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HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 3.0

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (20 April 2026) | Viewed by 12990

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Dr. Sonia Moretti

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National HIV/AIDS Research Center, Istituto Superiore di Sanità, 00161 Rome, Italy
Interests: infectious diseases; clinical virology; HIV infection; HIV persistence; immune responses to viral infections
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Special Issue "HIV-1 infection and immunometabolism: relevance to HIV pathogenesis and persistence" and "HIV-1 infection and immunometabolism: relevance to HIV pathogenesis and persistence 2.0" that was launched last two years, collected some interesting manuscripts regarding this topic. It is a great pleasure for me to introduce a third volume of this Special Issue that continues to be dedicated to the interplay between immunometabolism, HIV-1 pathogenesis and viral persistence. There is now an increasing body of evidence that dysfunctional immunometabolism represents a pivotal element to the biased immunity against HIV-1 infection, that leads to viral dissemination and establishment of virus reservoir. HIV-1 infection causes upregulated glycidic and lipidic metabolism and elevated oxidative stress in immune cells. How HIV-1 infection reprograms immunometabolism and the role of these metabolic alterations in the development and maintenance of HIV-1 latency have not been fully elucidated. The immunometabolic defects during HIV-1 infection, even under ART, may have a role also in non-AIDS defining cancers and neurocognitive diseases, representing a potential link between HIV-associated stimuli and age-related comorbidities, such as cardiovascular, bone and renal diseases, and frailty in HIV-positive individuals. Investigation of these topics will be important to more completely understand the role of immunometabolism in HIV-1 pathogenesis, and to have a clearer insight into how these processes interplay and affect HIV persistence.

This Special Issue will collect research or review articles addressing recent advances in the field of this topic. Also, novel approaches and technical advances, allowing for more precise measurements of metabolic activities in immune cells during HIV-1 infection, may be interesting in order to develop metabolic targeted therapies aiming at decreasing inflammation and HIV reservoir size in ART-treated HIV-infected people.

Dr. Sonia Moretti
Guest Editor

Manuscript Submission Information

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Keywords

immunometabolism
HIV-1
inflammation
immune activation
HIV pathogenesis
HIV latency
innate/adaptive immunity
metabolic diseases
non-AIDS-associated comorbidities

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Related Special Issues

HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence in Viruses (9 articles)
HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0 in Viruses (9 articles)

Published Papers (7 papers)

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Research

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14 pages, 2342 KB

Open AccessArticle

Reversible Effects of Integrase Inhibitors on Newly Differentiated Adipocytes

by Richard Taylor Pickering, Archana Asundi, Alex Olson, Katie Soden and Nina H. Lin

Viruses 2026, 18(1), 149; https://doi.org/10.3390/v18010149 - 22 Jan 2026

Viewed by 887

Abstract

Weight gain has been associated with integrase strand transfer inhibitors (INSTIs) in real-world studies; however, the causality of this relationship is unclear. Thus, we examined the effects of the INSTI, Dolutegravir (DTG), on human adipose cells in vitro and the reversibility of these effects by switching to a protease inhibitor, Darunavir (DRV). We established cultures of human adipose stem cells (ASCs) and newly differentiated adipocytes from individuals without HIV. For adipocytes, cells were exposed to DTG or DRV for 7 days, after which cells were maintained or switched to another ART. Experiments examining ASCs and the effects on adipogenesis initiated exposure during proliferation and continued throughout differentiation. Adipogenic outcomes included triglyceride content, gene expression, and adipokine secretion. Metabolic outcomes included lactate production, lipolysis, and oxygen consumption rates. DTG suppressed the secretion of adiponectin and leptin, and this was reversed following the switch to DRV in adipocytes without the altered expression of adipogenic genes. DTG exposure increased markers of endoplasmic reticulum stress, elevated lactate production, and suppressed oxygen consumption in ASCs. Exposure to DTG during differentiation lowered triglyceride accumulation and adiponectin secretion without altering the expression of adipogenic markers. Thus, DTG exposure resulted in changes in adipocyte function consistent with the progression of metabolically adverse phenotypes, and these effects were reversible. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 3.0)

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20 pages, 7161 KB

Open AccessArticle

Single-Cell Transcriptomics of Human Tonsils Reveals Nicotine Enhances HIV-1-Induced NLRP3 Inflammasome and Mitochondrial Activation

by Nadine Schrode, Trinisia Fortune, Aislinn M. Keane, Jesse F. Mangold, Benjamin Tweel, Kristin G. Beaumont and Talia H. Swartz

Viruses 2024, 16(11), 1797; https://doi.org/10.3390/v16111797 - 20 Nov 2024

Cited by 5 | Viewed by 2732

Abstract

Background: HIV-1 infection, even with effective antiretroviral therapy (ART), is associated with chronic inflammation and immune dysfunction, contributing to long-term health complications. Nicotine use, prevalent among people with HIV (PWH), is known to exacerbate immune activation and disease progression, but the precise biological mechanisms remain to be fully understood. This study sought to uncover the synergistic effects of HIV-1 infection and nicotine on immune cell function, focusing on beneficial insights into NLRP3 inflammasome activation, oxidative stress, and mitochondrial pathways. Methods: Human tonsil explants were infected with HIV-1 and exposed to nicotine. Single-cell RNA sequencing was used to profile immune cell populations and gene expression linked to inflammasome activation, oxidative stress, and mitochondrial function. Gene set enrichment analysis (GSEA) and synergy assessments were conducted to investigate how nicotine modulates immune responses in the context of HIV. Results: The combination of HIV infection and nicotine exposure significantly increased NLRP3 inflammasome activation, thioredoxin, and components of oxidative phosphorylation. Conclusions: This study highlights how the combined effects of HIV-1 and nicotine offer valuable insights into immune modulation, opening doors for future therapeutic strategies. Targeting the NLRP3 inflammasome and addressing nicotine use may contribute to improved outcomes for PWH. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 3.0)

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18 pages, 2878 KB

Open AccessArticle

New Associations with the HIV Predisposing and Protective Alleles of the Human Leukocyte Antigen System in a Peruvian Population

by Daisy Obispo, Oscar Acosta, Maria L. Guevara, Susan Echavarría, Susan Espetia, María Dedios, Carlos Augusto Yabar and Ricardo Fujita

Viruses 2024, 16(11), 1708; https://doi.org/10.3390/v16111708 - 30 Oct 2024

Cited by 1 | Viewed by 2612

Abstract

The accurate determination of an individual’s unique human leukocyte antigen (HLA) allele holds important significance in evaluating the risk associated with autoimmune and infectious diseases, such as human immunodeficiency virus (HIV) infection. Several allelic variants within the HLA system have been linked to either increased protection or susceptibility in the context of infectious and autoimmune diseases. This study aimed to determine the frequency and association of HLA alleles between people living with HIV (PLHIV) as the case group and Peruvian individuals without HIV with high-risk behaviors of sexually transmitted diseases as the control group. Whole exome sequencing (WES) was used to determine high-resolution HLA allelotypes using the OptiType and arcas HLA tools. The HLA alleles present in HLA classes I (A, B, and C loci) and II (DPB1, DQA1, DQB1, and DRB1 loci) were determined in a cohort of 59 PLHIV (cases) and 44 individuals without HIV (controls). The most frequent HLA alleles were A*02:01, DPB1*04:02, and DQB1*03:419 at 36%, 30%, and 28% prevalence in general population. We found that C*07:01 (p = 0.0101; OR = 10.222, 95% IC: 1.40–74.55), DQA1*03:02 (p = 0.0051; OR = 5.297, 95% IC: 1.48–19.02), and DRB1*09:01 (p = 0.0119; OR = 4.788, 95% IC: 1.39–16.44) showed an association with susceptibility to HIV infection, while DQB1*03:419 (p = 0.0478; OR = 0.327, 95% IC: 0.11–0.96) was associated with protection from HIV infection. Our findings contribute to the knowledge of HLA allele diversity in the Peruvian population (around 70% South American indigenous ancestry) lays the groundwork for further valuable large-scale use of HLA typing and offers a novel association with HIV infection that is relevant to vaccine studies. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 3.0)

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Review

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20 pages, 7625 KB

Open AccessReview

Immunometabolism in HIV Reservoirs: Implications for Latency and Comorbidities

by Mary-Elizabeth Zipparo and Rebecca T. Veenhuis

Viruses 2026, 18(8), 813; https://doi.org/10.3390/v18080813 - 24 Jul 2026

Viewed by 798

Abstract

Compelling research has consistently demonstrated a strong relationship between immunometabolism and infectious disease, including the ways in which viral infections alter the metabolic state of immune cells to promote survival. Human immunodeficiency virus (HIV) has been particularly noted for its ability to reprogram the metabolism of cells that contribute to viral persistence. The purpose of this review is to summarize current knowledge of the metabolic state of CD4 T cells and myeloid cells (monocytes/macrophages), two of the primary cell types targeted by HIV. The studies discussed reveal distinct metabolic profiles in both cell types during initial infection, active replication, and latency. In addition, we examine how these metabolic alterations may contribute to the increased frequency and severity of comorbidities observed in people with HIV (PWH). Understanding the impact of HIV infection and latency on immunometabolism may provide deeper insight into long-term viral persistence and support the identification of novel therapeutic targets to reduce chronic inflammation and inform future cure strategies for PWH. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 3.0)

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20 pages, 1393 KB

Open AccessReview

The Gene Encoding the Antisense Protein ASP of HIV-1: Origin, Distribution and Maintenance

by Myriam Abla Houmey, Sara Sadek, Coralie F. Daussy and Nathalie Chazal

Viruses 2026, 18(3), 381; https://doi.org/10.3390/v18030381 - 18 Mar 2026

Viewed by 1215

Abstract

Human Immunodeficiency Virus Type 1 (HIV-1), the causative agent of the acquired immune deficiency syndrome (AIDS), originated from zoonotic transmissions of simian immunodeficiency viruses (SIVs) infecting African great apes, following complex cross-species transmission events and virus–host co-evolution. These processes were accompanied by multiple viral adaptations, particularly within structural and accessory genes, enabling evasion of host restriction factors and long-term viral persistence. In 1988, an antisense open reading frame (ORF) overlapping the env gene was proposed and subsequently confirmed by the identification of antisense transcripts and the antisense protein (ASP). An “intact” ASP ORF (defined as >150 codons) is predominantly conserved in pandemic HIV-1 group M viruses and shows evidence of positive selection, suggesting a selective advantage. Increasing evidence supports the hypothesis that the asp gene emerged de novo during the evolution of group M and contributed to viral adaptation and global spread in humans. This review combines a narrative review of the literature with original in silico analyses of HIV-1 and SIV sequences retrieved from the Los Alamos National Laboratory database. We systematically reassessed the distribution, length variability and conservation of the ASP ORF across HIV-1 groups (M, N, O, P), subtypes, circulating recombinant forms (CRFs), unique recombinant forms (URFs) and related SIV lineages. Our updated analyses confirmed the strong association between the presence of an “intact” ASP ORF and pandemic HIV-1 group M lineages, while revealing rare but notable antisense ORFs in selected SIVcpz and SIVgor strains. By integrating evolutionary, epidemiological and sequence-based evidence, we aim to clarify the origin and maintenance of the ASP ORF and to contextualize its emergence within the broader framework of overlapping gene evolution, de novo gene birth and the selective pressures shaping viral fitness and pandemic potential. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 3.0)

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24 pages, 3493 KB

Open AccessReview

Elevated Methylglyoxal: An Elusive Risk Factor Responsible for Early-Onset Cardiovascular Diseases in People Living with HIV-1 Infection

by Mahendran Ramasamy, Zachary L. Venn, Fadhel A. Alomar, Ali Namvaran, Benson Edagwa, Santhi Gorantla and Keshore R. Bidasee

Viruses 2025, 17(4), 547; https://doi.org/10.3390/v17040547 - 8 Apr 2025

Cited by 1 | Viewed by 2959

Abstract

People living with HIV (PLWH) develop cardiovascular diseases (CVDs) about a decade earlier and at rates 2–3 times higher than the general population. At present, pharmacological strategies to delay the onset of CVDs in PLWH are unavailable, in part because of an incomplete understanding of its molecular causes. We and others recently uncovered elevated levels of the toxic glycolysis and inflammation-induced byproduct methylglyoxal (MG) in plasma from PLWH and from HIV-infected humanized mice (Hu-mice). We also found a reduction in expression of the primary MG-degrading enzyme glyoxalase I (Glo-I) in autopsied cardiac tissues from HIV-1-infected individuals and HIV-1-infected Hu-mice. Increasing the expression of Glo-I in HIV-1-infected Hu-mice not only attenuated heart failure but also reduced endothelial cell damage, increased the density of perfused microvessels, prevented microvascular leakage and micro-ischemia, and blunted the expression of the inflammation-induced protein vascular protein-1 (VAP-1), key mediators of CVDs. In this narrative review, we posit that elevated MG is a contributing cause for the early onset of CVDs in PLWH. Pharmacological strategies to prevent MG accumulation and delay the development of early-onset CVDs in PLWH are also discussed. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 3.0)

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Other

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9 pages, 4359 KB

Open AccessBrief Report

Preferential Exhaustion and Loss of Predominant Reservoir in Gut-Associated Lymph Nodes of a SIVmac239-Infected Rhesus Macaque with Terminal AIDS

by Cong-Jiao Bai, Yu Zhang, Zhang-Ran Du, Yu-Qiu Wang, Meng-Xue Sun, Liu-Meng Yang, Yong-Tang Zheng and Tian-Zhang Song

Viruses 2026, 18(8), 855; https://doi.org/10.3390/v18080855 - 4 Aug 2026

Viewed by 195

Abstract

Gut-associated lymph nodes (GALNs) constitute an important anatomical reservoir during early and chronic human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, but the fate of this compartment during terminal AIDS remains unclear. This study investigated viral persistence and lymph node injury in a rhesus macaque with long-term SIVmac239 infection and end-stage AIDS, characterized by profound CD4+ T cell depletion (30 cells/μL) and persistent viremia (1192 copies/mL). At necropsy, GALNs, including mesenteric, paracolic, and ileocecal lymph nodes, and non-gut-associated lymph nodes (NGALNs), including hepatic hilar, common iliac, and inguinal lymph nodes, were collected for viral RNA/DNA quantification, histopathology, immunofluorescence, and transcriptomics. SIV DNA was markedly lower in GALNs than in NGALNs, whereas SIV RNA was detectable only in NGALNs. GALNs exhibited extensive fibrotic remodeling, paracortical collapse, severe CD4+ T cell loss across B cell and paracortical regions, and pronounced CD8+ T cell accumulation within B cell zones. Transcriptomic profiling further revealed an exhaustion signature in GALNs, with reduced DNA replication and repair, impaired cell-cycle activity, and suppressed RNA processing, accompanied by activation of innate immune programs and attenuation of adaptive immune responses. These findings indicate that, during terminal AIDS, GALNs no longer serve as the predominant viral reservoir but instead undergo preferential and severe structural and functional exhaustion. This case highlights marked anatomical heterogeneity in lymph node vulnerability during advanced disease and supports a model in which collapse of the gut-associated immune barrier contributes to disease progression toward terminal AIDS. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 3.0)

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