Elite controllers (EC) currently represent the only existing model of spontaneous virological remission in people with HIV (PWH) off antiretroviral treatment (ART). Therefore, understanding novel immunological and virological mechanisms that enable these remarkable individuals to achieve spontaneous control of the virus remains essential for developing immunotherapeutic strategies for achieving an HIV cure. This issue brings together a series of outstanding reviews summarizing the main controversies and current advances on the heterogeneity of the EC phenotype. This heterogeneity is central for identifying novel factors associated with permanent spontaneous HIV remission and for understanding how these factors relate to distinct characteristics of the HIV reservoir, which is shaped by innate and adaptive immune responses, partly influenced by host genetic background, and in some cases results in permanent spontaneous HIV control. Most studies of EC were cross-sectional, providing a biased view of the mechanisms underlying this phenomenon. Given the dynamic and heterogeneous nature of the EC phenotype 1, Nicolas Noel and Olivier Lambotte describe how longitudinal studies of EC have been essential in identifying the heterogeneity of this phenotype. These approaches have revealed distinct trajectories within EC, distinguishing between people who eventually lose virological control – the so-called transient controllers – from those who maintain indefinitely spontaneous control over time – referred to as persistent or exceptional controllers. The latter are considered by the authors to be a model of persistent virological remission, or in other words, a potential cure of HIV infection. In contrast, transient controllers, ultimately experience immunological exhaustion that leads to loss of control and disease progression. In this context, the authors discuss the potential role of ART across different controller phenotypes. Furthermore, the authors associate these phenotypes with distinct HIV-reservoir profiles, as demonstrated by seminal studies analyzing HIV-reservoir profile using high-resolution techniques based on massive single-provirus sequencing 2. This is in accordance with the review of the distinct HIV-reservoir landscape in EC, where Moral-Turón et al. linked the heterogeneity of the HIV-reservoir with the phenotypes described above 3. Therefore, on one hand, persistent controllers would have a reservoir characterized by the absence of intact viruses or in those in which there are intact viruses by their integration into heterochromatin regions where replication is not possible. This profile would be compatible with an HIV cure. On the other hand, transient controllers have a high-resolution HIV profile more similar to most of the people on ART, with the virus integrated in euchromatin regions that are permissive to transcription. However, notably, this process is highly dynamic, with some transient controllers losing spontaneous viral control after >30 years of infection 4. These reservoir profiles are the consequence of the sustained immune pressure on the cells that produce infectious viruses, potentially exerted since seroconversion. Several genetic factors that have predisposed the effective immune response, thereby shaping the reservoir toward these favorable configurations, are discussed. Ryan et al. explore both classical genetic determinants associated with HIV nonprogression and spontaneous control, as well as distinct genetic factors identified in African American populations that point to novel mechanisms of viral control 5. In addition, this review describes other unconventional genetic factors, such as transposable elements and epigenetic regulation as emerging mechanisms to consider in the spontaneous HIV control. Genetic determinants appear to facilitate early and sustained immune pressure on the virus since the onset of the infection particularly through cellular immunity. This is the case of T-cell response. The main novel attributes of the HIV-specific T cell response are interestingly discussed by DeLucas et al. who describe the unique characteristics of HIV-specific CD8+ T cells from EC, emphasizing the novel stem-memory-like attributes that facilitate their localization to privilege anatomical sites and promote reservoir elimination. Importantly, some of these attributes have also been associated with HIV remission following therapeutic intervention 6 opening the door to personalize strategies to harness CD8+ T-cell response independently of the genetic background. In this sense, the authors discuss innovative therapies to achieve this goal. The contribution of humoral immunity is addressed by Pons-Grifols et al., who provide a comprehensive review of antibody-mediated mechanisms in spontaneous HIV control. Beyond neutralization, they discuss the immunomodulatory effects of antibodies mediated through Fc receptor engagement, in cooperation with natural killer (NK) cells and macrophages. The polyfunctional antibody responses associated with persistent viral control in cohort studies are examined, as is the potential use of declining antibody levels as a proxy for durable spontaneous remission. Sánchez-Campaña and María José Buzón provides emerging insights of the new attributes found in NK cells, thanks in part to the expression of various receptors compatible with a memory-like function 7, that enhances a potent antibody-dependent cellular cytotoxicity. They also discuss the important role of dendritic cells, which in EC display intrinsic systems for interferon detection and production, as well as metabolic reprogramming, all of which have been linked with long-term spontaneous viral control. While most of these studies and findings have been conducted in peripheral blood, the primary battle against viruses, which in the case of spontaneous control is carried out very efficiently, takes place primarily in tissues, where the major HIV reservoirs reside. In this regard, Mastrangelo et al. focus on novel characteristics of immunological factors present in tissues, demonstrating that many of the immunological mechanisms and features associated with the spontaneous control of HIV differ substantially from what occurs in peripheral blood. They describe tissue-specific cytolytic mechanisms that facilitate immune cell access to anatomical sanctuaries, such as lymphoid follicles, thereby contributing to reservoir reduction. These mechanisms are particularly efficient in EC and are explored in detail in their review. Collectively, this issue highlights EC as a unique and invaluable model of HIV remission, offering insights that can be translated into immunotherapeutic targets. Dissecting the distinguishing immunological and virological features of persistent or exceptional controllers, as opposed to controllers who eventually progress, will be essential for advancing strategies aimed at achieving a cure for HIV. Acknowledgements The author would like to thank to all the authors that have participated in the series of reviews about HIV-1 elite controllers. Financial support and sponsorship This work was supported by the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, FEDER, “a way to make Europe”, research projects PI22/01796 and PI25/00632 to E.R.M.) and Gilead Fellowships (GLD25/00015 to E.R.M.). E.R.M. was granted by the Spanish National Research Council (CSIC). The project that gave rise to these results has received funding from ”la Caixa” Foundation under the grant agreement LCF/PR/HR25/52450063. This work was also supported by Consejería de Salud y Consumo, grant PI-0146-2025 of Junta de Andalucia. Conflicts of interest There are no conflicts of interest. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: ▪ of special interest ▪▪ of outstanding interest
Carles Moreno-Soriano (Mon,) studied this question.