• The study, published in the journal Med (Cell Press), sheds light on the protective mechanisms of HIV patients who, despite not receiving antiretroviral treatment, are not affected by the disease's infections.
• The researchers discovered that these patients have the genetic mutation CCR5Δ32 and an uncommon immune response, characterised by lower immune system activation and reduced levels of markers associated with intestinal mucosa alterations.
• The pioneering research has been made possible through the application of the most advanced technologies from CNAG, which have conducted single-cell analysis and characterisation of the immune cells.
• The study opens new opportunities for the development of innovative therapies that could benefit people with HIV who, despite being on antiretroviral treatment, are unable to combat infections.

October, 2024. In the medical field, they are known as viremic non-progressors (VNPs). These are people with HIV who, despite not receiving antiretroviral treatment, do not experience disease progression. Among all people with HIV worldwide, this subgroup represents a tiny fraction—just 0.1%. Until now, the scientific community has known very little about this subgroup, primarily that they maintain stable levels of CD4+ T lymphocytes, a type of immune cell that helps activate other cells to defend the body and is essential in fighting infections such as HIV. Delving deeper into the immune profile of this subgroup, who are unaffected by HIV, is key to enhancing future treatments for the disease. With this goal in mind, a group of researchers from IrsiCaixa and the Centro Nacional de Análisis Genómico (CNAG) has just presented a study on the unique immune profile of VNPs, published in the Journal Med by Cell Press.

The research, in which participates the Wistar Institute of Philadelphia, compared various viral, genetic, and metabolic factors of 16 VNPs with those of 29 people with HIV who exhibit standard progression of the viral infection. Thanks to this multidisciplinary approach and the application of state-of-the-art genomic tecnologies, researchers have defined a unique immune profile in VNP patients, characterised by the presence of crucial immune protection mechanisms. These findings represent a significant advancement in the design of new therapeutic interventions for other patients who do experience HIV disease progression.

According to one of the authors of the research and our Single Cell Genomics Group Leader, Holger Heyn: "We are pleased that our high-resolution single-cell profiling has helped uncover the unique immune mechanisms of viremic non-progressors. By revealing distinct cellular compositions and protective immune traits, this study opens new possibilities for innovative therapies that could benefit broader patient populations resistant to standard treatments”.

Immune cell dynamics in HIV patients, key to this pionnering research

One of the main advancements of this research has been the study of immune cells in the blood of both types of HIV patients, including those who show resistance to disease progression and those who do not. After recreating the cellular atlas of both groups and annotating and characterising all their immune cells, a transcriptomic analysis was conducted to understand their behavior in their context. All these steps, carried out by researchers from the Single Cell Group at CNAG, were crucial in discovering that VNP patients have a distinct cellular composition that provides them with a unique immune profile.

In the words of Juan Nieto, immunologist at CNAG and one of the authors of the study: “Our single cell analyses showed, while HIV-specific CD8+ T cell responses are typically key in controlling viral replication, in VNPs, these cells show lower levels of activation and cytotoxicity. Instead, they display traits linked to long-term survival and homeostatic proliferation, which may help suppress chronic viral coinfections like hepatitis B or cytomegalovirus, thereby reducing immune activation without controlling HIV replication. These findings open new avenues for understanding the unique immune responses in VNPs and could inform future therapeutic strategies aimed at managing HIV without the need for continuous antiretroviral therapy. Further investigation is needed to fully explore the potential of preserving mucosal immunity in combating HIV”.

The study reveals four protective features that makes VNP patients highly resistant

Until now, the presence of the CCR5Δ32 mutation in VNP individuals was already known, but the scientific community was still unaware of its exact role. This study has revealed the link between these patients' resistance to stages of immune deterioration, associated with stable CD4+ T lymphocyte levels, and the presence of this mutation. This is the first protective feature of the unique immune profile in these patients.

Ángel Bayón, the first author of the article and a predoctoral researcher at IrsiCaixa during the study, states: “This mutation leads to lower levels of the CCR5 receptor in the target cells of the infection, which is one of the entry points the virus uses to infect cells. Without this access point, HIV cannot infect as many cells, and the infection is more contained.”

Furthermore, VNPs exhibit more moderate immune activation of cytotoxic T cells (CD8+ T), which are specialised in identifying and eliminating virus-infected and tumor cells. Chronic overactivation would lead to T cell exhaustion and depletion, weakening the immune system. This factor, along with an attenuated interferon response—a protein that plays a crucial role in defending against viruses and regulating immune responses—constitutes the second feature of the VNPs' highly resistant profile.

The third characteristic is a low level of gut tissue disruption. Associated with the interferon response, which protects patients from chronic inflammation, this immune modulation appears to be closely related to intestinal health. In individuals with HIV, decreased mucosal integrity is often observed. The intestinal wall is affected, weakening the barrier against bacteria and leading to infections and inflammation. Additionally, a reduction in interferon levels is associated with a lower level of degradation of tryptophan (Trp), an essential amino acid in the immune response. This serves as the fourth factor that helps mitigate the impact of infections in these patients, constituting an immune profile of great value for therapies for the remaining groups with HIV.

REFERENCE

Bayón-Gil, Ángel, et al. ‘Host Genetic and Immune Factors Drive Evasion of HIV-1 Pathogenesis in Viremic Non-Progressors’. Med, Oct. 2024, p. S266663402400374X. DOI.org (Crossref), https://doi.org/10.1016/j.medj.2024.09.007.

GROUP PHOTO

Authors of this study (from left to right): Ginevra Caratú, Laboratory Technician in the Single Cell Genomics Group at CNAG; Juan Nieto, Postdoctoral Fellow in the Single Cell Genomics Group at CNAG; Holger Heyn, Single Cell Genomics Group Leader at CNAG.