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.
Highlights
Antiretroviral therapy (ART) effectively blocks new rounds of HIV-1 infection and suppresses HIV-1 plasma viral load to clinically undetectable levels
(6) Clonally expanding HIV-1-infected cells can contribute to viral rebound. (b) Unlike antigen-driven proliferation and homeostatic proliferation, which are under host control, HIV-1 insertional mutagenesis may induce uncontrolled proliferation of infected cells
When HIV-1 integrates into specific locations of cancer-related genes and causes a gain of function in oncogenes or a loss of function in tumor suppressor genes, HIV-1 can drive aberrant proliferation of the infected cells
Summary
Antiretroviral therapy (ART) effectively blocks new rounds of HIV-1 infection and suppresses HIV-1 plasma viral load to clinically undetectable levels. Despite decades of suppressive ART, the latent reservoir [1,2,3] persists lifelong [6,7]. Infected cells should be recognized and eliminated by the host innate and adaptive immune system [8,9,10,11]. Under effective ART, HIV-1 evades innate and adaptive host immune clearance. Cytosolic viral RNA should induce recognition by cytosolic RIG-I-like receptors. HIV-1-infected cells evade immune clearance by cytotoxic. The HIV-1 latent reservoir persists despite long-term suppressive ART
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