HIV-1 Persists in Enlarged Cytotoxic T Cell Clones, According to Single-Cell Multiomics

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Summary

In an effort to eradicate HIV-1, researchers used ECCITE-seq to analyze HIV-1-infected CD4⁺ T cell clones from six patients, both during active infection and post-treatment, and two uninfected individuals. They observed that even with antiretroviral therapy, specific immune responses influenced T cell clone growth. Notably, HIV-1 was predominantly found in specific T cells resistant to cell death. These HIV-positive T cell clones, originating during active infection, persisted even after the virus was suppressed, suggesting that focusing on these specific T cells might offer a new strategy for HIV-1 elimination.

Fig.1 Graphical abstract¹.

Research Criteria

The researchers wanted to learn more about the drivers and indicators of clonally growing HIV-1-infected CD4⁺ T cells, which is critical for HIV-1 eradication. The study used single-cell ECCITE-seq to track clonal expansion dynamics in samples from six HIV-1-infected people (during viremia and after suppressive antiretroviral therapy) and two uninfected people, both in unstimulated conditions and after CMV and HIV-1 antigen stimulation.

Fig.2 Experimental design¹.

Sample Type

The samples used in the single-cell tests were from six HIV-1-infected people (during viremia and after suppressive antiretroviral medication) and two uninfected people. These samples were examined both before and after CMV and HIV-1 antigen stimulation.

Result—Single-Cell ECCITE-Seq: Immune, HIV, T Cells

Researchers sought to understand the effects of HIV-1 on CD4⁺ T cell responses, clonal expansion, and virus persistence. They used single-cell ECCITE-seq to look at the transcriptome, surface protein expression, T cell clonality, and HIV-1 expression in CD4⁺ T cells from six HIV-1 patients. This method allowed them to capture data from the same single cell, providing a comprehensive view of the cell's state. The study utilized longitudinally archived blood samples from the Sabes study, profiling CD4⁺ T cells at two critical time points: during viremia and after a year of viral suppression. Comparison was made with CD4⁺ T cells from two uninfected individuals, serving as controls. The data revealed insights into the clonal expansion dynamics and the impact of HIV-1 infection on the immune system. However, the findings should be interpreted with caution due to potential age and ethnicity differences in the control group.

Fig.3 Through multiomic ECCITE-seq techniques, they profiled CD4⁺ T cells during viral activity and post-viral suppression. Their findings highlighted that, even with effective antiretroviral therapy (ART), TNF reactions persist¹.

Result— Antigen and TNF Responses Alter the Clonal Growth Dynamics of Cytotoxic Th1 CD4⁺ T Cells

To understand the dynamics of T cell clonal expansion during HIV-1 infection, researchers examined the impact of cytokine responses on T cell clones. Utilizing a combination of bulk TCR sequencing and single-cell ECCITE-seq, over a million TCR sequences were profiled, revealing significant insights into T cell clone sizes. The study found that proliferating cells and specific effector memory cells, including GZMB Th1 and GZMK Th1, were the most clonal. Antigen responses, TNF signaling, and Th1 cytotoxic responses were identified as three critical pathways that were linked with T cell clone size using gene set enrichment analysis. Despite the administration of suppressive ART, these pathways continued to influence T cell clonal size. Elastic net regression further pinpointed genes that predicted T cell clone size, revealing that T cell polarization and activation were significant predictors of T cell clonality. Notably, during HIV-1 infection, T cell polarization and cytokine signaling had a pronounced effect on T cell clonal expansion.

Fig.4 Antigen response, TNF signaling, and Th1 cytotoxic response all influence T cell clone size¹.

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Reference

1. Collora, Jack A., et al. "Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones." Immunity 55.6 (2022): 1013-1031.