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HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 12429

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Dr. Sonia Moretti

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National HIV/AIDS Research Center, Istituto Superiore Di Sanità, 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", which was launched last year, collected several interesting manuscripts regarding this topic. It is a great pleasure for me to introduce a second volume of this Special Issue dedicated to the interplay between immunometabolism, HIV-1 pathogenesis and viral persistence. There is now an increasing body of evidence suggesting that dysfunctional immunometabolism represents a pivotal element to biased immunity against HIV-1 infection, leading to viral dissemination and the 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. Immunometabolic defects during HIV-1 infection, even under ART, may also have a role 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 and review articles addressing recent advances in the field of this topic. Novel approaches and technical advances allowing for more precise measurements of metabolic activities in immune cells during HIV-1 infection may also 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

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Keywords

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

Published Papers (9 papers)

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Research

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25 pages, 3945 KiB

Open AccessArticle

Autophagy Deregulation in HIV-1-Infected Cells Increases Extracellular Vesicle Release and Contributes to TLR3 Activation

by Catherine DeMarino, Maria Cowen, Anastasia Williams, Pooja Khatkar, Fardokht A. Abulwerdi, Lisa Henderson, Julia Denniss, Michelle L. Pleet, Delores R. Luttrell, Iosif Vaisman, Lance A. Liotta, Joseph Steiner, Stuart F. J. Le Grice, Avindra Nath and Fatah Kashanchi

Viruses 2024, 16(4), 643; https://doi.org/10.3390/v16040643 - 20 Apr 2024

Viewed by 452

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection can result in HIV-associated neurocognitive disorder (HAND), a spectrum of disorders characterized by neurological impairment and chronic inflammation. Combined antiretroviral therapy (cART) has elicited a marked reduction in the number of individuals diagnosed with HAND. However, there is continual, low-level viral transcription due to the lack of a transcription inhibitor in cART regimens, which results in the accumulation of viral products within infected cells. To alleviate stress, infected cells can release accumulated products, such as TAR RNA, in extracellular vesicles (EVs), which can contribute to pathogenesis in neighboring cells. Here, we demonstrate that cART can contribute to autophagy deregulation in infected cells and increased EV release. The impact of EVs released from HIV-1 infected myeloid cells was found to contribute to CNS pathogenesis, potentially through EV-mediated TLR3 (Toll-like receptor 3) activation, suggesting the need for therapeutics to target this mechanism. Three HIV-1 TAR-binding compounds, 103FA, 111FA, and Ral HCl, were identified that recognize TAR RNA and reduce TLR activation. These data indicate that packaging of viral products into EVs, potentially exacerbated by antiretroviral therapeutics, may induce chronic inflammation of the CNS observed in cART-treated patients, and novel therapeutic strategies may be exploited to mitigate morbidity. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0)

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13 pages, 1887 KiB

Open AccessArticle

Plasma Lipidomic Profiles in cART-Treated Adolescents with Perinatally Acquired HIV Compared to Matched Controls

by Julie van der Post, Thiara E. J. Guerra, Malon van den Hof, Frédéric M. Vaz, Dasja Pajkrt and Jason G. van Genderen

Viruses 2024, 16(4), 580; https://doi.org/10.3390/v16040580 - 09 Apr 2024

Viewed by 447

Abstract

Children with perinatally acquired human immunodeficiency virus (PHIV) are growing into adulthood with HIV and treatment-associated comorbidities, such as dyslipidemia and insulin resistance. HIV is identified as independent risk factor for cardiovascular disease (CVD). The hypothesis behind increased CVD risk associated with HIV includes vascular inflammation, dyslipidemia and combination antiretroviral therapy (cART) metabolomic toxicity. To investigate differences in lipid profiles and pathophysiological mechanisms of CVD risk in adolescents with PHIV, we compared the plasma lipidome of PHIV adolescents and HIV-negative controls. We additionally investigated the influence of current cART regimens and increased lipoprotein(a) (Lp(a)) levels on the plasma lipidome. We included 20 PHIV-infected adolescents and 20 HIV-negative controls matched for age, sex, ethnic origin and socio-economic status. Plasma lipidome was measured using Thermo Scientific Ultimate 3000 binary high-performance liquid chromatography (HPLC)–mass spectrometry. We evaluated the plasma lipidome in PHIV adolescents using different cART regimens (including those known to be associated with lipid alterations). The median age was 17.5 years (15.5–20.7) and 16.5 years (15.7–19.8) for PHIV adolescents and controls, respectively. Of PHIV adolescents, 45% used a non-nucleotide reverse transcriptase inhibitor (NNRTI)-based (25%) or protease inhibitor (PI)-based (20%) cART regimen. In this pilot study, we observed no significant differences between lipidomic profiles between PHIV adolescents and controls. We observed no differences in the plasma lipidome in participants with increased versus normal Lp(a) levels. Different cART regimens appear to influence chain length differences in the plasma lipidome of PHIV adolescents; however, the significance and causality of this observation remains undetermined. Further research on the influence of cART on lipid composition could further identify these alterations. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0)

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14 pages, 1122 KiB

Open AccessArticle

Dynamics of Low-Level Viremia and Immune Activation after Switching to a Darunavir-Based Regimen

by Arjen J. Stam, Ninée V. E. J. Buchholtz, Wouter F. W. Bierman, Reinout van Crevel, Andy I. M. Hoepelman, Mark A. A. Claassen, Heidi S. M. Ammerlaan, Berend J. van Welzen, Marjo E. E. van Kasteren, Steven F. L. van Lelyveld, Dorien de Jong, Kiki Tesselaar, Matthijs van Luin, Monique Nijhuis, Annemarie M. J. Wensing and LOWERIT Study Team

Viruses 2024, 16(2), 182; https://doi.org/10.3390/v16020182 - 25 Jan 2024

Viewed by 846

Abstract

There is an ongoing debate regarding whether low-level viremia (LLV), in particular persistent LLV, during HIV treatment with optimal adherence originates from low-level viral replication, viral production, or both. We performed an observational study in 30 individuals with LLV who switched to a boosted darunavir (DRV)-based therapy. In-depth virological analyses were used to characterize the viral population and the (activity) of the viral reservoir. Immune activation was examined using cell-bound and soluble markers. The primary outcome was defined as the effect on HIV-RNA and was categorized by responders (<50 cp/mL) or non-responders (>50 cp/mL). At week 24, 53% of the individuals were considered responders, 40% non-responders, and 7% could not be assigned. Sequencing showed no evolution or selection of drug resistance in the non-responders. Production of defective virus with mutations in either the protease (D25N) or RT active site contributed to persistent LLV in two individuals. We show that in about half of the study participants, the switch to a DRV-based regimen resulted in a viral response indicative of ongoing low-level viral replication as the cause of LLV before the switch. Our data confirm that in clinical management, high genetic barrier drugs like DRV are a safe choice, irrespective of the source of LLV. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0)

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20 pages, 3442 KiB

Open AccessArticle

Evaluation of Clinical Biomarkers Related to CD4 Recovery in HIV-Infected Patients—5-Year Observation

by Agnieszka Lembas, Andrzej Załęski, Tomasz Mikuła, Tomasz Dyda, Wojciech Stańczak and Alicja Wiercińska-Drapało

Viruses 2022, 14(10), 2287; https://doi.org/10.3390/v14102287 - 18 Oct 2022

Cited by 1 | Viewed by 1571

Abstract

Human Immunodeficiency Virus infection leads to the impairment of immune system function. Even long-term antiretroviral therapy uncommonly leads to the normalization of CD4 count and CD4:CD8 ratio. The aim of this study was to evaluate possible clinical biomarkers which may be related to CD4 and CD4:CD8 ratio recovery among HIV-infected patients with long-term antiretroviral therapy. The study included 68 HIV-infected patients undergoing sustained antiretroviral treatment for a minimum of 5 years. Clinical biomarkers such as age, gender, advancement of HIV infection, coinfections, comorbidities and applied ART regimens were analyzed in relation to the rates of CD4 and CD4:CD8 increase and normalization rates. The results showed that higher rates of CD4 normalization are associated with younger age (p = 0.034), higher CD4 count (p = 0.034) and starting the therapy during acute HIV infection (p = 0.012). Higher rates of CD4:CD8 ratio normalization are correlated with higher CD4 cell count (p = 0.022), high HIV viral load (p = 0.006) and acute HIV infection (p = 0.013). We did not observe statistically significant differences in CD4 recovery depending on gender, HCV/HBV coinfections, comorbidities and opportunistic infections. The obtained results advocate for current recommendations of introducing antiretroviral therapy as soon as possible, preferably during acute HIV infection, since it increases the chances of sufficient immune reconstruction. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0)

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12 pages, 525 KiB

Open AccessArticle

Autopsy Study Defines Composition and Dynamics of the HIV-1 Reservoir after Allogeneic Hematopoietic Stem Cell Transplantation with CCR5Δ32/Δ32 Donor Cells

by Laura E. P. Huyveneers, Anke Bruns, Arjen Stam, Pauline Ellerbroek, Dorien de Jong, Noémi A. Nagy, Stephanie B. H. Gumbs, Kiki Tesselaar, Kobus Bosman, Maria Salgado, Gero Hütter, Lodewijk A. A. Brosens, Mi Kwon, Jose Diez Martin, Jan T. M. van der Meer, Theun M. de Kort, Asier Sáez-Cirión, Julian Schulze zur Wiesch, Jaap Jan Boelens, Javier Martinez-Picado, Jürgen H. E. Kuball, Annemarie M. J. Wensing and Monique Nijhuis Show full author list Hide full author list

Viruses 2022, 14(9), 2069; https://doi.org/10.3390/v14092069 - 17 Sep 2022

Cited by 5 | Viewed by 3076

Abstract

Allo-HSCT with CCR5Δ32/Δ32 donor cells is the only curative HIV-1 intervention. We investigated the impact of allo-HSCT on the viral reservoir in PBMCs and post-mortem tissue in two patients. IciS-05 and IciS-11 both received a CCR5Δ32/Δ32 allo-HSCT. Before allo-HSCT, ultrasensitive HIV-1 RNA quantification; HIV-1-DNA quantification; co-receptor tropism analysis; deep-sequencing and viral characterization in PBMCs and bone marrow; and post-allo-HSCT, ultrasensitive RNA and HIV-1-DNA quantification were performed. Proviral quantification, deep sequencing, and viral characterization were done in post-mortem tissue samples. Both patients harbored subtype B CCR5-tropic HIV-1 as determined genotypically and functionally by virus culture. Pre-allo-HSCT, HIV-1-DNA could be detected in both patients in bone marrow, PBMCs, and T-cell subsets. Chimerism correlated with detectable HIV-1-DNA LTR copies in cells and tissues. Post-mortem analysis of IciS-05 revealed proviral DNA in all tissue biopsies, but not in PBMCs. In patient IciS-11, who was transplanted twice, no HIV-1-DNA could be detected in PBMCs at the time of death, whereas HIV-1-DNA was detectable in the lymph node. In conclusion, shortly after CCR5Δ32/Δ32, allo-HSCT HIV-1-DNA became undetectable in PBMCs. However, HIV-1-DNA variants identical to those present before transplantation persisted in post-mortem-obtained tissues, indicating that these tissues play an important role as viral reservoirs. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0)

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Review

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20 pages, 2382 KiB

Open AccessReview

Mechanisms and Cardiorenal Complications of Chronic Anemia in People with HIV

by Kingsley Kamvuma, Benson M. Hamooya, Sody Munsaka, Sepiso K. Masenga and Annet Kirabo

Viruses 2024, 16(4), 542; https://doi.org/10.3390/v16040542 - 30 Mar 2024

Viewed by 739

Abstract

Chronic anemia is more prevalent in people living with HIV (PLWH) compared to the general population. The mechanisms that drive chronic anemia in HIV are multifaceted and include functional impairment of hematopoietic stem cells, dysregulation of erythropoietin production, and persistent immune activation. Chronic inflammation from HIV infection adversely affects erythropoiesis, erythrocyte lifespan, and erythropoietin response, leading to a heightened risk of co-infections such as tuberculosis, persistent severe anemia, and increased mortality. Additionally, chronic anemia exacerbates the progression of HIV-associated nephrotoxicity and contributes to cardiovascular risk through immune activation and inflammation. This review highlights the cardinal role of chronic inflammation as a link connecting persistent anemia and cardiovascular complications in PLWH, emphasizing the need for a universal understanding of these interconnected pathways for targeted interventions. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0)

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22 pages, 766 KiB

Open AccessReview

Examining Chronic Inflammation, Immune Metabolism, and T Cell Dysfunction in HIV Infection

by Wenli Mu, Vaibhavi Patankar, Scott Kitchen and Anjie Zhen

Viruses 2024, 16(2), 219; https://doi.org/10.3390/v16020219 - 31 Jan 2024

Viewed by 1537

Abstract

Chronic Human Immunodeficiency Virus (HIV) infection remains a significant challenge to global public health. Despite advances in antiretroviral therapy (ART), which has transformed HIV infection from a fatal disease into a manageable chronic condition, a definitive cure remains elusive. One of the key features of HIV infection is chronic immune activation and inflammation, which are strongly associated with, and predictive of, HIV disease progression, even in patients successfully treated with suppressive ART. Chronic inflammation is characterized by persistent inflammation, immune cell metabolic dysregulation, and cellular exhaustion and dysfunction. This review aims to summarize current knowledge of the interplay between chronic inflammation, immune metabolism, and T cell dysfunction in HIV infection, and also discusses the use of humanized mice models to study HIV immune pathogenesis and develop novel therapeutic strategies. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0)

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17 pages, 2120 KiB

Open AccessReview

PSGL-1, a Strategic Biomarker for Pathological Conditions in HIV Infection: A Hypothesis Review

by Silvere D. Zaongo and Yaokai Chen

Viruses 2023, 15(11), 2197; https://doi.org/10.3390/v15112197 - 31 Oct 2023

Viewed by 1625

Abstract

P-selectin glycoprotein ligand-1 (PSGL-1) has been established to be a cell adhesion molecule that is involved in the cellular rolling mechanism and the extravasation cascade, enabling the recruitment of immune cells to sites of inflammation. In recent years, researchers have established that PSGL-1 also functions as an HIV restriction factor. PSGL-1 has been shown to inhibit the HIV reverse transcription process and inhibit the infectivity of HIV virions produced by cells expressing PSGL-1. Cumulative evidence gleaned from contemporary literature suggests that PSGL-1 expression negatively affects the functions of immune cells, particularly T-cells, which are critical participants in the defense against HIV infection. Indeed, some researchers have observed that PSGL-1 expression and signaling provokes T-cell exhaustion. Additionally, it has been established that PSGL-1 may also mediate virus capture and subsequent transfer to permissive cells. We therefore believe that, in addition to its beneficial roles, such as its function as a proinflammatory molecule and an HIV restriction factor, PSGL-1 expression during HIV infection may be disadvantageous and may potentially predict HIV disease progression. In this hypothesis review, we provide substantial discussions with respect to the possibility of using PSGL-1 to predict the potential development of particular pathological conditions commonly seen during HIV infection. Specifically, we speculate that PSGL-1 may possibly be a reliable biomarker for immunological status, inflammation/translocation, cell exhaustion, and the development of HIV-related cancers. Future investigations directed towards our hypotheses may help to evolve innovative strategies for the monitoring and/or treatment of HIV-infected individuals. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0)

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9 pages, 1471 KiB

Open AccessOpinion

Cholesterol Metabolism in Antigen-Presenting Cells and HIV-1 Trans-Infection of CD4⁺ T Cells

by Daniel Okpaise, Nicolas Sluis-Cremer, Giovanna Rappocciolo and Charles R. Rinaldo

Viruses 2023, 15(12), 2347; https://doi.org/10.3390/v15122347 - 29 Nov 2023

Viewed by 1010

Abstract

Antiretroviral therapy (ART) provides an effective method for managing HIV-1 infection and preventing the onset of AIDS; however, it is ineffective against the reservoir of latent HIV-1 that persists predominantly in resting CD4⁺ T cells. Understanding the mechanisms that facilitate the persistence of the latent reservoir is key to developing an effective cure for HIV-1. Of particular importance in the establishment and maintenance of the latent viral reservoir is the intercellular transfer of HIV-1 from professional antigen-presenting cells (APCs—monocytes/macrophages, myeloid dendritic cells, and B lymphocytes) to CD4⁺ T cells, termed trans-infection. Whereas virus-to-cell HIV-1 cis infection is sensitive to ART, trans-infection is impervious to antiviral therapy. APCs from HIV-1-positive non-progressors (NPs) who control their HIV-1 infection in the absence of ART do not trans-infect CD4⁺ T cells. In this review, we focus on this unique property of NPs that we propose is driven by a genetically inherited, altered cholesterol metabolism in their APCs. We focus on cellular cholesterol homeostasis and the role of cholesterol metabolism in HIV-1 trans-infection, and notably, the link between cholesterol efflux and HIV-1 trans-infection in NPs. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 2.0)

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