High HTLV-1 Proviral Load Predates and Predicts HTLV-1-Associated Disease: Literature Review and the London Experience.

Human T cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects lymphocytes and causes severe diseases. HTLV-1 proviral load (PVL), i.e., the number of host cells that carry HTLV-1 proviral DNA integrated into their genome, can be measured in peripheral blood mononuclear cells (PBMCs) using quantitative polymerase chain reaction. In this narrative review, we discuss the usefulness of HTLV-1 PVL quantification and share our experience acquired during more than 30 years of follow-up of people living with HTLV-1 in the UK. Patients with HTLV-1-associated myelopathy have higher PVL than those with asymptomatic infection. This is consistent across studies in different countries. High PVL predates symptom onset for both inflammatory and proliferative diseases. High PVL is essential but not sufficient for the development of HTLV-1-associated diseases. Therefore, PVL quantification can be used to support the care of people living with HTLV-1 by identifying those most at risk of HTLV-1-associated diseases.

Impact and economic analysis of human T-cell lymphotropic virus type 1 (HTLV-1)-targeted antenatal screening, England and Wales, 2021.

BackgroundHuman T-cell lymphotropic virus type 1 (HTLV-1) is a neglected virus that can cause severe disease and be transmitted from mother to child through breastfeeding. Avoidance of breastfeeding prevents 80% of vertical transmission. The United Kingdom (UK) is currently assessing whether HTLV-1-targeted antenatal screening should be implemented.AimWe aimed to assess the impact and cost-effectiveness of a targeted programme to prevent HTLV-1 vertical transmission in England and Wales.MethodsWe estimated the number of pregnant women who have high risk of HTLV-1 infection based on their or their partner's country of birth. With data from 2021, we used a mathematical model to assess cost-effectiveness of HTLV-1 antenatal screening. We also estimated the annual number of infant infections and the number that could be prevented with screening and intervention.ResultsWe estimate that ca 99,000 pregnant women in England and Wales have high risk of HTLV-1 infection. In the absence of screening, 74 (range: 25-211) HTLV-1 infections in infants would be expected to occur every year in England and Wales. Implementation of targeted screening would prevent 58 (range: 19-164) infant infections annually. The intervention is effective (incremental 0.00333 quality-adjusted life years (QALY)) and cost-saving (GBP -57.56 (EUR -66.85)).ConclusionOur findings support implementation of HTLV-1 targeted antenatal screening to reduce vertical transmission from mothers to infants in the UK.

Pregnancy Management in HIV Viral Controllers: Twenty Years of Experience.

(1) Background: The evidence base for the management of spontaneous viral controllers in pregnancy is lacking. We describe the management outcomes of pregnancies in a series of UK women with spontaneous HIV viral control (<100 copies/mL 2 occasions before or after pregnancy off ART). (2) Methods: A multi-centre, retrospective case series (1999-2021) comparing pre- and post-2012 when guidelines departed from zidovudine-monotherapy (ZDVm) as a first-line option. Demographic, virologic, obstetric and neonatal information were anonymised, collated and analysed in SPSS. (3) Results: A total of 49 live births were recorded in 29 women, 35 pre-2012 and 14 post. HIV infection was more commonly diagnosed in first reported pregnancy pre-2012 (15/35) compared to post (2/14), p = 0.10. Pre-2012 pregnancies were predominantly managed with ZDVm (28/35) with pre-labour caesarean section (PLCS) (24/35). Post-2012 4/14 received ZDVm and 10/14 triple ART, p = 0.002. Post-2012 mode of delivery was varied (5 vaginal, 6 PLCS and 3 emergency CS). No intrapartum ZDV infusions were given post-2012 compared to 11/35 deliveries pre-2012. During pregnancy, HIV was detected (> 50 copies/mL) in 14/49 pregnancies (29%) (median 92, range 51-6084). Neonatal ZDV post-exposure prophylaxis was recorded for 45/49 infants. No transmissions were reported. (4) Conclusion: UK practice has been influenced by the change in guidelines, but this has had little impact on CS rates.

Comprehensive Insight into the Functional Roles of NK and NKT Cells in HTLV-1-Associated Diseases and Asymptomatic Carriers.

Human T cell leukemia virus type 1 (HTLV-1) is the first human oncogenic retrovirus to be discovered and causes two major diseases: a progressive neuro-inflammatory disease, termed HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and an aggressive malignancy of T lymphocytes known as adult T cell leukemia (ATL). Innate and acquired immune responses play pivotal roles in controlling the status of HTLV-1-infected cells and such, the outcome of HTLV-1 infection. Natural killer cells (NKCs) are the effector cells of the innate immune system and are involved in controlling viral infections and several types of cancers. The ability of NKCs to trigger cytotoxicity to provide surveillance against viruses and cancer depends on the balance between the inhibitory and activating signals. In this review, we will discuss NKC function and the alterations in the frequency of these cells in HTLV-1 infection.

How do socioeconomic determinants of health affect the likelihood of living with HTLV-1 globally? A systematic review with meta-analysis.

Introduction: Human T Lymphotropic Virus type 1 (HTLV-1) is a neglected retrovirus associated with many clinical disorders, most notably Adult T-cell Leukemia/Lymphoma and HTLV-1-Associated Myelopathy (HAM). Found in endemic clusters across the world, high prevalence has been reported in minoritized groups who suffer from health inequities. This study investigates the association between HTLV-1 prevalence and the following socioeconomic determinants of health: education, income, and employment, which are markers of health inequity. Methods: A systematic review was conducted by searching the following databases: Ovid/Medline, Embase, Global Health Database, Web of Science, LILACS and SciELO. Primary studies in English, Spanish and Portuguese mentioning HTLV-1 and one of education, income and/or employment were included. A random-effects meta-analysis was performed, and odds ratios (OR) were calculated to determine the association between these socioeconomic determinants of health and HTLV-1 prevalence. Results: 42 studies were included. The likelihood of having HTLV-1 was higher in individuals with less than completed primary education compared to those who completed primary education (OR 1.86 [95% CI 1.34-2.57]; p < 0.01). This may be because individuals with low education have reduced access to and understanding of health information, thus increasing the prevalence of risk factors associated with HTLV-1 infection. No other determinants were found to be statistically significant. Conclusion: Fewer years of schooling are associated with increased likelihood of contracting HTLV-1. Therefore, health promotion materials and public health policies regarding HTLV-1 must consider those with lower educational levels to effectively reduce disease transmission. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=335004, identifier (CRD42022335004).

HTLV-1 induces an inflammatory CD4+CD8+ T cell population in HTLV-1-associated myelopathy.

Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus with preferential CD4+ T cell tropism that causes a range of conditions spanning from asymptomatic infection to adult T cell leukemia and HTLV-1-associated myelopathy (HAM), an inflammatory disease of the CNS. The mechanisms by which HTLV-1 induces HAM are poorly understood. By directly examining the ex vivo phenotype and function of T cells from asymptomatic carriers and patients with HAM, we show that patients with HAM have a higher frequency of CD4+CD8+ double-positive (DP) T cells, which are infected with HTLV-1 at higher rates than CD4+ T cells. Displaying both helper and cytotoxic phenotypes, these DP T cells are highly proinflammatory and contain high frequencies of HTLV-1-specific cells. Mechanistically, we demonstrate that DP T cells arise by direct HTLV-1 infection of CD4+ and CD8+ T cells. High levels of CD49d and CXCR3 expression suggest that DP T cells possess the ability to migrate to the CNS, and when cocultured with astrocytes, DP T cells induce proinflammatory astrocytes that express high levels of CXCL10, IFN-γ, and IL-6. These results demonstrate the potential of DP T cells to directly contribute to CNS pathology.

Multiplexed detection of viral antigen and RNA using nanopore sensing and encoded molecular probes.

We report on single-molecule nanopore sensing combined with position-encoded DNA molecular probes, with chemistry tuned to simultaneously identify various antigen proteins and multiple RNA gene fragments of SARS-CoV-2 with high sensitivity and selectivity. We show that this sensing strategy can directly detect spike (S) and nucleocapsid (N) proteins in unprocessed human saliva. Moreover, our approach enables the identification of RNA fragments from patient samples using nasal/throat swabs, enabling the identification of critical mutations such as D614G, G446S, or Y144del among viral variants. In particular, it can detect and discriminate between SARS-CoV-2 lineages of wild-type B.1.1.7 (Alpha), B.1.617.2 (Delta), and B.1.1.539 (Omicron) within a single measurement without the need for nucleic acid sequencing. The sensing strategy of the molecular probes is easily adaptable to other viral targets and diseases and can be expanded depending on the application required.