2 with replicant-competent virus [15–17]. One study has shown that CD4+ cells from controllers are less susceptible to HIV compared to CD4+ cells from progressors and healthy controls [18], while another study showed that CD4+ cells from controllers were as susceptible or even more susceptible to HIV entry and productive infection [19]. Thus, genes and viral factors play a role in non-pro- gression, but these components do not provide a thorough explanation. For this reason the immune system is to be con- sidered a key element in non-progression. This is supported by the recent demonstrations of better control of hepatitis C virus (HCV) in HCV-infected controllers compared to HCV- infected progressors [20, 21]. The immunological response to HIV infection can be divided into (1) an immune home- ostasis resistant to HIV in LTNP and (2) the immune- mediated control of the virus in controllers. However, despite these two possible interactions between HIV and the immune system both resulting in preserved CD4+ cell counts, few studies have compared immune homeostasis in LTNP and controllers. The scope of this paper is to describe immunology in non-progressing HIV infection and to propose involved immunological mechanisms in LTNP and controllers. 2. Deﬁnitions of Nonprogressors It is well-established that LTNP and controllers are diﬀerent subpopulations [22–25], supporting the idea that diﬀerent immunological mechanisms are responsible for the pre- served CD4+ cell counts. LTNP and controllers are described as rare populations comprising few percentages of all HIV- infected individuals, and with little overlap between them [22–27], although the deﬁnition of the populations suﬀers from lack of consensus in terminology and inclusion criteria, impeding the comparison of ﬁndings. Controllers can be further divided into elite controllers (EC) and viremic controllers (VCs), most commonly with HIV RNA <50 copies/mL and 50–2000 copies/mL, respec- tively, although variations with higher levels are found as well ([25], reviewed in[27, 28]). This is in particular a problem because LTNP can thereby be categorized as VC due to their often relatively low viremia. In addition, a central problem in deﬁning the non-progressor phenotype is a complete lack of inclusion of the viral load, thereby including LTNP who fulﬁll controller-criteria with low or undetectable viral loads. Patients need not necessarily be infected for a long period of time in order to be categorized as controllers. Thus, two measurements of a low viral load during one year are some- times used as suﬃcient, whereas others demand duration of infection for several years. In contrast, LTNPs due to the nature of the case deﬁnition have a long duration of infec- tion, most commonly a minimum of 7–10 years. Both groups present with a CD4+ cell count within the normal range (350–1600 cells/μL) [22, 23, 25, 29]. Due to the low preva- lence of these non-progressors, it is tempting to relax the inclusion criteria. However, clinical outcomes seem to improve with the stringency of criteria, and it has been demonstrated that the clinical outcome for patients infected for 7 versus 10 years and with stable CD4+ cell counts AIDS Research and Treatment Table 1: Deﬁnitions of non-progressors. EC VC LTNP CD4+ cell count (cells/μL) >350 >350 >350 Viral load (copies/mL) <50 50–200 >2000 Duration of infection (years) >7 ∗ ∗ cART No No No ∗ Duration of infection is not used in the deﬁnition of controllers in this review. is diﬀerent. Thus, a better survival among LTNP deﬁned by 10 years of stable infection versus 7 years is reported [25], suggesting that even 7 years of stable infection do not distinguish properly between true LTNP and progressors. In this paper, unless anything else mentioned, the term “non-progressors” is used as a collective name for controllers and LTNP, while the term “controllers” is used for VC and EC. The LTNP term is only used when studied patients had substantial viremia above 2000 copies/mL and had been infected for a minimum of 7 years. Although 7 years may not be enough to exclusively distinguish LTNP from progressors, 7 years are chosen as most studies have used this deﬁnition. The duration of infection in controllers is not included in our deﬁnitions as we consider viral control at any time point to be a suﬃcient determinant for controller status (Table 1). 3. Immunology in Non-Progressors The CD4+ cell count in a given patient at any time is the result of production, destruction, and traﬃc between blood and lymphatic tissue, and when the destruction exceeds the production the CD4+ cell count decreases. Thus, LTNP and controllers may have diﬀerences in production, destruction, or distribution of CD4+ cells compared to progressors in order to maintain a normal CD4+ cell count. 4. Production of Cells 4.1. Bone Marrow and Progenitor Cells. T cells mature in the thymus, but they originate from hematopoietic progenitor cells (HPCs) in the bone marrow (BM). Thus, a functional BM is crucial for thymopoiesis. In the hope of developing a cure for HIV infection HPC has been given greater attention, even more so after the report on eradication of HIV by trans- plantation of CCR5-deﬁcient HPC in the so-called Berlin patient [30]. HIV inﬂuences BM and HPC, and impaired hematopoiesis in HIV infection is well documented [31–34]. Furthermore, several studies have shown that some HPCs express the HIV receptors CD4, CXCR4, and CCR5 making them potentially susceptible to HIV infection (reviewed in [35]). HIV infection of HPC has recently been suggested [36], although the complexities of purifying and maintaining HPC in culture make it diﬃcult to determine if these HPCs are actually infected, as signs of infection may be due to contamination with other cell types or maturation of HPC to monocytes during in vitro culture. However, HIV proteins seem suﬃcient to disturb the haematopoiesis [37]. Neverthe- less, in addition to T cells, natural killer cells and B cells,