Background
Antiretroviral therapy (ART) is not a cure, and HIV rapidly rebounds upon ART interruption. Furthermore, people with HIV (PWH) on ART have elevated immune activation and inflammation which has been associated with increased risk of aging-associated diseases which may be driven by this viral persistence.
Methods
To identify the potential mechanisms by which HIV persistence may drive ongoing inflammation and immune activation, we leveraged published data from 154 PWH treated during early (<6 months) and later (>2+ years) HIV infection from the UCSF SCOPE and Options cohorts. These data included host gene and HIV reservoir measures (HIV total DNA, HIV unspliced RNA) from peripheral CD4+ T cells, as well as plasma cytokine levels.
Results
Using a novel dimensionality reduction tool (PaCMAP) that preserves both local and global data structure, we identified three distinct CD4+ T cell transcriptomic clusters. By analyzing differentially expressed genes between the clusters, we found that clustering was significantly associated with differential expression of genes that encode for members of the transcription factor NF-kB family (NF-ĸB1, NF-ĸB2, RelA, RelB and cREL), NF-kB inhibitor genes and downstream effector genes such as pro-inflammatory cytokines (IL-1A, IL-1B) or antiviral pathways (IFNG). Clustering was not associated with HIV reservoir size or HIV unspliced RNA but was associated with the timing of ART: early treated PWH (<6 months) were enriched in the cluster with the lowest NF-kB activity. Interestingly, distinct patterns of plasma IL-1b, TNF-a and GCSF were strongly associated with cluster membership.
Conclusions
Collectively, these results suggest that specific patterns of cytokine secretion and NF-kB signaling are major drivers of CD4 T cell transcriptomic diversity in PWH on ART. These findings demonstrate the power of dimensionality reduction and data visualization tools to define subgroups of PWH with distinct clinical or immunological characteristics which may serve to risk stratify PWH on ART for future HIV cure strategies.
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