AIDS Research and Treatment 9. Eradication, Latency, and Reservoirs Despite eﬀective cART complete eradication of HIV seems unlikely, and complete eradication of HIV is so far only obtained once in the Berlin-patient [30]. In general, low- level HIV replication continues despite cART. This is in part due to the capability of HIV to conceal itself and persist in cellular reservoirs. Furthermore, a major impediment to the eradication of HIV is latently infected resting CD4+ cells that are characterized by proviral DNA integration into the host genome; particulary memory CD4+ cells have proven to be a major cellular reservoir for HIV [151]. The major anatomical site for HIV reservoir is SLT including GALT [152–154]. Thus, viral reservoirs are considered a major obstacle to eradicate HIV and considered to be the reason for rebound viraemia during cART interruptions. Notably, the concept of a functional cure has emerged where lifelong control of viral replication is obtained and disease progression is avoided although provirus is detectable. This might be illustrated by the viral control found EC. Few studies have examined the capability of non pro- gressors to eradicate or reduce HIV reservoirs and latency. However, low proviral DNA in PBMC in EC compared to patients on cART has been demonstrated [155, 156]. One study even reported diﬀerences in the level of proviral loads in EC compared to VC, implying that even low viral repli- cation is of importance [17]. Furthermore, autologous viral replication ex vivo was detected in only 2 out of 14 EC com- pared to 9 out of 10 VCs, suggesting ECs to have a diminished viral reservoir in peripheral CD4+ cell compartment [17]. Furthermore, impaired viral replication in the early phase of HIV seems to be predictive for VC [157]. The anatomical reservoir in GALT has been examined in a small study revealing lower levels of HIV DNA in rectal tissue in LTNP compared to progressors [158]. However, an SIV macaque model demonstrated that colon mucosa and associated lymph nodes are a major SIV reservoir even in controllers [159]. Conclusively, non-progressors and especially EC seem to have diminished cellular reservoirs, whereas the size of the anatomical viral reservoirs in SLT is uncertain. However, the described traﬃc of CD4+ cells between plasma and SLT and the reduced microbial translocation indicate that non- progressors harbor a lower viral reservoir in SLT than do progressors. Understanding how ECs control and reduce cellular reservoir might provide the basis to elucidate the needs for a functional cure. 10. Clinical Implications A common feature in non-progressors is preserved immu- nology. However, reports of loss of the non-progressor status with declining CD4+ cell counts in LTNP have been observed, and these patients may eventually require cART. Likewise, a loss of viral control in controllers is reported. Interestingly, progression and AIDS events in controllers despite low or undetectable viral loads events are reported as well [2, 8, 22, 29, 39, 48, 73, 160]. As a result of this, cART has been suggested to controllers. 7 In EC viral replication cannot be measured in com- mercial assays in EC. However, using ultrasensitive assays HIV RNA can be detected in the majority of these patients [161, 162], and it has been shown that loss of CD4+ cells is more common among ECs with low level viremia [162]. Furthermore, low-level viremia is reported to be associated with measurable T cell dysfunction in EC [163]. Finally, is has been shown that blips are associated with a nonfavourable clinical outcome [26]. Taken together, this indicates that even very low levels of viremia have clinical implications and are involved in disease progression. This is supported by ﬁndings of higher levels of immune activation in controllers compared to patients on cART [73, 164]. Moreover, it seems plausible that cART would normalize immunological parameters in controllers. This is conﬁrmed by ﬁndings of declining immune activation in EC and increasing CD4+ cell counts in EC as well as EC as due to cART initiation [165, 166]. Thus, cART may be considered in progressing controllers despite undetectable viral replication. 11. Conclusion and Future Directions Rare groups of HIV-infected patients that do not progress to AIDS or death have been known since the beginning of the HIV epidemic. Some of these non-progressors control viral replication, that is, the controllers, while LTNP, have ongoing viral replication. So far, it is not clear why these patients do not progress, but immunological mechanisms have been suggested. The immunological response to HIV infection can be divided into an immune homeostasis resistant to HIV and an immune response leading to viral control. This paper has focused on immunology in non-progressors. We suggest that two diﬀerent mechanisms are responsible for preserved CD4+ cell counts in controllers and LTNP. In summary, data unambiguously show that controllers are immunologically diﬀerent from progressors in produc- tion, destruction, and regulation of cells. Thus, controllers have a preserved CD4+ cell production with a bone marrow function, a lymphopoiesis, a thymic output, and an IL- 7/IL7-R balance resembling HIV-negative individuals. Fur- thermore, controllers have lower destruction of CD4+ cells as evidenced by lower microbial translocation, immune activation, and apoptosis. Likewise, the balance between Tregs and Th17 cells is less disturbed and HIV reservoirs seem to be lower compared to progressors. However, non- progression and preserved CD4+ cells counts in controllers may not be entirely surprising since they are characterized by viral control and thus to be compared with HIV-infected patients on treatment. Thus, preserved immune homeostasis may be a reﬂection of rather than a reason for the viral control. In contrast, high level of HIV-speciﬁc immune response in controllers is probably a contributing factor to non-progression in controllers. The really intriguing question is how non-progression occurs in LTNP where continuous viral replication is evident and ought to result in destruction of CD4+ cells. Unfor- tunately, the literature of LTNP is limited, often because they are included in study populations of controllers as viral load is not included in the deﬁnitions. An extraordinary