HIV-1 Preferentially Integrates into Host Genomic R-Loops to Establish Persistent Infection

Core Concepts

HIV-1 preferentially targets host genomic R-loops, three-stranded nucleic acid structures composed of DNA-RNA hybrids, for viral genome integration, which enables the virus to establish persistent infection in the host.

Abstract

The content explores the relationship between HIV-1 infection and the formation of host genomic R-loops, as well as the role of R-loops in HIV-1 integration site selection. Key highlights: HIV-1 infection induces the accumulation of host genomic R-loops, which are enriched in both transcriptionally active and silent regions. Using an R-loop inducible cell model, the authors demonstrate that R-loop formation, rather than transcriptional activity alone, directs HIV-1 integration site selection. HIV-1 integrase proteins physically bind to host genomic R-loops, suggesting that R-loops serve as a key determinant for HIV-1 integration site targeting. The preferential integration of HIV-1 into R-loop-rich regions, including non-genic areas, provides insights into the mechanisms underlying the establishment of persistent, "invisible" HIV-1 infection. The findings reveal a novel role for host genomic R-loops in governing HIV-1 integration site selection and highlight their importance in the viral life cycle and persistence.

Stats

"HIV-1 infection induces host cellular R-loop formation and the R-loop rich regions of the host genome are preferred by HIV-1 integration." "Approximately three to four times more HIV-1 integration events were detected in the R-loop regions as in other genomic regions without R-loops in HeLa cells, CD4+ and Jurkat T cells."

Quotes

"HIV-1 preferentially integrates into regions rich in R-loops, suggesting that R-loops are a novel host factor governing HIV-1 integration site selection." "Our data show that HIV-1 targets host genomic R-loops for viral genome integration and its integrase proteins physically interact with genomic R-loops in vitro and in cells."

Key Insights Distilled From

Human immunodeficiency virus-1 induces and targets host genomic R-loops for viral genome integration

by Park,K., Lee... at www.biorxiv.org 03-06-2024

https://www.biorxiv.org/content/10.1101/2024.03.06.583715v1

Deeper Inquiries

How might the targeting of host genomic R-loops by HIV-1 be exploited for the development of new antiviral therapies?

The targeting of host genomic R-loops by HIV-1 presents a potential target for the development of new antiviral therapies. By understanding the mechanism by which HIV-1 integrates into R-loop-rich regions, researchers can explore the possibility of disrupting this interaction to prevent viral integration. One approach could involve the development of small molecules or inhibitors that specifically target the binding between HIV-1 integrase proteins and R-loops. By disrupting this interaction, it may be possible to inhibit viral integration and replication, leading to the development of novel antiviral therapies. Additionally, targeting R-loop formation itself could be explored as a strategy to prevent HIV-1 integration, potentially through the modulation of cellular factors involved in R-loop formation.

What other host factors or cellular processes might interact with or be influenced by the formation of R-loops during HIV-1 infection?

The formation of R-loops during HIV-1 infection may interact with various host factors and cellular processes, influencing the viral life cycle and host response. One key interaction could be with DNA repair and damage response pathways, as R-loops are known to be involved in DNA damage and repair processes. The presence of R-loops may activate DNA repair mechanisms, which could impact the integration of viral DNA into the host genome. Additionally, R-loops may interact with transcriptional regulators and chromatin remodeling factors, influencing gene expression patterns and potentially affecting viral gene expression. Furthermore, the immune response to HIV-1 infection may be modulated by the presence of R-loops, as they can trigger innate immune signaling pathways and affect the production of cytokines and chemokines.

Could the induction of R-loops by HIV-1 have broader implications for our understanding of virus-host interactions and the evolution of persistent viral infections?

The induction of R-loops by HIV-1 could have significant implications for our understanding of virus-host interactions and the evolution of persistent viral infections. R-loops play a crucial role in shaping the genomic landscape and regulating gene expression, and their manipulation by HIV-1 highlights the intricate interplay between viruses and host cells. The targeting of R-loops by HIV-1 for integration suggests a sophisticated mechanism by which the virus exploits host factors for its own benefit. This interaction may have broader implications for the evolution of persistent viral infections, as it demonstrates the ability of viruses to adapt and utilize host cellular processes for their survival. Understanding the role of R-loops in virus-host interactions could provide valuable insights into the development of novel antiviral strategies and shed light on the mechanisms underlying chronic viral infections.