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HIV Expression in Diverse Cell Types: Mechanisms, Regulation, and Pathogenesis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 20 October 2026 | Viewed by 6170

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Dr. Rosemary Kiernan

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Institut de génétique humaine, UMR 9002, CNRS, Université de Montpellier, Gene Regulation Laboratory, 141, Rue de la Cardonille, 34396 Montpellier, France
Interests: transcription; ncRNAs; miRNAs; HIV; cancer
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Special Issue Information

Dear Colleagues,

More than 40 years since the discovery of Human Immunodeficiency Virus (HIV), the Acquired Immunodeficiency Syndrome (AIDS) remains a major global health challenge. HIV is characterized by its ability to persist in diverse cellular reservoirs and evade immune surveillance, which prevents curative therapies and the development of an efficient vaccine. This special issue aims to explore the intricate molecular and cellular mechanisms that govern HIV transcription, latency, and reactivation across different cell types, including CD4+ T cells, macrophages, dendritic cells, and other cellular reservoirs. Recent advances in single-cell transcriptomics and genome editing technologies have provided new insights into HIV dynamics across different cell types. These findings have significant implications for the design of novel latency-reversing agents, immune-based interventions, and potential curative strategies. By elucidating the complex regulatory networks governing HIV expression, this special issue aims to bridge gaps in our understanding of HIV persistence and reactivation, paving the way for improved therapeutic interventions against HIV/AIDS.

We invite researchers and experts to submit original research articles, reviews, and perspectives that address key aspects of HIV expression, including:

Host transcription factors, chromatin modifications, and signaling pathways involved in HIV regulation
Epigenetic control of viral latency and reactivation mechanisms
The role of the cellular microenvironment in HIV persistence and immune evasion
Interactions between viral proteins, host restriction factors, and immune responses
Insights from single-cell transcriptomics and genome-editing technologies for HIV research
Novel therapeutic strategies targeting HIV persistence and reactivation

This Special Issue is led by Dr. Rosemary Kiernan and assisted by our Topical Advisory Panel Member Charbel Akkawi (Institut de Génétique Humaine).

We especially welcome submissions from across disciplines to contribute to this timely collection.

Dr. Rosemary Kiernan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

hiv transcription
latency
reactivation
host transcription factors
chromatin modifications
viral-host protein interactions

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Published Papers (6 papers)

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Research

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16 pages, 6167 KB

Open AccessArticle

Pulmonary Immune Cell Landscape Altered by Exposure to HIV, Schistosoma and Their Combination

by Daniel Morales-Cano, Sandra Medrano-Garcia, Bianca Barreira, Ana Hernández-García, Rahul Kumar, Brian B. Graham, Rajkumar Savai, Soni Savai Pullamsetti, Francisco Perez-Vizcaino, Ghazwan Butrous, Angel Cogolludo and Edgar Fernández-Malavé

Int. J. Mol. Sci. 2026, 27(12), 5426; https://doi.org/10.3390/ijms27125426 - 16 Jun 2026

Viewed by 457

Abstract

Local immune cell activation and vascular remodelling are characteristic pathogenic features of pulmonary arterial hypertension (PAH). HIV and schistosome infections have been individually associated with PAH. However, whether co-infection with these pathogens has a distinct impact on the development of pulmonary vascular disease remains poorly understood, partly due to the lack of experimental animal models. In a novel non-infectious model of HIV and Schistosoma pulmonary co-exposure based on lung embolisation of S. mansoni eggs in HIV-transgenic (HIV) mice, we previously reported exacerbated endothelial remodelling and dysfunction, along with increased pulmonary arterial pressure; which were associated with a unique profile of pro-inflammatory cytokines in the lung. In the present study, we used flow cytometric analysis of isolated lung leukocytes and immunofluorescence staining to characterise the pulmonary immune cell landscape associated with individual or combined exposure to HIV and schistosome. Compared with mice exposed to HIV (untreated HIV mice) or schistosome (egg-treated wild-type mice), co-exposed (egg-treated HIV mice) animals showed significantly increased numbers of interstitial and alveolar macrophages, patrolling-type monocytes, NKT and γδ T cells, and reduced CD8⁺ αβ T cells. Other lung immune cells, including inflammatory-type monocytes, eosinophils/neutrophils, dendritic cells, CD4⁺ αβ T cells, NK cells and B cells were not significantly affected in the co-exposure condition. Taken together, these results show for the first time that combined pulmonary exposure to HIV and Schistosoma, as it may occur in co-infected individuals, alters the local immune cell landscape in a manner distinct from that of individual exposure. Furthermore, these findings may contribute to a better understanding of the complex inflammatory processes involved in the pathogenesis of PAH, thereby supporting the development of therapies targeting pathogenic immune cells in pulmonary vascular disease associated with HIV and Schistosoma co-morbidity. Full article

(This article belongs to the Special Issue HIV Expression in Diverse Cell Types: Mechanisms, Regulation, and Pathogenesis)

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21 pages, 6214 KB

Open AccessArticle

Premature Skeletal Aging and Immunological Recovery in Romanian PLWH: A Cross-Sectional Analysis of Gender-Specific and Metabolic Risk Factors

by Ioana-Melinda Luput-Andrica, Adelina-Raluca Marinescu, Talida-Georgiana Cut, Alexandra Herlo, Ruxandra Laza, Andra-Elena Saizu, Andreea-Cristina Floruncut, Narcisa Nicolescu, Romanita Jumanca, Daniela-Ica Rosoha and Voichita Elena Lazureanu

Int. J. Mol. Sci. 2026, 27(9), 4079; https://doi.org/10.3390/ijms27094079 - 2 May 2026

Cited by 1 | Viewed by 553

Abstract

As life expectancy for people living with human immunodeficiency virus (HIV) (PLWH) increases, long-term comorbidities, such as bone mineral density (BMD) loss, have emerged as significant clinical challenges. This study evaluated the prevalence and determinants of skeletal demineralization in a contemporary Romanian HIV cohort. A cross-sectional study was conducted among 180 PLWH (mean age 41.86 ± 12.69 years) undergoing stable antiretroviral therapy. Bone health was assessed via dual-energy X-ray absorptiometry (DXA), while body composition and metabolic status were evaluated using bioelectrical impedance analysis (BIA) and serum lipid profiling. A high prevalence of reduced skeletal mass (58.3%) was observed, with 10% of the cohort diagnosed with osteoporosis at a mean age of only 45.7 years. Significant correlations were identified between osteoporosis and a history of AIDS, active smoking, and hypertriglyceridemia. Notably, women with osteoporosis exhibited significantly lower current CD4+ T-cell counts (268.4 ± 180.5 cells/μL) compared to those with normal BMD. While the body mass index was an inconsistent predictor of bone health, BIA-derived bone mass effectively identified subclinical depletion. Our findings underscore a phenotype of premature skeletal aging in PLWH, driven by an interplay of immunological history, metabolic disturbances, and lifestyle factors. Early screening via DXA and BIA, alongside aggressive management of modifiable risks, is essential for mitigating fragility fractures in this aging population. Full article

(This article belongs to the Special Issue HIV Expression in Diverse Cell Types: Mechanisms, Regulation, and Pathogenesis)

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22 pages, 2969 KB

Open AccessArticle

Time- and Dose-Dependent PSP-Induced Modulation of Antiviral Signaling Networks in CD4+ T Cells

by Glamaris N. Rosario-Sanfiorenzo, Giovanni O. Alicea-Pérez, Ashlin N. Álvarez-Flores, Naiara I. Hernández-Santisteban, Amanda C. Rivera-Payán, Jeshua J. Colón-Fernández, Abigail M. Rivera-Berganzo, Victoria Bermudez-Fosse, Ileanmarie Santana-Costas, Carolina Nieves-Moreno, Fabiola I. Colón-Santiago, Julieness M. Correa-Haifa, Natalia I. Sánchez-Otero, Geraldine Cintrón-Vélez, Génesis M. Matos-Morales and Eduardo Álvarez-Rivera

Int. J. Mol. Sci. 2026, 27(8), 3661; https://doi.org/10.3390/ijms27083661 - 20 Apr 2026

Viewed by 808

Abstract

Natural bioactive polysaccharides have been investigated for their ability to modulate antiviral immune responses. Polysaccharide peptide (PSP) from Coriolus versicolor previously restricted human immunodeficiency virus type 1 (HIV-1) entry into monocytic cells through a protein kinase R (PKR)-dependent cytoskeletal mechanism. However, its impact on antiviral signaling in adaptive cluster of differentiation 4 (CD4)+ T-cell models remains incompletely defined. Here, we evaluated concentration- and time-dependent effects of PSP (50–1000 µg/mL) in Jurkat T cells over 3 and 6 days. Cell viability was assessed by MTT, trypan blue exclusion, and viable cell density analysis. Immunoblotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were performed to examine Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 1 and 2 (STAT1/STAT2), PKR, interferon gamma (IFN-γ), and cofilin-1 signaling. PSP did not induce cytotoxicity at any concentration. Instead, PSP promoted dose- and time-dependent upregulation of intracellular TLR4, PKR, phospho-PKR (Thr446), Cofilin-1, phospho-Cofilin-1 (Ser3), phospho-STAT1 (Tyr701), phospho-STAT2 (Tyr690), phospho-NF-κB (Ser536), and IFN-γ, with amplified responses at Day 6. These changes were paralleled by transcriptional induction of antiviral-associated genes. Collectively, PSP induces coordinated interferon (IFN)-associated and cytoskeletal regulatory signaling in Jurkat T cells without cytotoxicity, providing a mechanistic framework for future evaluation of viral permissiveness and antiviral responses in adaptive immune models. Full article

(This article belongs to the Special Issue HIV Expression in Diverse Cell Types: Mechanisms, Regulation, and Pathogenesis)

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18 pages, 3312 KB

Open AccessArticle

HIV Promoters Isolated from Brain and Peripheral Tissue of Virally Suppressed PWH Are Phylogenetically and Functionally Similar

by Janna Jamal Eddine, Emily K. Chalmers, Jingling Zhou, Sarah J. Byrnes, Trisha A. Jenkins, Narin Osman, Anna C. Hearps, Michael Roche, Thomas A. Angelovich and Melissa J. Churchill

Int. J. Mol. Sci. 2026, 27(7), 3185; https://doi.org/10.3390/ijms27073185 - 31 Mar 2026

Cited by 1 | Viewed by 832

Abstract

Despite viral suppression with antiretroviral therapy (ART), reservoirs of Human Immunodeficiency Virus (HIV) persist in anatomical compartments throughout the body, including the brain. We have previously demonstrated that the HIV long terminal repeats (LTRs) isolated from the brains of non-virally suppressed people with HIV (PWH) are phylogenetically and functionally distinct from those isolated from matched peripheral tissue. While intact, transcriptionally competent HIV genomes persist within the brains of virally suppressed PWH, whether HIV LTRs are intact, functional, and compartmentalized relative to the periphery, as in non-virally suppressed PWH, remains unclear. HIV LTRs were extracted from frontal cortex post-mortem brain and matched peripheral tissues of virally suppressed PWH (n = 5). Following single-genome amplification, sequences were phylogenetically analyzed and transcriptional activity was assessed. In contrast to non-virally suppressed PWH, LTR sequences failed to compartmentalize between the brain and peripheral compartments. Identical LTR sequences were observed across brain and peripheral tissues in 2/5 PWH. While the LTRs remain transcriptionally active, mutations, insertions and deletions predicted to reduce transcription factor binding affinity at key binding sites, including C/EBP, NF-κB, and Sp1 sites, were observed and found to result in reduced basal transcriptional activity. The role of these mutations in latency and viral persistence remains unclear. Full article

(This article belongs to the Special Issue HIV Expression in Diverse Cell Types: Mechanisms, Regulation, and Pathogenesis)

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16 pages, 1793 KB

Open AccessArticle

Transcriptomic Signatures of Immune Suppression and Cellular Dysfunction Distinguish Latent from Transcriptionally Active HIV-1 Infection in Dendritic Cells

by Shirley Man, Jade Jansen, Neeltje A. Kootstra and Teunis B. H. Geijtenbeek

Int. J. Mol. Sci. 2026, 27(2), 844; https://doi.org/10.3390/ijms27020844 - 14 Jan 2026

Cited by 1 | Viewed by 760

Abstract

Dendritic cells (DCs) are essential for antiviral immunity but are also susceptible to HIV-1 infection. Although sensing and restriction pathways in DCs are well described, the mechanisms underlying latent infection and its functional consequences remain unclear. In this study, we performed transcriptomic profiling of monocyte-derived DCs harboring transcriptionally active (Active-HIV) or latent HIV-1 (Latent-HIV) proviruses using a dual-reporter virus. Gene set enrichment analysis revealed suppression of metabolic and stress-modulatory programs in Active-HIV compared to unexposed DCs. In contrast, Latent-HIV showed broad downregulation of pathways, including interferon and innate responses and metabolic programs, indicating a hyporesponsive and dampened antiviral state despite the absence of differentially expressed genes (DEGs). DEG analysis of Active-HIV versus Latent-HIV showed that active transcription associates with cellular stress, cytoskeletal remodeling, and RNA processing. Functional analyses further demonstrated the activation of RNA processes, the suppression of antigen-presentation pathways, and altered membrane and cytoskeletal signaling in Active-HIV. These pathways suggest that transcriptionally active HIV-1 is linked to cellular programs supporting replication, coinciding with a metabolically strained yet immunologically engaged state that may impair antigen presentation. Conversely, latently infected DCs display a hyporesponsive state consistent with proviral silencing. This dichotomy reveals distinct mechanisms of DC dysfunction that may facilitate HIV-1 persistence and immune evasion. Full article

(This article belongs to the Special Issue HIV Expression in Diverse Cell Types: Mechanisms, Regulation, and Pathogenesis)

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Review

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41 pages, 3341 KB

Open AccessReview

Molecular Regulation of HIV-1 Expression and Persistence Across Diverse Cellular Reservoirs

by Ashlin N. Álvarez-Flores, Fabiola I. Colón-Santiago, Naiara I. Hernández-Santisteban, Julieness M. Correa-Haifa, Samuel E. Caldero-Reyes, Glamaris N. Rosario-Sanfiorenzo, Giovanni O. Alicea-Pérez, Gabriela V. Arvelo-Colón, Amanda C. Rivera-Payán, Jeshua J. Colón-Fernández, Amanda S. Jové-Bravo, Carolina Nieves-Moreno, Génesis Matos-Morales, Yariselis Cardona-Maldonado, Agneris Z. Irizarry-Marquez, Solianne Martínez-Jiménez and Eduardo Álvarez-Rivera

Int. J. Mol. Sci. 2026, 27(7), 3244; https://doi.org/10.3390/ijms27073244 - 2 Apr 2026

Cited by 1 | Viewed by 1720

Abstract

Despite the remarkable success of antiretroviral therapy (ART) in suppressing human immunodeficiency virus type 1 (HIV-1) replication, viral persistence remains a major barrier to cure. This persistence is sustained by heterogeneous cellular reservoirs in which viral expression is tightly regulated by host-dependent molecular mechanisms. Beyond the canonical cluster of differentiation 4 (CD4+) T-cell reservoirs, HIV-1 establishes long-lived infection in myeloid cells, glial populations within the central nervous system (CNS), and additional non-canonical cellular niches, each characterized by distinct transcriptional, epigenetic, and immune environments. In this review, we synthesize recent advances in understanding how HIV-1 expression, latency, and reactivation are shaped across diverse susceptible cell types. We highlight cell-type-specific mechanisms governing viral integration, chromatin organization, transcriptional elongation, innate immune sensing, host restriction factors, and cytoskeletal regulation. Particular emphasis is placed on how host signaling pathways and immune microenvironments contribute to reservoir stability and heterogeneity, complicating eradication strategies. We further discuss immunomodulatory approaches that seek to modulate viral expression without exacerbating immune activation. By integrating molecular, cellular, and immunological perspectives, this review provides a framework for understanding HIV-1 persistence as a context-dependent process and underscores the need for cell-type-tailored strategies in HIV cure research. Full article

(This article belongs to the Special Issue HIV Expression in Diverse Cell Types: Mechanisms, Regulation, and Pathogenesis)

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