However, in HIV-infected individuals it is well estab- lished that chronic IA is linked to and predictive of disease progression, and IA has an additive or stronger prognostic value than does CD4+ cell count or viral load alone [61– 68]. The inﬂuence of IA on disease progression can be partly explained by elevated levels of senescent and apoptotic cells as a consequence of IA, thereby leading to increased loss of CD4+ cells. Elevated markers of activation are to be found in most cell compartments, but especially expression of the surface AIDS Research and Treatment markers CD38 and HLA-DR on CD8+ cells have proven to be predictive of disease progression [64–68]. Thus, IA is a cen- tral player in disease progression, as illustrated by the devel- opment of pneumocystic pneumonia in rats solely as a con- sequence of IA [69]. In light of this, it is obvious to assume that IA in non-progressors is diﬀerent from progressors and partly explains lack of progression. IA is one of the more well-examined features in non-progressors and has in several studies been found to be lower in EC as well as VC compared to progressors [70–74]. In support of the signiﬁcance of low IA on lack of disease progression a study of EC revealed that the individuals with the highest IA presented with the lowest CD4+ cell counts [73] (Table 2). Also, the natural hosts of simian immunodeﬁciency virus (SIV), sooty mangabeys and African green monkeys, who do not progress despite a high viral load (and thus can be seen as a simian pendant to LTNP), do not show any signs of increased IA or T-cell turnover [75, 76]. IA is inadequately examined in LTNP. One study did not ﬁnd any diﬀerences in IA between EC and LTNP, while they were both diﬀerent from progressors [77], while another study did not ﬁnd any diﬀerences between the three groups [78]. Interestingly, this latter study, one of the only studies to have compared controllers and LTNP, also evaluated the phenotypic and functional properties of CD56/CD16 natural killer (NK) cells, a major component of the innate immune system. Cytolytic activity against autolo- gous CD4+ cells was found to be abrogated after treatment with an antibody to NKp44L, the cellular ligand of the natu- ral cytotoxicity receptor NKp44, which is speciﬁcally induced on CD4+ T cells during HIV-1 infection, in LTNP and HIV progressors. In contrast, in HIV controllers and healthy donors, NKp44L expression on CD4+ cells and autologous NK lysis were both poorly detected [78]. This is strongly sup- portive of LTNP and controllers as being immunologically diﬀerent. Another component of the innate immune system that may be involved in non-progression is the plasmacytoid Dendritic Cells (pDCs). PDCs have been suggested as induc- ers of IA and CD4+ cell apoptosis as they recognize HIV single-stranded RNA (ssRNA) via Toll-like receptors (TLR) resulting in interferon (INF) α production [79–82]. Further- more, polymorphisms in TLR7 and the interferon regulator 7 of INFα may inﬂuence disease progression and the ability of pDCs to produce INFα [83, 84]. In controllers, the number and function of pDCs are reported to be preserved [85]. In addition, pDCs from rhesus macaques produce large amounts of INFα when stimulated with SIV or HIV, while the natural hosts, sooty mangabeys, seem to have lower levels of INFα [86]. Altogether, this suggests pDCs to induce IA, and they may therefore be involved in non-progression of HIV infection. IA is accompanied by apoptosis and immunological senescence, and HIV-infected patients present with elevated levels of both features [87, 88]. Senescent cells in EC and progressors have been examined in a single study, and com- parable levels were found [8]. In contrast, in a study of non- progressors with unknown viral load the level of apoptosis was found to be similar to healthy controls and lower than in progressors [89], and others have reported lower levels