World AIDS Day
World AIDS Day, marked on December 1st since 1988, is an important date to not only raise awareness but also address challenges and necessary measures to end the HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) epidemic (1, 2). Currently, there are more than 38 million people living with HIV (PLWH) (1, 2). Globally, HIV/AIDS accounted for more than 36 million deaths, reaching its highest mortality rate in 2006 (3, 4). Although the annual incidence is showing a constant decrease after peaking in the late 90’s, 1.7 million new infections and 700.000 estimated deaths were still reported in 2019 (4-7).
Antiretroviral therapy (ART) is the standard treatment for an HIV infection that uses a combination of ARTs to suppress viral transmission. ARTs have led to a marked reduction of HIV/AIDS-related morbidity and mortality, turning HIV into a chronic, but controllable disease (6, 7). Yet, ARTs are often accompanied with side effects such as neutropenia, anemia, fever, or drug-induced resistance (7, 8). Additionally, PLWH have a higher risk of developing other malignancies including different cancer types due to a dysfunctional immune system associated with the on-going HIV infection (9).
Additional research is required to develop advanced treatment strategies with increased efficiency but reduced toxicity. Given the heterogenous and multi-layered nature of an HIV infection, single cell sequencing technologies have become a powerful tool to better understand its pathogenesis (8, 10). In the course of World AIDS Day, we would like to highlight some of these studies to show how single cell sequencing can be used to advance HIV research.
Two distinct CD4 T cell clusters were identified in a primary HIV latency model using single cell sequencing
Golumbeanu and colleagues (11) applied single cell sequencing to decipher the cellular heterogeneity of human CD4 T cells in an in vitro model addressing HIV latency. Upon infection, HIV can establish latent reservoirs in some infected cells, particularly CD4 T cells, to escape ART treatment. HIV reactivation, induced by different latency reversing agents, is a potential treatment strategy, however, treatments showed varying efficiencies and the underlying mechanisms are still not fully understood. This study identified two subgroups of CD4 T cells in three different treatment conditions (untreated, SAHA and TCR) that represent different resting stages. These two clusters showed distinct expression profiles (defined by 134 genes), with cluster 2 being the more responsive subpopulation. In summary, the results obtained in this study deepen our knowledge on HIV latency and could be used to predict and improve the efficiency of latency reversing agents (11).
Figure 1. Principal component analysis and differentially expressed genes between the two clusters and the three indicated treatments (image modified from Golumbeanu et al. (11), http://creativecommons.org/licenses/by/4.0/).
Immune non-responders show low MAIT cell counts accompanied with mitochondrial dysfunction
Reduction in CD4 T cell numbers in PLWH can lead to a dysfunctional immune system. ART is reported to at least partially restore CD4 T cell counts and immune function in PLWH. However, in 15-20% of patients treated with ARTs, CD4 T cell levels remain dampened. Such immune non-responders (INRs) have an increased risk of being affected by infections and non-AIDS-related malignancies and therefore higher mortality compared to immune responders (IR) (12). In the study by Li et al. (12), the authors compared peripheral blood mononuclear cells from INR and IR to investigate potential mechanisms of differential ART effects. The number of mucosal-associated invariant T (MAIT) cells is shown to be lower in INR compared to IR. In addition, MAIT cells from INR showed expression profiles that corresponded with increased apoptotic cell death and mitochondrial dysfunction. This study provides insights into potential mechanisms that could render INR more sensitive towards infections (12).
Figure 2. Two-dimensional UMAP and comparison of cell clusters isolated from peripheral blood mononuclear cells of INR and IR (image modified from Li et al. (12), http://creativecommons.org/licenses/by/4.0/).
These two recent studies demonstrate the power of single cell sequencing to reveal the heterogeneity of HIV infections and some of the mechanisms and pathways involved in HIV immunopathogenesis. Single cell multi-omics approaches, such as Singleron’s FocuSCOPE® products, can detect viral RNA together with the host transcriptome from the same single cells and bring further insights that can potentially be used to develop more effective vaccination or treatment strategies in the future.
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