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 production, 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. Furthermore, 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. Unfortunately, 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 ability to produce cells or a lower rate of destruction is expected in these patients according to the preservation of normal CD4+ cell counts. However, increased rate of production has not been shown so far, and the finding of similar levels of IL-7 between LTNP and progressors suggests that a different CD4+ production is not the explanation for non-progression in LTNP. Likewise, evidence of reduced turnover of cells in LTNP has not been found, and in general LTNPs appear to have an immune system very much like progressors. However, findings of elevated levels of Th17 cells have been reported, suggesting that the immune regulation by pro- and anti-inflammatory cells is different in LTNP compared to progressors. Indeed, it would be interesting to further evaluate immunological parameters, includingTh17 cells, Tregs, and microbial translocation in LTNP, ideally in prospective studies in order to clarify cause and effect. Also, it would be of interest to elucidate immunological parameters in former LTNP who have lost their non-progressor status.
Finally, due to distinct immunologically profiles in LTNP and controllers, we suggest that a clear distinction between patients with and without viral replication is made in future studies in order to improve the possibility to understand the different mechanisms for non-progression in these fascinating patients.