Jul 2026· Journal of Immunology· Vol 215· 0 citations
TL;DR
It is proposed a model that innate immune sensing of these transcripts activates a MAVS-dependent pathway to contribute to chronic inflammation and HIV-associated comorbidities.
Abstract
The persistent HIV reservoir includes latently infected cells, which upon antiretroviral treatment (ART) interruption, reactivate HIV-1 expression and fuel rebound of disease progression. People living with HIV, even on ART, experience chronic inflammation associated with accelerated aging and comorbidities of the central nervous system, gut, and heart. The persistent reservoir is mostly composed of defective proviral genomes, unable to produce infectious virus due to deleterious mutations. However, the contribution of these defective viruses to chronic disease has not been well characterized. We have demonstrated that an intragenic element in the Env region of the HIV genome drives transcription of non-canonical RNA in defective proviruses. We hypothesize that these transcripts from defective proviruses contribute to chronic inflammation.
To model defective proviruses, we used CRISPR-Cas9 to engineer cells harboring HIV genomes with a nonfunctional 5’ LTR.
We observed a correlation between levels of internally driven transcripts and in vitro pro-inflammatory cytokine production in Jurkats, macrophage-like ThP1 cells, and cells differentiated into macrophages. Additionally, we confirmed nuclear export of these transcripts and that shRNA-mediated MAVS knockdown in ThP1s decreases the inflammatory response.
We propose a model that innate immune sensing of these transcripts activates a MAVS-dependent pathway to contribute to chronic inflammation and HIV-associated comorbidities.
NIH RO1 AI187175, NIH RO1 AI138960, NIH RO1 DA055488, CFAR P30AI042853, Boston University Undergraduate Research Opportunities Program Faculty Matching Grant
Viral Immunology (VIR)
It is proposed that defective HIV proviruses contribute to chronic inflammation in PWH through an MDA5-dependent induction of type I interferon pathways.
Jonathan Kilroy, Aparna Deokar, Samantha D. Patalano et al.· Journal of Virology· 0 citations
The viral reservoir established after HIV-1 infection remains the primary barrier to curing HIV. Recent studies suggest that proviral HIV-1 DNA, low-level viral transcripts, and other reservoir-derived viral products may contribute to persistent innate immune activation and type I interferon (IFN-I)-related inflammatory programs. This sustained activation drives a state of chronic immune activation, which induces and maintains exhaustion in immune cells such as CD4
+
T cells. Exhaustion is characterized by loss of effector function and upregulation of inhibitory receptors (immune checkpoints), severely compromising the host’s antiviral immune response. In this review, we systematically examine the molecular and cellular mechanisms by which the HIV-1 reservoir fuels immune exhaustion through the IFN-I signaling pathway. We further explore potential intervention targets along this pathway, providing a theoretical framework for the development of novel therapeutic strategies aimed at reservoir elimination or reversal of immune exhaustion.
Zhihui Zhang, Peng-Fei Ren, Meng Deng et al.· Frontiers in Immunology· 0 citations
PURPOSE OF REVIEW
People with HIV (PWH) require lifelong antiretroviral therapy (ART) to maintain viral suppression, yet integrated HIV DNA persists in long-lived cellular reservoirs in blood and tissues. Most integrated proviruses are defective, meaning they contain deletions, hypermutation, packaging-signal defects, splice defects, or other defects that prevent production of replication-competent viruses. However, these genomes are not necessarily biologically inert as many remain capable of transcription and, in some cases, translation of viral proteins.
RECENT FINDINGS
Recent evidence has demonstrated that the brain is a stable reservoir of both intact and defective HIV despite viral suppression with ART. Whilst intact replication capable proviruses are known to induce cell activation and pathology, recent studies suggest that defective proviruses with large internal deletions and hypermutation can remain transcriptionally, and in some cases, translationally active and have now been linked with persistent immune activation during ART. Therefore, transcriptionally active defective proviral DNA may be a contributor to underlying neuropathogenesis in ART-suppressed PWH.
SUMMARY
Defective HIV proviruses make up the majority of the proviral reservoir across blood and tissue compartments. Although they are replication-incompetent, many remain transcriptionally and translationally competent and may contribute to chronic inflammation, antigen persistence, and neuropathology in ART-suppressed PWH.
Emily K Chalmers, Janna Jamal Eddine, Liam Yucel et al.· Current Opinion in HIV and A...· 0 citations
HIV-SCRIBE is developed, a CRISPR-based molecular recorder in which a self-targeting guide RNA locus is placed under a Tat-responsive minimal HIV-1 5'LTR promoter, coupling Cas9-mediated cleavage and error-prone repair to Tat-driven transcriptional activation to generate a durable molecular record of HIV-1 reactivation and, more broadly, of cell-type-specific CRISPR editing dynamics.
Nahia Urturi Ortiz, M. Nonnemacher, Brian Wigdahl· 0 citations
Nef is a non-structural regulatory protein of human immunodeficiency virus (HIV) that exerts pleiotropic effects on the immune system. In infected cells, Nef modulates the surface expression of molecules critical for immune responses and regulates cytokine production, vesicular trafficking, and lipid metabolism as well as apoptosis and autophagy. Despite significant improvements in antiretroviral therapy (ART), Nef is detected in the circulation of HIV-infected individuals as a soluble protein and in association with virions and extracellular vesicles, and it is regarded as a driver of a broad spectrum of HIV-associated comorbidities. Serum Nef concentrations range from a few to several tens of ng/mL, comparable to systemic levels of certain proinflammatory cytokines in inflammatory diseases. This reflects the fact that the primary sources of Nef are cellular viral reservoirs in which ART does not suppress viral protein expression. Among these reservoirs, long-lived HIV-infected memory CD4+ T cells and tissue-resident macrophages are considered the major contributors to systemic Nef production. Due to the need for a more comprehensive understanding of the in vivo functions of Nef and the molecular mechanisms by which it contributes to HIV-associated pathogenesis, a variety of mouse models expressing Nef were developed. This review summarizes existing transgenic mouse models with cell type-specific Nef expression and humanized mouse models used in HIV research, including models based on Nef-deficient strains. The development and systematic characterization of such models are essential for providing experimental validation for the clinical implementation of Nef inhibitors in combination with established ART.
A. Yakovleva, E. Gorshkova, E. Gubernatorova et al.· Frontiers in Immunology· 0 citations
The results suggest that intracellular T. annulata and T. parva parasites could drive an immune evasion cancer hallmark in host lymphocytes by epigenetic silencing of genes for innate and adaptive immunity.
Marisol Giacomini, Aristeidis Panagiotou, Steve G. Odette et al.· PLoS Pathogens· 0 citations
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