International Journal of Molecular Sciences

Research

Jump to: Review

12 pages, 1498 KiB

Open AccessArticle

HLA-A*24 Increases the Risk of HTLV-1-Associated Myelopathy despite Reducing HTLV-1 Proviral Load

by Masakazu Tanaka, Norihiro Takenouchi, Shiho Arishima, Toshio Matsuzaki, Satoshi Nozuma, Eiji Matsuura, Hiroshi Takashima and Ryuji Kubota

Int. J. Mol. Sci. 2024, 25(13), 6858; https://doi.org/10.3390/ijms25136858 - 22 Jun 2024

Viewed by 228

Abstract

Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301–309 [...] Read more.

Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301–309 has been identified as an immunodominant epitope restricted to HLA-A*2402. We investigated whether HLA-A*24 reduces HTLV-1 PVL and the risk of HAM/TSP using blood samples from 152 HAM/TSP patients and 155 asymptomatic HTLV-1 carriers. The allele frequency of HLA-A*24 was higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers (72.4% vs. 58.7%, odds ratio 1.84), and HLA-A*24-positive patients showed a 42% reduction in HTLV-1 PVL compared to negative patients. Furthermore, the PVL negatively correlated with the frequency of Tax 301–309-specific CTLs. These findings are opposite to the effects of HLA-A*02, which reduces HTLV-1 PVL and the risk of HAM/TSP. Therefore, we compared the functions of CTLs specific to Tax 11–19 or Tax 301–309, which are immunodominant epitopes restricted to HLA-A*0201 or HLA-A*2402, respectively. The maximum responses of these CTLs were not different in the production of IFN-γ and MIP-1β or in the expression of CD107a—a marker for the degranulation of cytotoxic molecules. However, Tax 301–309-specific CTLs demonstrated 50-fold higher T-cell avidity than Tax 11–19-specific CTLs, suggesting better antigen recognition at low expression levels of the antigens. These findings suggest that HLA-A*24, which induces sensitive HTLV-1-specific CTLs, increases the risk of HAM/TSP despite reducing HTLV-1 PVL. Full article

(This article belongs to the Special Issue Molecular Research on Human Retrovirus Infection)

► Show Figures

Figure 1

11 pages, 758 KiB

Open AccessCommunication

Evaluating HIV-1 Infectivity and Virion Maturation across Varied Producer Cells with a Novel FRET-Based Detection and Quantification Assay

by Aidan McGraw, Grace Hillmer, Jeongpill Choi, Kedhar Narayan, Stefania M. Mehedincu, Dacia Marquez, Hasset Tibebe, Kathleen L. DeCicco-Skinner and Taisuke Izumi

Int. J. Mol. Sci. 2024, 25(12), 6396; https://doi.org/10.3390/ijms25126396 - 10 Jun 2024

Viewed by 1175

Abstract

The maturation of HIV-1 virions is a crucial process in viral replication. Although T-cells are a primary source of virus production, much of our understanding of virion maturation comes from studies using the HEK293T human embryonic kidney cell line. Notably, there is a [...] Read more.

The maturation of HIV-1 virions is a crucial process in viral replication. Although T-cells are a primary source of virus production, much of our understanding of virion maturation comes from studies using the HEK293T human embryonic kidney cell line. Notably, there is a lack of comparative analyses between T-cells and HEK293T cells in terms of virion maturation efficiency in existing literature. We previously developed an advanced virion visualization system based on the FRET principle, enabling the effective distinction between immature and mature virions via fluorescence microscopy. In this study, we utilized pseudotyped, single-round infectious viruses tagged with FRET labels (HIV-1 Gag-iFRET∆Env) derived from Jurkat (a human T-lymphocyte cell line) and HEK293T cells to evaluate their virion maturation rates. HEK293T-derived virions demonstrated a maturity rate of 81.79%, consistent with other studies and our previous findings. However, virions originating from Jurkat cells demonstrated a significantly reduced maturation rate of 68.67% (p < 0.0001). Correspondingly, viruses produced from Jurkat cells exhibited significantly reduced infectivity compared to those derived from HEK293T cells, with the relative infectivity measured at 65.3%. This finding is consistent with the observed relative maturation rate of viruses produced by Jurkat cells. These findings suggest that initiation of virion maturation directly correlates with viral infectivity. Our observation highlights the dynamic nature of virus–host interactions and their implications for virion production and infectivity. Full article

(This article belongs to the Special Issue Molecular Research on Human Retrovirus Infection)

► Show Figures

Figure 1

12 pages, 2510 KiB

Open AccessArticle

Ripasudil as a Potential Therapeutic Agent in Treating Secondary Glaucoma in HTLV-1-Uveitis: An In Vitro Analysis

by Mingming Yang, Koju Kamoi, Yuan Zong, Jing Zhang, Yaru Zou and Kyoko Ohno-Matsui

Int. J. Mol. Sci. 2024, 25(6), 3229; https://doi.org/10.3390/ijms25063229 - 12 Mar 2024

Viewed by 1175

Abstract

Human T-cell leukemia virus type 1 (HTLV-1), a virus that affects 5–10 million people globally, causes several diseases, including adult T-cell leukemia-lymphoma and HTLV-1-associated uveitis (HU). HU is prevalent in Japan and often leads to secondary glaucoma, which is a serious complication. We [...] Read more.

Human T-cell leukemia virus type 1 (HTLV-1), a virus that affects 5–10 million people globally, causes several diseases, including adult T-cell leukemia-lymphoma and HTLV-1-associated uveitis (HU). HU is prevalent in Japan and often leads to secondary glaucoma, which is a serious complication. We investigated the efficacy of ripasudil, a Rho-associated coiled coil-forming protein kinase inhibitor, in alleviating changes in human trabecular meshwork cells (hTM cells) infected with HTLV-1. HTLV-1-infected hTM cells were modeled in vitro using MT-2 cells, followed by treatment with varying concentrations of ripasudil. We assessed changes in cell morphology, viability, and inflammatory cytokine levels, as well as NF-κB activation. The results showed that ripasudil treatment changed the cell morphology, reduced the distribution of F-actin and fibronectin, and decreased the levels of certain inflammatory cytokines, such as interleukin (IL)-6, IL-8, and IL-12. However, ripasudil did not significantly affect NF-κB activation or overall cell viability. These findings suggest that ripasudil has the potential to treat secondary glaucoma in patients with HU by modulating cytoskeletal organization and alleviating inflammation in HTLV-1-infected hTM cells. This study lays the foundation for further clinical studies exploring the effectiveness of ripasudil for the treatment of secondary glaucoma associated with HU. Full article

(This article belongs to the Special Issue Molecular Research on Human Retrovirus Infection)

► Show Figures

Figure 1

13 pages, 1808 KiB

Open AccessArticle

Interaction of TSG101 with the PTAP Motif in Distinct Locations of Gag Determines the Incorporation of HTLV-1 Env into the Retroviral Virion

by Yosuke Maeda, Kazuaki Monde, Hiromi Terasawa, Yuetsu Tanaka and Tomohiro Sawa

Int. J. Mol. Sci. 2023, 24(22), 16520; https://doi.org/10.3390/ijms242216520 - 20 Nov 2023

Viewed by 1146

Abstract

Human T-cell tropic virus type 1 (HTLV-1) is known to be mainly transmitted by cell-to-cell contact due to the lower infectivity of the cell-free virion. However, the reasons why cell-free HTLV-1 infection is poor remain unknown. In this study, we found that the [...] Read more.

Human T-cell tropic virus type 1 (HTLV-1) is known to be mainly transmitted by cell-to-cell contact due to the lower infectivity of the cell-free virion. However, the reasons why cell-free HTLV-1 infection is poor remain unknown. In this study, we found that the retrovirus pseudotyped with HTLV-1 viral envelope glycoprotein (Env) was infectious when human immunodeficiency virus type 1 (HIV-1) was used to produce the virus. We found that the incorporation of HTLV-1 Env into virus-like particles (VLPs) was low when HTLV-1 Gag was used to produce VLPs, whereas VLPs produced using HIV-1 Gag efficiently incorporated HTLV-1 Env. The production of VLPs using Gag chimeras between HTLV-1 and HIV-1 Gag and deletion mutants of HIV-1 Gag showed that the p6 domain of HIV-1 Gag was responsible for the efficient incorporation of HTLV-1 Env into the VLPs. Further mutagenic analyses of the p6 domain of HIV-1 Gag revealed that the PTAP motif in the p6 domain of HIV-1 Gag facilitates the incorporation of HTLV-1 Env into VLPs. Since the PTAP motif is known to interact with tumor susceptibility gene 101 (TSG101) during the budding process, we evaluated the effect of TSG101 knockdown on the incorporation of HTLV-1 Env into VLPs. We found that TSG101 knockdown suppressed the incorporation of HTLV-1 Env into VLPs and decreased the infectivity of cell-free HIV-1 pseudotyped with HTLV-1 Env. Our results suggest that the interaction of TSG101 with the PTAP motif of the retroviral L domain is involved not only in the budding process but also in the efficient incorporation of HTLV-1 Env into the cell-free virus. Full article

(This article belongs to the Special Issue Molecular Research on Human Retrovirus Infection)

► Show Figures

Figure 1

16 pages, 5356 KiB

Open AccessArticle

Retrovirus-Derived RTL9 Plays an Important Role in Innate Antifungal Immunity in the Eutherian Brain

by Fumitoshi Ishino, Johbu Itoh, Masahito Irie, Ayumi Matsuzawa, Mie Naruse, Toru Suzuki, Yuichi Hiraoka and Tomoko Kaneko-Ishino

Int. J. Mol. Sci. 2023, 24(19), 14884; https://doi.org/10.3390/ijms241914884 - 4 Oct 2023

Cited by 2 | Viewed by 2079

Abstract

Retrotransposon Gag-like (RTL) genes play a variety of essential and important roles in the eutherian placenta and brain. It has recently been demonstrated that RTL5 and RTL6 (also known as sushi-ichi retrotransposon homolog 8 (SIRH8) and SIRH3) are microglial genes [...] Read more.

Retrotransposon Gag-like (RTL) genes play a variety of essential and important roles in the eutherian placenta and brain. It has recently been demonstrated that RTL5 and RTL6 (also known as sushi-ichi retrotransposon homolog 8 (SIRH8) and SIRH3) are microglial genes that play important roles in the brain’s innate immunity against viruses and bacteria through their removal of double-stranded RNA and lipopolysaccharide, respectively. In this work, we addressed the function of RTL9 (also known as SIRH10). Using knock-in mice that produce RTL9-mCherry fusion protein, we examined RTL9 expression in the brain and its reaction to fungal zymosan. Here, we demonstrate that RTL9 plays an important role, degrading zymosan in the brain. The RTL9 protein is localized in the microglial lysosomes where incorporated zymosan is digested. Furthermore, in Rtl9 knockout mice expressing RTL9ΔC protein lacking the C-terminus retroviral GAG-like region, the zymosan degrading activity was lost. Thus, RTL9 is essentially engaged in this reaction, presumably via its GAG-like region. Together with our previous study, this result highlights the importance of three retrovirus-derived microglial RTL genes as eutherian-specific constituents of the current brain innate immune system: RTL9, RTL5 and RTL6, responding to fungi, viruses and bacteria, respectively. Full article

(This article belongs to the Special Issue Molecular Research on Human Retrovirus Infection)

► Show Figures

Figure 1

13 pages, 3035 KiB

Open AccessArticle

HIV and SIV Envelope Glycoproteins Interact with Glycolipids and Lipids

by Rémi Planes and Elmostafa Bahraoui

Int. J. Mol. Sci. 2023, 24(14), 11730; https://doi.org/10.3390/ijms241411730 - 21 Jul 2023

Viewed by 1143

Abstract

The present study demonstrates that, in addition to interacting with galactosylceramide (GalCer), HIV-1, HIV-2, and SIV envelope glycoproteins are able to interact with glucosylceramide (GlcCer), lactosylceramide (LacCer), and ceramide. These interactions were characterized by using three complementary approaches based on molecular binding and [...] Read more.

The present study demonstrates that, in addition to interacting with galactosylceramide (GalCer), HIV-1, HIV-2, and SIV envelope glycoproteins are able to interact with glucosylceramide (GlcCer), lactosylceramide (LacCer), and ceramide. These interactions were characterized by using three complementary approaches based on molecular binding and physicochemical assays. The binding assays showed that iodinated radiolabeled HIV-1 and HIV-2 glycoproteins (¹²⁵I-gp) interact physically with GalCer, GlcCer, LacCer, and ceramide previously separated by thin layer chromatography (TLC) or directly coated on a flexible 96-well plate. These interactions are specific as demonstrated, on the one hand, by the dose-dependent inhibition in the presence of various dilutions of immune, but not non-immune, sera, and, on the other hand, by the absence of interaction of these glycolipids/lipids with ¹²⁵I-IgG used as an unrelated control protein. These interactions were further confirmed in a physicochemical assay, based on the capacity of these glycolipids for insertion in a pre-established monomolecular film, as a model of the cell membrane, with each glycolipid/lipid. The addition of HIV envelope glycoproteins, but not ovomucoid protein used as a negative control, resulted in a rapid increase in surface pressure of the glycolipid/lipid films, thus indirectly confirming their interactions with GalCer, GlcCer, LacCer, and ceramide. In summary, we show that HIV and SIV envelope glycoproteins bind to GalCer, GlcCer, LacCer, and ceramide in a dose-dependent, saturable, and specific manner. These interactions may function as receptors of attachment in order to facilitate infection of CD4 low or negative cells or promote interactions with other receptors leading to the activation of signaling pathways or pathogenesis. Full article

(This article belongs to the Special Issue Molecular Research on Human Retrovirus Infection)

► Show Figures

Figure 1

Review

Jump to: Research

24 pages, 877 KiB

Open AccessReview

May I Help You with Your Coat? HIV-1 Capsid Uncoating and Reverse Transcription

by Laura Arribas, Luis Menéndez-Arias and Gilberto Betancor

Int. J. Mol. Sci. 2024, 25(13), 7167; https://doi.org/10.3390/ijms25137167 (registering DOI) - 28 Jun 2024

Viewed by 210

Abstract

The human immunodeficiency virus type 1 (HIV-1) capsid is a protein core formed by multiple copies of the viral capsid (CA) protein. Inside the capsid, HIV-1 harbours all the viral components required for replication, including the genomic RNA and viral enzymes reverse transcriptase [...] Read more.

The human immunodeficiency virus type 1 (HIV-1) capsid is a protein core formed by multiple copies of the viral capsid (CA) protein. Inside the capsid, HIV-1 harbours all the viral components required for replication, including the genomic RNA and viral enzymes reverse transcriptase (RT) and integrase (IN). Upon infection, the RT transforms the genomic RNA into a double-stranded DNA molecule that is subsequently integrated into the host chromosome by IN. For this to happen, the viral capsid must open and release the viral DNA, in a process known as uncoating. Capsid plays a key role during the initial stages of HIV-1 replication; therefore, its stability is intimately related to infection efficiency, and untimely uncoating results in reverse transcription defects. How and where uncoating takes place and its relationship with reverse transcription is not fully understood, but the recent development of novel biochemical and cellular approaches has provided unprecedented detail on these processes. In this review, we present the latest findings on the intricate link between capsid stability, reverse transcription and uncoating, the different models proposed over the years for capsid uncoating, and the role played by other cellular factors on these processes. Full article

(This article belongs to the Special Issue Molecular Research on Human Retrovirus Infection)

14 pages, 1006 KiB

Open AccessReview

HIV Reservoirs and Treatment Strategies toward Curing HIV Infection

by Kouki Matsuda and Kenji Maeda

Int. J. Mol. Sci. 2024, 25(5), 2621; https://doi.org/10.3390/ijms25052621 - 23 Feb 2024

Viewed by 1558

Abstract

Combination antiretroviral therapy (cART) has significantly improved the prognosis of individuals living with human immunodeficiency virus (HIV). Acquired immunodeficiency syndrome has transformed from a fatal disease to a treatable chronic infection. Currently, effective and safe anti-HIV drugs are available. Although cART can reduce [...] Read more.

Combination antiretroviral therapy (cART) has significantly improved the prognosis of individuals living with human immunodeficiency virus (HIV). Acquired immunodeficiency syndrome has transformed from a fatal disease to a treatable chronic infection. Currently, effective and safe anti-HIV drugs are available. Although cART can reduce viral production in the body of the patient to below the detection limit, it cannot eliminate the HIV provirus integrated into the host cell genome; hence, the virus will be produced again after cART discontinuation. Therefore, research into a cure (or remission) for HIV has been widely conducted. In this review, we focus on drug development targeting cells latently infected with HIV and assess the progress including our current studies, particularly in terms of the “Shock and Kill”, and “Block and Lock” strategies. Full article

(This article belongs to the Special Issue Molecular Research on Human Retrovirus Infection)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Molecular Research on Human Retrovirus Infection

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI