3 Progressor Thymic output ↓ Haematopoiesis exhausted IL-7 ↑ IL-7R ↓ Immune activation ↑↑↑ Turnover/apoptosis ↑↑ ↑↑↑Microbial translocation Damaged architecture ↑↑Tregs ↓Th17 Blunted High Table 2: Immunological distinctions between progressors and non-progressors. Controller Thymic output preserved Haematopoiesis preserved IL-7 Normal IL-7R Normal Immune activation ↑ Turnover/apoptosis ↑ Microbial translocation ↑ Preserved architecture ↓Tregs ↑Th17 Strong Low LTNP Thymus output? Haematopoiesis? IL-7 ↑ IL-7R ↓ Immune activation ↑↑ Turnover/apoptosis? ? Microbial translocation ? Tregs ↑Th17 ? ? ? AIDS Research and Treatment Production of T cells IL-7/IL-7R Destruction of T cells Secondary lymphoid tissue Pro- and anti-inﬂammatory cells HIV-speciﬁc immune response Viral reservoir ↑/↓: Indicates slightly, ↑↑/↓↓: moderate, ↑↑↑/↓↓↓: highly diﬀerent from HIV-negative individuals. LTNP: long-term non-progressors, Tregs: regulatory T cells. ?: Indicates unknown. including na¨ıve B cells, seem to be depleted during HIV infection [38]. HIV-associated lymphopenia may therefore be explained by more upstream elements of lymphocyte development than reduced thymic output. Circulating HPCs have been found to decrease with dis- ease progression and to be associated with CD4+ cell count [39], supporting the idea of BM and HPC as being essential in preservation of CD4+ cell count and suggesting preserved haematopoiesis in non-progressors. The haematopoiesis has only been assessed in a single study of elite controllers (Table 2). This study included progressing as well as non- progressing EC. Interestingly, the progressing EC showed signs of exhausted lymphopoiesis compared the non- progressing EC measured as CD34+ cells and lymphoid- HPC [39]. This is supportive of a suﬃcient haematopoiesis as a contributing factor to non-progression in controllers. Also, it indicates that the viral replication itself is not the only reason for disease progression. 4.2. Thymus and Naive Cells. The CD4+ cell count is maintained by proliferation of already existing CD4+ cells or by de novo production in the thymus. Earlier, it was believed that the thymus was only active in childhood and replaced by fatty tissue with increasing age. It is now evident that the thymus can also be active in adulthood, particularly during circumstances with lymphopenia, as is the case with HIV infection [40, 41]. Often thymic function is assessed as T- cell receptor excision circles (TRECs) or as the naive CD4+ cell count. TRECs are stable circular DNA fragments that are excised during the formation of TCR in the maturing T cell in the thymus, and TRECs are not replicated during cell division. Thus, the more immature CD4+ cells the higher the TREC content. A large thymus on CT scans has been associated with a higher CD4+ TREC frequency in HIV- infected patients [42]. Thus, TRECs and naive cells are all reasonable indirect measurements of thymic size and output. HIV leads to a disruption in the number and function of na¨ıve CD4+ cells in blood as well as in lymphoid tissue [43–45]. To our knowledge, no studies of na¨ıve cells have discriminated between controllers and LTNP. In non- progressors, similar and lower numbers of na¨ıve CD4+ cells have been found compared to progressors [8, 46, 47], suggesting that the level of na¨ıve CD4+ cells itself is not associated with non-progression (Table 2). In contrast, increased expression of the na¨ıve marker CCR7, higher levels of central memory cells with preserved ability to secrete interleukin 2 (IL-2), and a much higher thymic output as deﬁned by TRECs in EC compared to progressors have been reported [46, 48], supporting preserved thymic function in non-progressors. The contribution of a well-functioning thymopoiesis to non-progression is further supported by the ﬁndings of strong correlations between TRECs and non- progression in SIV-infected rhesus macaques [49]. Also, normal levels of memory cells and preserved IL-2 secretion capacities have been shown in non-progressing SIV-infected rhesus macaques compared to progressors [50]. For this reason, it seems plausible that the thymic function is better in non-progressors compared to progressors, improving their ability to maintain a normal CD4+ cell count. However, these ﬁndings only explain the preserved CD4+ cell count in non- progressors, not the viral control in controllers. In fact, the high thymic output may indirectly be a consequence of and not a reason for the low viral replication, since lower viral replication does not lead to the exhaustion of lymphopoiesis normally seen in progressors [39]. Thus, it would be of great interest to compare the thymic output in LTNP and progressors since both populations have viral replication. It is tempting to assume that one of the main diﬀerences between these progressors and LTNP is an extraordinary capacity to produce cells. This is supported by ﬁndings of higher levels of na¨ıve cells in a study of slow-compared to fast progressors based on the slope of their CD4+ cell loss, although this did