Ezequiel Ruiz- Mateos1 & Eva Poveda2
1 Institute of Biomedicine of Seville (IBIS), Virgen de Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain.
2 Group of Virology and Pathogenesis, Galicia Sur Health Research Institute (IIS Galicia Sur)-Complexo Hospitalario Universitario de Vigo, Vigo, SERGAS-UVigo, Spain.
There is an extraordinary group (<1%) of people living with the human immunodeficiency virus - HIV (PLWH) who are capable of controlling the virus, that is, the virus cannot be detected in their blood without the need for taking antiretroviral treatment (ART), are the so-called “HIV elite controllers” (EC). Since their discovery, they have aroused great interest, since the knowledge of the mechanisms that have managed to ensure that these people keep the virus at bay can be applicable to other people who are not able to control the virus naturally and to do so they have to do it by receiving specific treatment and on a chronic basis.
Thanks to the study of large groups of these individuals, it is now known that ECs are a heterogeneous group, so that approximately 25% of these people can lose control of the virus so that it can return to be detected in the blood and 40% suffer a significant loss of specific cells of our immune system that are the target of the virus, the CD4+ T lymphocytes (León et al., AIDS 2016). In this way, ECs have been classified into two groups: “transient controllers” (TC), those who reach a point where they lose control of the viral load, and “persistent controllers” (PC), those that maintain control of the viral load indefinitely over time (Pernas et al., J Virol 2018, and Chereau et al., PLoS One 2017). It is essential to be able to differentiate these two groups of people to predict loss of control in TCs through the search for biomarkers that differentiate them from PCs. If we are able to differentiate them, on the one hand, we will be able to design therapies so that the TCs do not lose control of the viral load and on the other hand, we will have a group of people in which we will be able to investigate in more depth the mechanisms by which they persistently maintain the control of the virus, which could be said to be the closest thing to a cure for the infection. But are these people really cured?
In recent years, different markers have been found that can differentiate these two groups of people, such that PCs have high levels of T cell response that specifically recognize and attack HIV (Pernas et al., J Virol 2018). compared to TCs. Furthermore, PCs also present a peculiar proteomic profile associated with lower levels of inflammation compared to TCs (Rodríguez-Gallego et al., J Infect Dis 2019, Poveda et al. J Infect Dis 2023). Additionally, the metabolomic and lipidomic profiles are clearly different between these two groups (Tarancón-Díaz et al., EBioMedicine 2019). However, a finding that clearly caught attention was that in half of the PCs HIV could not be detected in cells and those viruses that could be detected within the same person were very similar, that is, they had very low diversity and viral variability (Pernas et al., J Virol 2018, Canouï et al., Open Forum Infect Dis 2017).
By studying in depth the characteristics of the viruses that remain latent at the cellular level and without spreading, what we call “the viral reservoir”, of three people with this profile using ultrasensitive techniques, it was possible to see that the virus levels were extremely low and that no infectious virus could be produced after very strongly stimulating these cells (Casado et al. Sci Rep 2020). At the same time, new technologies were developed to measure the virus inside cells. These techniques not only provide ultra-sensitive information on the amount of virus, but also allowed us to know the amount of virus that is complete or intact, and that could therefore give rise to a new generation of viruses with the capacity to infect, versus those cells that harbored pieces of virus, not complete and, therefore, could not give rise to infectious viruses. In addition, we could know the sites in the cell's genome where these viral species are integrated or inserted, so that, if a virus is intact or complete and is integrated in an area of the cellular genome, where due to its structure it cannot access to the cellular machinery, what we call “genetic deserts”, these viruses will never be able to copy their genetic material and therefore give rise to new viruses. These new techniques have revealed that ECs have a very small reservoir of complete viruses and that there is also a subgroup of these people whose complete viruses are integrated in areas of genetic deserts, unlike people who only control the virus if they receive treatment. (Jiang et al Nature 2020).
Subsequently, we have been able to make these ultrasensitive determinations in both types of controllers, TCs and PCs, and we have verified that the TCs, despite having a small number of complete viruses compared to people undergoing treatment, have the complete viruses integrated in an area accessible to the cellular machinery to copy and produce new viruses, and that, therefore, eventually, they could generate new viruses and be detected in blood. However, the PCs, in addition to having a lower number of complete viruses, were very similar to each other and integrated into gene deserts (Gasca-Capote et al. CROI 2023).
What do all these findings mean? That, on the one hand, there are PC people who do not have complete viruses, as has been demonstrated in a case of an Argentinian, the “Esperanza patient”, where after analyzing a large number of her cells in blood and tissue, it has been impossible to find complete viruses (Turk et al. Ann Intern Med 2022), or that PC people who have a complete virus, these, were integrated into the gene deserts, where the virus will never be able to replicate.
These fascinating findings strongly indicate that some PCs could be virtually cured of HIV, since either we do not find complete viruses or the one we find, at a very low level, will never replicate. This information opens the door for us to investigate in greater detail the mechanisms that have cornered the virus in this dead end in PC people, in order to find targets on which to develop immunotherapies to ensure that the vast majority of people who living with HIV manage to control the virus to the level that PCs have achieved and, therefore, cure this infection.