The Dynamic Linkage between Provirus Integration Sites and the Host Functional Genome Property Alongside HIV-1 Infections Associated with Antiretroviral Therapy

Abstract

(1) Background: The HIV-1 latent reservoir harboring replication-competent proviruses is the major barrier in the quest for an HIV-1 infection cure. HIV-1 infection at all stages of disease progression is associated with immune activation and dysfunctional production of proinflammatory soluble factors (cytokines and chemokines), and it is expected that during HIV-1 infection, different immune components and immune cells, in turn, participate in immune responses, subsequently activating downstream biological pathways. However, the functional interaction between HIV-1 integration and the activation of host biological pathways is presently not fully understood. (2) Methods: In this work, I used genes targeted by proviruses from published datasets to seek enriched immunologic signatures and host biological pathways alongside HIV-1 infections based on MSigDb and KEGG over-representation analysis. (3) Results: I observed that different combinations of immunologic signatures of immune cell types and proinflammatory soluble factors appeared alongside HIV-1 infections associated with antiretroviral therapy. Moreover, enriched KEGG pathways were often related to “cancer specific types”, “immune system”, “infectious disease viral”, and “signal transduction”. (4) Conclusions: The observations in this work suggest that the gene sets harboring provirus integration sites may define specific immune cells and proinflammatory soluble factors during HIV-1 infections associated with antiretroviral therapy.

Distinguishable topological properties of functional genome networks in HIV-1 reservoirs

“…(b) A box plot displaying the enrichment of signatures represented by rich factors. Details on the commands used for rich factors calculation and the inclusion of a random control “hg38” are described in Chen (2023) 15 and in Online Methods . Statistical significance was determined using the Wilcoxon test in R with default options.…”

“…We previously hypothesized that alterations in enriched immunologic signatures are significant, and display a high degree of specificity concerning different immune cell types and proinflammatory soluble factors required alongside HIV-1 infections (Chen, 2023) 15 . In line with this, we applied the same rationale, as described above, to investigate whether the network architecture of enriched signatures changes alongside HIV-1 infections associated with ART, and comparing them to that depicted in elite controllers ( Extended data Fig.…”

“…1a ). Host genes targeted by HIV-1 integration, as reported by Jiang et al (2020) (Jiang et al, 2020), were previously analyzed and documented in Chen (2023) (Chen, 2023). Transcriptome sequencing data for ART-treated patients were retrieved from Einkauf et al (2022) (Einkauf et al, 2022) (GEO: GSE144334) and Clark et al (2023) (Clark et al, 2023).…”

“…The command lines for calculating rich factors and generating a random control labeled “hg38” in Fig. 1b were detailed in Chen (2023) (Chen, 2023). In brief, the rich factor, representing the enrichment score for each enriched immunologic signature, was calculated by dividing GeneRatio by BgRatio.…”

“…We previously hypothesized that the frequency of HIV-1 integration could serve as a proxy for enriched immunologic signatures during HIV-1 infection (Chen, 2023). Building on this hypothesis, in our current study we employ various theorems and principles involved in graph theory (Diestel, 2017) to obtain a fresh perspective on latent HIV-1 reservoirs.…”