Thirty Years with HIV Infection—Nonprogression Is Still Puzzling: Lessons to Be Learned from Controllers and Long-Term Nonprogressors

In the early days of the HIV epidemic, it was observed that a minority of the infected patients did not progress to AIDS or death and maintained stable CD4+ cell counts. As the technique for measuring viral load became available it was evident that some of these nonprogressors in addition to preserved CD4+ cell counts had very low or even undetectable viral replication. They were therefore termed controllers, while those with viral replication were termed long-term nonprogressors (LTNPs). Genetics and virology play a role in nonprogression, but does not provide a full explanation. Therefore, host differences in the immunological response have been proposed. Moreover, the immunological response can be divided into an immune homeostasis resistant to HIV and an immune response leading to viral control. Thus, non-progression in LTNP and controllers may be due to different immunological mechanisms. Understanding the lack of disease progression and the different interactions between HIV and the immune system could ideally teach us how to develop a functional cure for HIV infection. Here we review immunological features of controllers and LTNP, highlighting differences and clinical implications.