Hindawi Publishing Corporation AIDS Research and Treatment Volume 2012, Article ID 161584, 14 pages doi:10.1155/2012/161584 Review Article Thirty Years with HIV Infection—Nonprogression Is Still Puzzling: Lessons to Be Learned from Controllers and Long-Term Nonprogressors Julie C. Gaardbo, Hans J. Hartling, Jan Gerstoft, and Susanne D. Nielsen Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark Correspondence should be addressed to Susanne D. Nielsen, sdn@dadlnet.dk Received 16 January 2012; Accepted 22 March 2012 Academic Editor: Jay A. Levy Copyright © 2012 Julie C. Gaardbo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 1. Introduction Prior to the introduction of combination antiretroviral ther- apy (cART) it was observed that a minority of the individuals infected with Human Immunodeﬁciency Virus type 1 (HIV- 1, from now on referred to as HIV) did not progress to Acquired Immunodeﬁciency Syndrome (AIDS) or death. This minority maintained normal CD4+ cell counts in the absence of treatment for several years—in some cases for more than two decades (reviewed in [1]) and therefore the terminology Long-Term Nonprogressors (LTNP) was pro- posed. When the technique for measuring the viral load was introduced it became evident that some of these patients, who did not clinically progress, had low or even nonde- tectable viral replication. This phenomenon leads to the additive deﬁnition of the non progressor-phenotype referred to as controllers due to their ability to control viral replica- tion in the absence of cART. Today, non-progressors are a collective name for controllers and LTNP who are clinically similar. Except for certain demands for the duration of the infection in LTNP, they are only to be diﬀerentiated according to control or not of viral replication, respectively. Understanding the mechanism for the lack of disease pro- gression in controllers and LNTP could ideally teach us how to develop a functional cure for HIV infection, and for this reason these subpopulations of HIV-infected patients have gained immense interest. Non-progressors are described to diﬀer from progressors in genetics, virology, and immunology. Genetically, certain factors seem to predispose to non-progressions. Thus, it has been shown that female gender, the presence of CCR5- delta32 polymorphism, and HLA genes, in particular the HLA B57 allele, are overrepresented among non-progressors ([2–9], reviewed in [10]). Virologically, a number of studies have indeed shown that some non-progressors are infected with less virulent strains of HIV resulting in a more benign infection [11–14]. However, there are now several lines of evidence that the majority of non-progressors are infected