The Clonal Expansion Dynamics of the HIV-1 Reservoir: Mechanisms of Integration Site-Dependent Proliferation and HIV-1 Persistence

Abstract

More than 50% of the HIV-1 latent reservoir is maintained by clonal expansion. The clonally expanded HIV-1-infected cells can contribute to persistent nonsuppressible low-level viremia and viral rebound. HIV-1 integration site and proviral genome landscape profiling reveals the clonal expansion dynamics of HIV-1-infected cells. In individuals under long-term suppressive antiretroviral therapy (ART), HIV-1 integration sites are enriched in specific locations in certain cancer-related genes in the same orientation as the host transcription unit. Single-cell transcriptome analysis revealed that HIV-1 drives aberrant cancer-related gene expression through HIV-1-to-host RNA splicing. Furthermore, the HIV-1 promoter dominates over the host gene promoter and drives high levels of cancer-related gene expression. When HIV-1 integrates into cancer-related genes and causes gain of function of oncogenes or loss of function of tumor suppressor genes, HIV-1 insertional mutagenesis drives the proliferation of HIV-1-infected cells and may cause cancer in rare cases. HIV-1-driven aberrant cancer-related gene expression at the integration site can be suppressed by CRISPR-mediated inhibition of the HIV-1 promoter or by HIV-1 suppressing agents. Given that ART does not suppress HIV-1 promoter activity, therapeutic agents that suppress HIV-1 transcription and halt the clonal expansion of HIV-1-infected cells should be explored to block the clonal expansion of the HIV-1 latent reservoir.

HIV reservoirs are dominated by genetically younger and clonally enriched proviruses

“…This is because they are at higher risk of elimination by cytopathic effects or immune responses after reactivation (at least some Ψdefective proviruses can produce HIV proteins 71 and even virions 72 ). As not all members of a clone will reactivate upon stimulation 73,74 , expansion enhances the likelihood that at least some members will persist 75 . In contrast, grossly defective proviruses rely less on clonal expansion for survival, as their risk of elimination is inherently lower due to limited or no viral antigen presentation 21,53 .…”

Clonal abundance patterns in hematopoiesis: Mathematical modeling and parameter estimation

“…Although different barcodes themselves may not influence cells, different VISs may. For example, aberrant self-renewal arises when using lentiviral vectors (Espinoza et al, 2019) and different VISs of HIV have been shown to affect cellular proliferation rates (e.g., if the VIS is near an oncogene) Yeh et al (2021). Besides the non-neutrality, we have also neglected stochastic or variable proliferative potential L and the time course of the HSC homing and engraftment into the bone marrow.…”

Potential multi-modal effects of provirus integration on HIV-1 persistence: lessons from other viruses

“…HPV integrations into introns and exons of RAD51 paralog B (RAD51B), a gene encoding a protein with DNA-repair and apoptotic functions, might indicate that this tumor-suppressor gene is disrupted by HPV integration [34]. However, for HIV-1, integration-dependent induction of proliferation appears to have a small overall contribution to clonal expansion [6,87], as recently reviewed elsewhere [88]. Similar to BACH2, the other RIGs of HIV-1 (STAT5B, MKL2, MKL1, IL2RB, MYB, and POU2F1) show enrichment for HIV-1 integrations in the same orientation as host gene transcription and into specific introns in PLWH [4,8,10,87,89,90].…”

“…This indicates that HIV-1 integration into those RIGs might provide a fitness advantage to cells [4,8,10,87,89,90]. Additional evidence for the functional importance of HIV-1 RIGs comes from their over-representation in mouse models compared with in vitro [88,91,92], and the accumulation of cells with integrations in these seven genes in response to ART [4,8,10,87,89,90]. Human T cell lymphotropic virus type 1 (HTLV-1): a deltaretrovirus that causes latent infection but can reactivate to cause various pathologies later on, including adult T cell lymphoma in ~10% of infected individuals.…”