Human Lymphotropic Virus Type Research Articles

Neurological aspects of HTLV-1 infection: symptoms in apparently asymptomatic carriers.

Human T-lymphotropic virus type 1 (HTLV-1) is classically associated with the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), although the mechanisms of this neurological disorder remain unclear. In addition, some patients who develop "minor" neurological signs that do not meet diagnostic criteria for HAM/TSP are classified as asymptomatic carriers. This study aims to demonstrate the neurological symptoms of Brazilian patients living with HTLV-1 classified as not-HAM.TSP.This observational study evaluated patients treated in an HTLV reference center in Bahia, Brazil, between February 2022 and July 2023. The data were obtained through the analysis of medical records and neurological consultation. Those individuals classified as HAM/ TSP were excluded from this study. 74 patients were submitted to a careful neurological evaluation: 23 HAM/TSP, 22 were classified with intermediate syndrome (IS), and 29 were oligosymptomatic. Self-reported symptoms were significantly more common in the IS group, including urinary symptoms such as nocturia, urgency, incontinence, dysuria, weakness, paresthesia, lumbar pain, xerostomia, and xerophthalmia. Physical examination findings consistent with reduced vibratory and tactile sensitivity were more common in the IS group (p = 0.017 and p = 0.013). Alterations in the V and VIII cranial nerves were present in both groups. HTLV-1 can lead to the development of important neurological signs and symptoms in apparently asymptomatic individuals. This data highlights the need for more research into the neurological aspects of HTLV-1 infection and emphasizes the importance of early diagnosis, treatment, and support for individuals living with this virus.

Dynamics of HIV-1 and HTLV-1 Coinfection with both CTL and Antibody Responses

Human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1) coinfection models with simply an antibody response or a CTL response have been the subject of several recent investigations. Thus, the primary objective of this paper is to formulate and examine a mathematical framework for analyzing the intricate dynamics of coinfection between HIV-1 and HTLV-1. The model takes into account the role of antibody response against free HIV-1 particles and CTL response against HTLV-1-infected cells. We prove that the model is well-posed and it admits eight equilibria. The stability and existence of the equilibria are precisely controlled by eight threshold parameters ℜi, i = 1, 2, ..., 8. By formulating suitable Lyapunov functions and applying LaSalle's invariance principle, we show the global asymptotic stability for all equilibria. To demonstrate the theoretical results, we conduct numerical simulations. We look at how the antibody and CTL responses affect the dynamical behavior of HIV-1/HTLV-1 coinfection. Although the parameters of antibody and CTL responses have no effect on the basic reproduction ratio of HIV-1 single-infection (ℜ₁) and HTLV-1 single-infection (ℜ₂), it has been demonstrated that viral coinfection can be inhibited by immunological activation of antibody and CTL responses. This could potentially facilitate the advancement of therapeutic approaches for HIV-1 and HTLV-1, which have the capability to enhance the HIV-1-specific antibody and HTLV-1-specific CTL reactions.

Geographic characteristics of HTLV-1 molecular subgroups and genetic substitutions in East Asia: Insights from complete genome sequencing of HTLV-1 strains isolated in Taiwan and Japan.

Although Japan is a major endemic area for human T-lymphotropic virus type 1 (HTLV-1) and the virus has been well-studied in this region, there is limited research on HTLV-1 in surrounding regions. In this study, we determined the complete genome sequences of HTLV-1 strains isolated from Taiwan and Japan and investigated the geographic characteristics of molecular subgroups and substitution mutations to understand the spread of HTLV-1 and its correlation with human migration. The complete genome sequences of 26 HTLV-1 isolates from Taiwan were determined using next-generation sequencing and were compared with those of 211 isolates from Japan in terms of subgroup and genetic mutations. In total, 15/26 (58%) isolates from Taiwan belonged to the transcontinental subgroup and 11/26 (42%) isolates belonged to the Japanese subgroup. The transcontinental subgroup was significantly more prevalent among Taiwanese isolates than Japanese isolates (58% vs 18%, P < 0.0001). The mutation rate for the complete HTLV-1 sequence was as low as 0.2%. On examining individual base substitutions, the G-to-A mutation was predominant. Bayesian phylogenetic tree analysis estimated the time to the most recent common ancestor for the transcontinental and Japanese subgroups to be 28447 years. The transcontinental subgroups from Taiwan and Japan appeared to form clusters according to their respective regions. The transcontinental subgroup of HTLV-1 is predominant in Taiwan, while the Japanese subgroup is common in Japan. The difference in subgroup distribution may be attributed to the initial spread of the transcontinental subgroup in East Asia, followed by the influx of the Japanese subgroup.

Development of Potential Inhibitors for Human T-lymphotropic virus type I Integrase enzyme: A molecular modeling approach.

Integration of viral DNA into the host cell genome, carried out by the HTLV-1 integrase enzyme, is a crucial step in the Human T-lymphotropic virus type I (HTLV-1) life cycle. Thus, HTLV-1 integrase is considered an attractive therapeutic target; however, no clinically effective inhibitors are available to treat HTLV-1 infection. Objective The main objective was to identify potential drug-like compounds capable of effectively inhibiting HTLV-1 integrase activity. In this study, a model of HTLV-1 integrase structure and three integrase inhibitors (dolutegravir, raltegravir, and elvitegravir as scaffolds) were used for designing new inhibitors. Designed molecules were used as templates for virtual screening to retrieve new inhibitors from PubChem, ZINC15, and ChEMBL databases. Drug-likeness and docked energy of the molecules were investigated using the SWISS-ADME portal and GOLD software. The stability and binding energy of the complexes were further investigated using molecular dynamic (MD) simulation. Four novel potential inhibitors were developed using a structure-based design protocol and three compounds from virtual screening. They formed hydrogen bonding interactions with critical residues Asp69, Asp12, Tyr96, Tyr143, Gln146, Ile13, and Glu105. In addition, π stacking, halogen, and hydrogen bond interactions were seen between compounds (especially halogenated benzyl moieties) and viral DNA similar to those seen in parent molecules. MD simulation confirmed higher stability of the receptor-ligand complex than the ligand-free enzyme. Combing structure-based design and virtual screening resulted in identifying three drug-like molecules (PubChem CID_138739497, _70381610, and _140084032) that are suggested as lead compounds for developing effective drugs targeting HTLV-1 integrase enzyme.

Disfunción eréctil e infecciones virales: una revisión narrativa

Description of the topic: Erectile dysfunction is a prevalent condition among the male population and can result from various factors such as hormonal, metabolic, infectious, or anatomical issues. Infections caused by viruses such as Human Immunodeficiency Virus (HIV), Herpes Simplex Virus, Varicella-Zoster Virus, Human Papillomavirus (HPV), Human T-lymphotropic Virus type 1 (HTLV-1), Dengue virus, and SARS-CoV-2 have been found to be associated with erectile dysfunction through different physiological mechanisms. In many cases, these infections interact with the immune system, leading to the development of a localized or generalized inflammatory response of varying intensity. Relevance: Certain viral infections can directly affect the tissues of the male reproductive system, resulting in erectile dysfunction. These infections can damage the nerves and blood vessels that are essential for achieving and maintaining an erection. Conclusion: Erectile dysfunction is of multifactorial origin, and according to the reviewed literature it can be triggered by some vascular sequelae induced by viral infections, including those produced by the acquired immunodeficiency virus (HIV), herpes simplex virus, zoster, human papilloma (HPV), human lymphotropic virus type I (HTL1), Dengue and SARS-CoV2.

Impaired humoral immunity following COVID-19 vaccination in HTLV-1 carriers

BackgroundWhether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown.MethodsTo investigate humoral immunity after COVID-19 vaccination in HTLV-1 carriers, a multicenter, prospective observational cohort study was conducted at five institutions in southwestern Japan, an endemic area for HTLV-1. HTLV-1 carriers and HTLV-1-negative controls were enrolled for this study from January to December 2022. During this period, the third dose of the COVID-19 vaccine was actively administered. HTLV-1 carriers were enrolled during outpatient visits, while HTLV-1-negative controls included health care workers and patients treated by participating institutions for diabetes, hypertension, or dyslipidemia. The main outcome was the effect of HTLV-1 infection on the plasma anti-COVID-19 spike IgG (IgG-S) titers after the third dose, assessed by multivariate linear regression with other clinical factors.ResultsWe analyzed 181 cases (90 HTLV-1 carriers, 91 HTLV-1-negative controls) after receiving the third dose. HTLV-1 carriers were older (median age 67.0 vs. 45.0 years, p < 0.001) and more frequently had diabetes, hypertension, or dyslipidemia than did HTLV-1-negative controls (60.0% vs. 27.5%, p < 0.001). After the third dose, the IgG-S titers decreased over time in both carriers and controls. Multivariate linear regression in the entire cohort showed that time since the third dose, age, and HTLV-1 infection negatively influenced IgG-S titers. After adjusting for confounders such as age, or presence of diabetes, hypertension, or dyslipidemia between carriers and controls using the overlap weighting propensity score method, and performing weighted regression analysis in the entire cohort, both time since the third dose and HTLV-1 infection negatively influenced IgG-S titers.ConclusionsThe humoral immunity after the third vaccination dose is impaired in HTLV-1 carriers; thus, customized vaccination schedules may be necessary for them.

HTLV-1 reverse transcriptase homology model provides structural basis for sensitivity to existing nucleoside/nucleotide reverse transcriptase inhibitors

The human T-lymphotropic virus type 1 (HTLV-1) infects millions of people globally and is endemic to various resource-limited regions. Infections persist for life and are associated with increased susceptibility to opportunistic infections and severe diseases including adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy-tropical spastic paraparesis. No HTLV-1-specific anti-retrovirals have been developed and it is unclear whether existing anti-retrovirals developed for treatment of human immunodeficiency virus (HIV) have efficacy against HTLV-1. To understand the structural basis for therapeutic binding, homology modelling and machine learning were used to develop a structural model of the HTLV-1 reverse transcriptase. With this, molecular docking experiments using a panel of FDA-approved inhibitors of viral reverse transcriptases to assess their capacity for binding, and in turn, inhibition. Importantly, nucleoside/nucleotide reverse transcriptase inhibitor but not non-nucleoside reverse transcriptase inhibitors were predicted to bind the HTLV-1 reverse transcriptase, with similar affinity to HIV-1 reverse transcriptase. By strengthening the rationale for clinical testing of therapies such as tenofovir alafenamide, zidovudine, lamivudine, and azvudine for treatment of HTLV-1, this study has demonstrated the power of in silico structural biology approaches in drug design and therapeutic testing.

Repurposing integrase inhibitors against human T-lymphotropic virus type-1: a computational approach

Adult T-cell Lymphoma (ATL) is caused by the delta retrovirus family member known as Human T-cell Leukaemia Type I (HTLV-1). Due to the unavailability of any cure, the study gained motivation to identify some repurposed drugs against the virus. A quick and accurate method of screening licensed medications for finding a treatment for HTLV-1 is by cheminformatics drug repurposing in order to analyze a dataset of FDA approved integrase antivirals against HTLV-1 infection. To determine how the antiviral medications interacted with the important residues in the HTLV-1 integrase active regions, molecular docking modeling was used. The steady behavior of the ligands inside the active region was then confirmed by molecular dynamics for the probable receptor-drug complexes. Cabotegravir, Raltegravir and Elvitegravir had the best docking scores with the target, indicating that they can tightly bind to the HTLV-1 integrase. Moreover, MD simulation revealed that the Cabotegravir-HTLV-1, Raltegravir-HTLV-1 and Elvitegravir-HTLV-1 interactions were stable. It is obvious that more testing of these medicines in both clinical trials and experimental tests is necessary to demonstrate their efficacy against HTLV-1 infection. Communicated by Ramaswamy H. Sarma

Development of Innate-Immune-Cell-Based Immunotherapy for Adult T-Cell Leukemia-Lymphoma.

γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia-lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL.

Molecular diagnosis of opportunistic infections in the central nervous system of HIV-infected adults in Manaus, Amazonas.

Opportunistic infections in the central nervous system (CNS) of people with HIV/AIDS (PLWHA) remain significant contributors to morbidity and mortality, especially in resource-limited scenarios. Diagnosing these infections can be challenging, as brain imaging is non-specific and expensive. Therefore, molecular analysis of cerebrospinal fluid (CSF) may offer a more accurate and affordable method for diagnosing pathogens. We conducted extensive real-time PCR testing (qPCR) on CSF to evaluate etiological agents in PLWHA with neurological manifestations. Primers targeting DNA from specific pathogens, including cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), John Cunningham virus (JCV), Toxoplasma gondii, and human T-lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2), were used. Cerebrospinal fluid samples revealed 90 pathogens (36.7%). Toxoplasma gondii was the most frequently detected pathogen, found in 22 samples (30.5%). Other pathogens included Cryptococcus sp. (7.7%), EBV (5.3%), CMV, VZV, and JCV (4.0% each). Despite antiretroviral therapy and medical follow-up, opportunistic central nervous system infections remain frequent in PLWHA. Herpesviruses are commonly detected, but T. gondii is the most prevalent opportunistic pathogen in our study population. Therefore, molecular diagnosis is a crucial tool for identifying opportunistic infections, even in patients undergoing treatment.

Abstract B043: Challenges in managing cancer patients with congenital coronary artery anomalies: A case report

Abstract Introduction: Congenital coronary artery anomalies are rare cardiac abnormalities that can increase the risk of sudden cardiac death, particularly during exercise. Patients with cancer and concurrent coronary artery disease face higher mortality risks, as they often receive delayed percutaneous coronary intervention. Additionally, anthracycline chemotherapy, commonly used in cancer treatment, can cause cardiotoxicity and worsen pre-existing cardiac abnormalities. Despite the complexity of managing cancer patients with coronary artery anomalies, there is a lack of clear guidelines and consensus on optimal approaches. This report presents a unique case of a patient with a malignant inter-arterial course of the right coronary artery and newly diagnosed Human T-lymphotropic virus type I-associated adult T-cell leukemia/lymphoma, discussing the challenges and implications of chemotherapy in such cases. Case Presentation: A 38-year-old male presented with weakness and palpitations, exhibiting abnormal laboratory findings. CT angiography revealed a malignant inter-arterial course of the right coronary artery with severe narrowing. Electrocardiograms showed ST elevations and subsequent T-wave inversions. Despite the increased risk of cardiomyopathy due to the coronary anomaly, the patient required chemotherapy for life-threatening tumor lysis syndrome and refractory lactic acidosis. Anthracycline-based chemotherapy was initiated, and a follow-up echocardiogram after six months showed no acute changes. Conclusion: Managing cancer patients receiving anthracycline chemotherapy remains challenging due to limited guidelines. Anthracycline-induced cardiotoxicity is a concern, especially in patients with pre-existing cardiac anomalies like the malignant inter-arterial course of the right coronary artery. This case emphasizes the importance of recognizing and managing such anomalies in cancer patients to reduce the risk of sudden cardiac death. The higher mortality risk in cancer patients with coronary artery disease highlights the need for guidelines in managing anomalous coronary vessels in cancer patients. Further research is necessary to develop evidence-based strategies for managing cardiac complications in cancer patients, particularly those with pre-existing cardiac anomalies. Citation Format: Aliya M. Khan, Sophia Navajas Urisote, Danish A. Sheikh. Challenges in managing cancer patients with congenital coronary artery anomalies: A case report [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B043.

Abstract B042: Chemotherapy in a patient with the malignant inter-arterial course of the right coronary artery A choice between cancer or the heart?

Abstract Introduction: Congenital coronary artery anomalies can increase the risk of sudden cardiac death, especially during exercise. Cancer patients with concurrent coronary artery disease face higher mortality rates due to delayed percutaneous coronary intervention. Furthermore, anthracycline chemotherapy, a common cancer treatment, can worsen pre-existing cardiac abnormalities. Despite the complexity of managing cancer patients with coronary artery anomalies, there is a lack of clear guidelines. This report presents a case of malignant interarterial course of the right coronary artery in a patient with Human T-lymphotropic virus type I-associated adult T-cell leukemia/lymphoma and discusses the challenges of chemotherapy in such cases. Case presentation: A 38-year-old male presented with weakness and palpitations. Laboratory findings revealed abnormalities, including elevated troponin and severe narrowing of the right coronary artery. Electrocardiograms showed ST elevations initially, followed by T-wave inversions. Although the patient had a pre-existing coronary anomaly, chemotherapy was initiated due to life-threatening tumor lysis syndrome and refractory lactic acidosis. Cardiac catheterization or surgical intervention was not possible due to comorbidities. A follow-up echocardiogram after six months of chemotherapy showed no acute changes. Discussion: Managing cancer patients with congenital coronary artery anomalies is challenging. Malignant interarterial course of the right coronary artery is particularly concerning due to the risk of sudden cardiac death. In this case, the patient's symptoms and abnormal electrocardiogram led to the identification of the coronary anomaly. However, immediate intervention was not feasible due to the patient's critical condition. The initiation of anthracycline-based chemotherapy in this patient posed a dilemma. Anthracyclines can cause cardiotoxicity, worsening pre-existing cardiac anomalies. Despite the lack of guidelines, chemotherapy was administered due to the urgent need for cancer treatment. Regular monitoring was essential to detect any cardiac changes. Conclusion: Managing cancer patients with coronary artery anomalies and administering anthracycline chemotherapy remains challenging due to limited guidelines. The case highlights the importance of recognizing and managing these anomalies to reduce the risk of sudden cardiac death. Guidelines for managing cardiac complications in cancer patients with pre-existing anomalies are needed. Further research is necessary to provide evidence-based guidance for such cases. Citation Format: Aliya M. Khan. Chemotherapy in a patient with the malignant inter-arterial course of the right coronary artery A choice between cancer or the heart? [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B042.

Examining Adult T-Cell Leukemia/Lymphoma in the United States: A Hospital Based Study of Demographics and Survival Outcomes Focused on Hispanics

BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive neoplasm of mature CD4(+) T-cells caused by infection by Human T-lymphotropic virus type1 (HTLV-1) ( Arch Pathol Lab Med PMID: 24476526). ATLL affects 5% of those infected by HTLV-1, mainly in Africa, the Caribbean, Japan, and South America ( Rev Assoc Med Bras (1992) PMID: 27925051). In the United States (US) it is usually seen in immigrants from these regions ( Arch Pathol Lab Med PMID: 24476526). While there are treatment options for ATLL, it is often refractory to conventional chemotherapy and in general has a poor prognosis ( Actas Dermosifiliogr (Engl Ed) PMID: 29685460, Cancer Treat Res PMID: 30596217). Considering its poor outcomes and unique epidemiology, more information is needed regarding its effect in Hispanics (HI) vs Non-hispanics (NH) in the US. METHODS: Data were analyzed on ATLL patients in the US reported to the National Cancer Database (NCDB) between 2004 and 2019. Demographic and treatment characteristics were compared between ethnic groups. Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS) between HI and NH populations. Multivariate analysis and propensity score matching was performed with adjustment for age, stage, comorbidity score, and insurance status, type of facility and great circle distance. RESULTS Of the 3073 ATLL patients studied between 2004 and 2019, 9% were HI, and 87% NH. In both groups, most here male with 65% of HI and 66% of NH. At diagnosis, HI patients were younger with a median age of 35 years vs. 42 years in NH (p&amp;lt;0.001). HI patients were more likely to be &amp;lt;65 at diagnosis 89% vs 83% (p=0.044). Most HI and NH patients identified as white (86% vs 68%), followed by black (4% vs 25%). Private insurance was the most common type in both groups (50% vs 57%), followed by government sponsored insurance (33% vs 36%). HI had a higher rate of being uninsured 12% vs 6% (p&amp;lt;0.001). Regarding Census Median Income (2008-2012), the most prevalent bracket for HI was $48,000 - $62,000 (28%), compared to NH $63,000+ (33%). HI were more likely to have an income of less than $38,000 (21% vs 18%) (p=0.512). HI also tended to live closer to their hospital (Great Circle Distance), with a median of 8.0 miles, vs NH at median of 11.6 miles (p=0.001). On survival analysis; the survival probability at 2, 5 and 10 years of HI vs NH were (64% vs 58%), (53% vs 48%), and (51% vs 43%), respectively. The median survival (MS) time was 3.7 years for NH and not reached for HI. The overall survival (OS) difference favoring HI was marginal and non-statistically significant (p=0.067). Independently, on multivariate analysis, NH ethnicity was not associated with worse OS (HR 1.25, CI 0.9-1.74, p=0.18). Interestingly, the propensity matched analysis demonstrated significant MS difference between HI vs NH (median 1.84 vs. 1.53 years). CONCLUSION Although the difference in OS in this study between HI and NH was not significant, there is a trend in the data showing increased survivability among HI despite patients in this group being more likely to be uninsured or in a lower income bracket. One possible explanation is that HI tended to present at an earlier age when compared to NH. It is evident that more data is needed to increase the power of these findings. Therefore, further study into the disease differences between these two groups, early detection, tumor markers, and targeted treatments will be necessary to improve the overall poor prognosis of this aggressive disease.

Final Results of a Multicenter Pilot Study Evaluating Brentuximab Vedotin with Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone (BV-CHEP) for the Treatment of Aggressive Adult T-Cell Leukemia/Lymphoma

Introduction: Aggressive adult T-cell leukemia/lymphoma (ATLL) is a type of non-Hodgkin lymphoma that is often fatal. ATLL is exceedingly rare in the United States (US), with most cases occurring in emigrants from human T-lymphotropic virus type 1 (HTLV-1) endemic regions. Studies focusing on ATLL in the US are sparse, and have shown poor response rates; because of this, there is no standard of care treatment approach. Brentuximab vedotin (BV) is a CD30 targeting antibody-drug conjugate that is effective in treating many types of lymphoma, including CD30+ peripheral T-cell lymphomas. Studies have shown efficacy even in lymphomas with very low CD30 expression. We developed a prospective, multicenter pilot study evaluating BV in combination with cyclophosphamide, doxorubicin, etoposide, and prednisone (BV-CHEP) for the treatment of ATLL. We report the final safety and efficacy analysis below. Methods: Adult patients (pts) from 5 centers were enrolled from October 2017 through June 2022. Newly diagnosed ATLL pts were eligible, including the acute, lymphomatous and chronic unfavorable subtypes. Pts did not have to express CD30 to be enrolled; pts were considered CD30+ if there was &amp;gt;1% expression. Frontline consolidation with allogeneic stem cell transplant (alloSCT) was permitted at any time after 2 cycles of BV-CHEP. Transplant-ineligible pts completed a total of 6 cycles of BV-CHEP and those who expressed CD30 were eligible for BV maintenance. Pts could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to enrollment. Prior antiviral therapy was allowed. Pts were treated with standard dosing every 21 days: BV 1.8 mg/kg on day 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, etoposide 100 mg/m2 days 1-3, and prednisone 100mg days 1-5. All pts received GCSF support. The primary endpoint was CR by PET-CT (and peripheral blood for leukemic types) after at least 2 cycles of therapy per adapted Lugano and ATLL criteria. Secondary endpoints were safety, overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: 16 pts were enrolled and evaluable for the safety and efficacy analysis. All pts were HTLV-1 positive. Seven of 16 were the acute type, 8 were lymphomatous, and 1 was chronic unfavorable. Seven of 16 (43.75%) expressed CD30. The median age was 56 (range 34 to 69) and 12 of 16 (75%) were female. 14 of 16 pts identified as Black, 1 identified as Asian, and 1 was other. Countries of origin included: Antigua and Barbuda N=1, Colombia N=1, Haiti N=7, Jamaica N=2, Japan N=1, Liberia N=1, and the US N=3. All pts were advanced stage (12 of 16 stage IV; 4 stage III). Four had positive cerebrospinal fluid at baseline, which cleared with intrathecal (IT) treatments, and 10 were given IT prophylaxis. Nine pts had an ATL-PI score &amp;gt;3 (56.25%) with a median score of 3 (range 2-4). No subjects received prior antiretroviral therapy. 12 of 16 pts completed at least 4 cycles of treatment (median 4.5 cycles; range 2 to 6). Ten of 16 pts achieved a CR (62.5%) and 4 pts achieved a PR (ORR of 87.5%) after &amp;gt;2 cycles of BV-CHEP. The median duration of follow-up was 47.2 mo. The median PFS (mPFS) was 7.11 mo (3.93 to NR) and the median OS (mOS) was 12.2 mo (9.29 to NR) (Fig.1). Of pts who achieved a CR, the mPFS was 11.07 mo and the mOS was 15.7 mo. There was no significant difference in PFS or OS by CD30 status or by ATLL subtype. One pt received 3 cycles of maintenance BV. 5 pts received alloSCT consolidation and there was an OS benefit for this group ( p=0.007; Fig.2). Grade 3 or higher toxicities included neutropenia (N=13), anemia (N=11), thrombocytopenia (N=9), febrile neutropenia (N=7), mucositis (N=6), colitis (N=3), infections (N=3; COVID19, thrush, clostridium difficile), hyponatremia (N=3), and vomiting (N=2). Nine of 16 patients had peripheral neuropathy (all grade 1/2). There were 11 pt deaths, 9 of which were disease-related and 2 were due to shock (hypovolemic and septic) off-treatment. No patients had to come off study due to toxicity and there were no treatment-related deaths. Conclusions: In this final analysis, BV-CHEP was safe and effective for the treatment of aggressive ATLL. High ORR and CR rates were achieved regardless of CD30 status, and compare favorably to prior clinical trials. AlloSCT had an OS benefit with 4 of 5 pts achieving long-term remission. Toxicity was manageable and cytopenias were expected. Peripheral neuropathy was common, but low-grade.

New Perspectives about Drug Candidates Targeting HTLV-1 and Related Diseases.

Among the human T-lymphotropic virus (HTLV) types, HTLV-1 is the most prevalent, and it has been linked to a spectrum of diseases, including HAM/TSP, ATLL, and hyperinfection syndrome or disseminated strongyloidiasis. There is currently no globally standard first-line treatment for HTLV-1 infection and its related diseases. To address this, a comprehensive review was conducted, analyzing 30 recent papers from databases PubMed, CAPES journals, and the Virtual Health Library (VHL). The studies encompassed a wide range of therapeutic approaches, including antiretrovirals, immunomodulators, antineoplastics, amino acids, antiparasitics, and even natural products and plant extracts. Notably, the category with the highest number of articles was related to drugs for the treatment of ATLL. Studies employing mogamulizumab as a new perspective for ATLL received greater attention in the last 5 years, demonstrating efficacy, safe use in the elderly, significant antitumor activity, and increased survival time for refractory patients. Concerning HAM/TSP, despite corticosteroid being recommended, a more randomized clinical trial is needed to support treatment other than corticoids. The study also included a comprehensive review of the drugs used to treat disseminated strongyloidiasis in co-infection with HTLV-1, including their administration form, in order to emphasize gaps and facilitate the development of other studies aiming at better-directed methodologies. Additionally, docking molecules and computer simulations show promise in identifying novel therapeutic targets and repurposing existing drugs. These advances are crucial in developing more effective and targeted treatments against HTLV-1 and its related diseases.

A case of acute kidney injury due to native kidney BK polyomavirus-associated nephropathy in a human T-lymphotropic virus type 1 carrier

BackgroundBK polyomavirus-associated nephropathy (BKPyVAN) has become a major cause of kidney dysfunction and graft loss in kidney transplant recipients. On rare occasion, polyomavirus has also been known to affect native kidneys of immunocompromised individuals. Only a small number of opportunistic infections have been reported in the carrier phase of human T-lymphotropic virus type 1 (HTLV-1). This is the first reported case of BKPyVAN in native kidneys of an HTLV-1 carrier.Case presentationA 61-year-old man was referred to our hospital from a primary care physician for work-up and treatment of pneumonia. He was diagnosed with Pneumocystis pneumonia and identified as a HTLV-1 carrier who had not yet developed adult T-cell leukemia (ATL). The pneumonia was successfully treated with sulfamethoxazole-trimethoprim. He had never been diagnosed with any kind of kidney dysfunction. Laboratory investigations showed a serum creatinine of 5.3 mg/dL, and urinary sediment showed cells with nuclear enlargement and inclusion bodies suggesting viral infection. The urinary Papanicolaou stain showed inclusions in swollen, ground-glass nuclei, typical of “decoy cells”. Renal biopsy showed degeneration of tubules with epithelial enlargement, vacuolar degeneration, nuclear inclusion bodies, and detachment from the tubular basement membrane. Tubular nuclei showed positive staining positive for simian virus 40 large-T antigen. Polymerase chain reaction tests for BK polyomavirus DNA of both urine and plasma were positive. These findings confirmed a diagnosis of BKPyVAN. Intravenous immunoglobulin therapy did not improve renal function, necessitating maintenance hemodialysis therapy.ConclusionsBKPyVAN should be considered when acute kidney injury occurs with opportunistic infection. HTLV-1 carriers can develop opportunistic infections even before the onset of ATL.

HTLV-1 biofilm polarization maintained by tetraspanin CD82 is required for efficient viral transmission.

The human T-lymphotropic virus type 1 (HTLV-1) is an oncogenic retrovirus whose transmission relies primarily on cell-to-cell contacts as cell-free viruses are poorly infectious. Among the intercellular transmission routes described, HTLV-1 biofilms are adhesive structures polarized at the cell surface that confine virions in a protective environment, which is believed to promote their simultaneous delivery during infection. Here, we show that several tetraspanins are enriched in HTLV-1 biofilms and incorporated into the viral envelope. However, we report that only the tetraspanin CD82 interacts with HTLV-1 Gag proteins which initiates their polarization into viral biofilms. Also, we demonstrate that CD82 maintains HTLV-1 biofilm polarization and favors viral transmission, as its silencing induces a complete reorganization of viral clusters at the cell surface and reduces the ability of infected T-cells to transmit the virus. Our results highlight the crucial role of CD82 and its glycosylation state in the architectural organization of HTLV-1 biofilms and their subsequent transfer through intercellular contacts.IMPORTANCEIn the early stages of infection, human T-lymphotropic virus type 1 (HTLV-1) dissemination within its host is believed to rely mostly on cell-to-cell contacts. Past studies unveiled a novel mechanism of HTLV-1 intercellular transmission based on the remodeling of the host-cell extracellular matrix and the generation of cell-surface viral assemblies whose structure, composition, and function resemble bacterial biofilms. These polarized aggregates of infectious virions, identified as viral biofilms, allow the bulk delivery of viruses to target cells and may help to protect virions from immune attacks. However, viral biofilms' molecular and functional description is still in its infancy, although it is crucial to fully decipher retrovirus pathogenesis. Here, we explore the function of cellular tetraspanins (CD9, CD81, CD82) that we detect inside HTLV-1 particles within biofilms. Our results demonstrate specific roles for CD82 in the cell-surface distribution and intercellular transmission of HTLV-1 biofilms, which we document as two essential parameters for efficient viral transmission. At last, our findings indicate that N-glycosylation of cell-surface molecules, including CD82, is required for the polarization of HTLV-1 biofilms and for the efficient transmission of HTLV-1 between T-lymphocytes.

Genetic typing and intrafamilial transmission of human T-lymphotropic virus type 1 in non-endemic areas of China.

The origin and intrafamilial transmission of Human T-Lymphotropic Virus Type 1 (HTLV-1) in non-endemic populations such as China is still unknown. In this study, donors from blood banks/centers in China (including 28 provinces and Shenzhen city) during 2019 and 2021 were screened for HTLV-1/2 antibody, and all the reactive samples were tested using a line immunoassay (LIA) and quantitative polymerase chain reaction (qPCR). Samples that can be detected using qPCR were amplified and sequenced for the long terminal repeat (LTR) region. The positive donors were contacted to identify their relatives. As a result, 4,451,883 blood donors were totally tested, and 50 of them were confirmed to be HTLV-1/2 positive. Viral LTR sequences genotyped from 26 HTLV-1 carriers demonstrated that all had the HTLV-1a genotype, of which Transcontinental and Japanese subgroups accounted for half each. There were 17 family members of 11 index donors detected, and the HTLV-1 infection rate in the spouses of male index donors (83.3%, 5/6) was significantly higher than that in the husbands of female index donors (0.0%, 0/4). However, 7 children of HTLV-1 positive women were tested and found negative. Therefore, our findings indicated that HTLV-1 is spreading silently from high-endemic to low-endemic areas in China. To prevent further HTLV-1/2 transmission, an efficient HTLV-1/2 screening strategy and counseling of the virus carriers are essential.

Serum Evaluation of Human T-lymphotropic Virus Type 1 and 2 (HTLV-I/II) and Human Immunodeficiency Virus (HIV) in Patients with Multiple Sclerosis (MS)

Background: Multiple Sclerosis (MS) is a multifactorial disease that causes neurological disability. Human retroviruses may have a role in the etiology of several acute and chronic neurological disorders. Objectives: We aimed to investigate the presence of HTLV-I/II and HIV antibodies in the sera of MS patients to assess the relationship between these infections and MS. Methods: This case-control study was conducted on serum samples of MS patients and individuals admitted to the same hospital with no symptoms of MS as the control group. Samples were examined for HIV and HTLV-I/II antibodies using ELISA kits. Results: A total of 79 people, including 38 MS patients and 41 healthy individuals, were evaluated. The frequency of HIV antibodies was 0.0% in both the case and control groups. The HTLV-I/II antibodies were detected in 1 patient in the control group and no patients in the MS group, with no statistically significant difference between the two groups (P: 0.999). Conclusions: This study could not establish a relationship between the presence of HTLV-I/II or HIV antibodies and MS.

Immune checkpoint inhibitor-induced neurotoxicity is not associated with seroprevalence of neurotropic infections

BackgroundImmune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1–5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs.MethodsNeurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy.ResultsThe association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity.ConclusionPrevious viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.