High level of genomic divergence in orf-I p12 and hbz genes of HTLV-1 subtype-C in Central Australia.

BACKGROUND: Human T cell lymphotropic virus type 1 (HTLV-1) infection remains a largely neglected public health problem, particularly in resource-poor areas with high burden of communicable and non-communicable diseases, such as some remote populations in Central Australia where an estimated 37% of adults are infected with HTLV-1. Most of our understanding of HTLV-1 infection comes from studies of the globally spread subtype-A (HTLV-1a), with few molecular studies reported with the Austral-Melanesian subtype-C (HTLV-1c) predominant in the Indo-Pacific and Oceania regions. RESULTS: Using a primer walking strategy and direct sequencing, we constructed HTLV-1c genomic consensus sequences from 22 First Nations participants living with HTLV-1c in Central Australia. Phylogenetic and pairwise analysis of this subtype-C proviral gDNA showed higher levels of genomic divergence in comparison to previously published HTLV-1a genomes. While the overall genomic homology between subtypes was 92.5%, the lowest nucleotide and amino acid sequence identity occurred near the 3' end of the proviral genome coding regulatory genes, especially overlapping hbz (85.37%, 77.46%, respectively) and orf-I product p12 (82.00%, 70.30%, respectively). Strikingly, the HTLV-1c genomic consensus sequences uniformly showed a defective translation start codon for the immune regulatory proteins p12/p8 encoded by the HTLV-1A orf-I. Deletions in the proviral genome were detected in many subjects, particularly in the structural gag, pol and env genes. Similarly, using a droplet digital PCR assay measuring the copies of gag and tax per reference host genome, we quantitatively confirmed that provirus retains the tax gene region at higher levels than gag. CONCLUSIONS: Our genomic analysis of HTLV-1c in Central Australia in conjunction with earlier Melanesian HTLV-1c sequences, elucidate substantial differences with respect to the globally spread HTLV-1a. Future studies should address the impact these genomic differences have on infection and the regionally distinctive frequency of associated pulmonary disease. Understanding the host and virus subtype factors which contribute to the differential morbidity observed, is crucial for the development of much needed therapeutics and vaccine strategies against this highly endemic infection in remote First Nations communities in Central Australia.

High Human T-Cell Leukemia Virus Type 1c Proviral Loads Are Associated With Diabetes and Chronic Kidney Disease: Results of a Cross-Sectional Community Survey in Central Australia.

BACKGROUND: A link between chronic inflammation and several noncommunicable diseases (NCDs) has been established. Although chronic infection with the human T-cell leukemia virus type 1 (HTLV-1) is the recognized cause of several inflammatory diseases and these are associated with a high number of HTLV-1-infected cells in peripheral blood (proviral load [PVL]), possible interactions between PVL and NCDs have not been studied at a community level. METHODS: Adult Aboriginal residents of 7 remote communities were invited to complete a health survey between 25 August 2014 and 30 June 2018. Blood was drawn for HTLV-1 serology and PVL, and relevant medical conditions were obtained from health records. Associations between HTLV-1 PVL and diabetes, chronic kidney disease (CKD), and coronary artery disease (CAD) were determined using logistic regression, adjusting for available confounders. RESULTS: Among 510 participants (56% of the estimated adult resident population, 922), 197 (38.6%) were HTLV-1-infected. A high HTLV-1 PVL was associated with a 2-fold increase in the odds of diabetes and CKD (diabetes, adjusted odds ratio [aOR], 1.95; 95% confidence interval [CI], 1.06-3.61; P = .033 and CKD: aOR, 2.00; 95% CI, 1.03-3.8; P = .041). A nonsignificant association between high PVL and CAD (aOR, 7.08; 95% CI, 1.00-50.18; P = .05) was found for participants aged <50 years at the time of angiography. CONCLUSIONS: In a community-based study in central Australia, people with HTLV-1 who had high HTLV-1 PVL were more likely to have diabetes and CKD. These findings have potential clinical implications.

Current pharmacotherapeutic strategies for Strongyloidiasis and the complications in its treatment.

INTRODUCTION: Strongyloidiasis, an infection caused by the soil-transmitted helminth Strongyloides stercoralis, can lead immunocompromised people to a life-threatening syndrome. We highlight here current and emerging pharmacotherapeutic strategies for strongyloidiasis and discuss treatment protocols according to patient cohort. We searched PubMed and Embase for papers published on this topic between 1990 and May 2022. AREAS COVERED: Ivermectin is the first-line drug, with an estimated efficacy of about 86% and excellent tolerability. Albendazole has a lower efficacy, with usage advised when ivermectin is not available or not recommended. Moxidectin might be a valid alternative to ivermectin, with the advantage of being a dose-independent formulation. EXPERT OPINION: The standard dose of ivermectin is 200 µg/kg single dose orally, but multiple doses might be needed in immunosuppressed patients. In the case of hyperinfection, repeated doses are recommended up to 2 weeks after clearance of larvae from biological fluids, with close monitoring and further dosing based on review. Subcutaneous ivermectin is used where there is impaired intestinal absorption/paralytic ileus. In pregnant or lactating women, studies have not identified increased risk with ivermectin use. However, with limited available data, a risk-benefit assessment should be considered for each case.

A Qualitative Study Exploring Perceptions to the Human T Cell Leukaemia Virus Type 1 in Central Australia: Barriers to Preventing Transmission in a Remote Aboriginal Population.

Background: Central Australia has the highest recorded prevalence of infection with the human T cell leukaemia virus type 1 (HTLV-1) worldwide. Each of the clinical diseases associated with HTLV-1 have been reported in this region, including deaths due to adult T cell leukaemia, which is causally linked to HTLV-1. Nevertheless, no public health response has been implemented to reduce HTLV-1 transmission among the affected Aboriginal population. In the first study to explore the perceptions of healthcare professionals along with those of Aboriginal people whose communities are actually impacted by HTLV-1, we sought to understand the barriers to preventing HTLV-1 transmission in this remote area. Methodology/Principal Findings: Semi and un-structured interviews were conducted with 30 Australian Aboriginal people, 26 non-Aboriginal healthcare professionals and 3 non-Aboriginal community workers. The purpose of the interviews was to explore perceptions towards HTLV-1 in a health context with a focus on sexual and reproductive rights. Deductive and inductive analyses were applied to the data and a decolonizing lens brought peripheral stories to the fore. A major finding was the contrast between views expressed by Aboriginal participants and healthcare professionals regarding the provision of knowledge to those affected. Aboriginal participants consistently articulated that they and their communities should be informed of, and can hold, knowledges pertaining to HTLV-1. This finding controverted the perceptions of healthcare professionals that the complexities of the virus would not be well-understood by their Aboriginal patients and that sharing HTLV-1 knowledges might overwhelm Aboriginal people. Further analyses revealed a spectrum of understanding and clinical practice, while also delineating signs of an imagined public health response. Conclusions/Significance: HTLV-1 remains a neglected infection in Australia. Knowledge of HTLV-1 is held by a privileged medical elite and does not flow to marginalised Aboriginal people living in affected communities. We demonstrate that differences in the perspectives of stakeholders presents a significant barrier to the development of cohesive, culturally safe prevention programs that foster a shared knowledge of HTLV-1. The interview data suggests that a successful public health program is likely to require a dual approach that includes clinical care and community-driven health promotion. Aspects of this approach, which would raise awareness and potentially reduce transmission and lower HTLV-1 prevalence in Central Australia, may be applicable to other endemic settings with similar conditions of social disadvantage, geographic remoteness, resource limitations and cross-cultural challenges.

The Association between Diabetes and Human T-Cell Leukaemia Virus Type-1 (HTLV-1) with Strongyloides stercoralis: Results of a Community-Based, Cross-Sectional Survey in Central Australia.

In central Australia, an area that is endemic for the human T-cell leukaemia virus type-1 (HTLV-1), the prevalence of Strongyloides stercoralis and its association with other health conditions are unknown. A cross-sectional community-based survey was conducted in seven remote Aboriginal communities in central Australia, from 2014 to 2018. All residents aged ≥10 years were invited to complete a health survey and to provide blood for Strongyloides serology, HTLV-1 serology and HTLV-1 proviral load (PVL). Risk factors for Strongyloides seropositivity and associations with specific health conditions including diabetes and HTLV-1 were determined using logistic regression. Overall Strongyloides seroprevalence was 27% (156/576) (children, 22% (9/40); adults (≥15 years), 27% (147/536), varied widely between communities (5-42%) and was not associated with an increased risk of gastrointestinal, respiratory or dermatological symptoms. Increasing age, lower HTLV-1 PVL (<1000 copies per 105 peripheral blood leucocytes) compared to the HTLV-1 uninfected group and community of residence were significant risk factors for Strongyloides seropositivity in an adjusted model. A modest reduction in the odds of diabetes among Strongyloides seropositive participants was found (aOR 0.58, 95% CI 0.35, 1.00; p = 0.049); however, this was lost when body mass index was included in the adjusted model (aOR 0.48, 95% CI 0.48, 1.47; p = 0.542). Strongyloides seropositivity had no relationship with anaemia. Exploring social and environmental practices in communities with low Strongyloides seroprevalence may provide useful lessons for similar settings.

Clinical and Public Health Implications of Human T-Lymphotropic Virus Type 1 Infection.

Human T-lymphotropic virus type 1 (HTLV-1) is estimated to affect 5 to 10 million people globally and can cause severe and potentially fatal disease, including adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The burden of HTLV-1 infection appears to be geographically concentrated, with high prevalence in discrete regions and populations. While most high-income countries have introduced HTLV-1 screening of blood donations, few other public health measures have been implemented to prevent infection or its consequences. Recent advocacy from concerned researchers, clinicians, and community members has emphasized the potential for improved prevention and management of HTLV-1 infection. Despite all that has been learned in the 4 decades following the discovery of HTLV-1, gaps in knowledge across clinical and public health aspects persist, impeding optimal control and prevention, as well as the development of policies and guidelines. Awareness of HTLV-1 among health care providers, communities, and affected individuals remains limited, even in countries of endemicity. This review provides a comprehensive overview on HTLV-1 epidemiology and on clinical and public health and highlights key areas for further research and collaboration to advance the health of people with and at risk of HTLV-1 infection.

Very high prevalence of infection with the human T cell leukaemia virus type 1c in remote Australian Aboriginal communities: Results of a large cross-sectional community survey.

Infection with the human T cell leukaemia virus type 1 (HTLV-1) subtype C is endemic among Aboriginal people in central Australia. To provide insights into the risk factors for transmission, we conducted the first large-scale, community-based prevalence study in seven remote Aboriginal communities. Residents >2 years old were invited to participate in the study between August 2014 and June 2018. HTLV-1 infection was defined as a positive western blot (WB) test or a positive HTLV-1 PCR. 720 community residents participated in the study (children <15 years, 142; adults, 578). Prevalences for children and adults were 3.5% (5/142) and 36.8% (213/578), respectively, reaching 49.3% (106/215) for those older than 45 years. A wide range of proviral loads were measured for both asymptomatic and symptomatic participants with no difference within groups according to age or gender; however, median PVL was 1.34 log10 higher for symptomatic participants. The adult prevalence of HTLV-1 infection in central Australia is the highest reported worldwide. Sexual contact is likely to be the predominant mode of transmission.

Risk factors for HTLV-1, acute kidney injury, and urinary tract infection among aboriginal adults with end stage kidney disease in central Australia.

Central Australia is a human T-cell leukemia virus type 1c (HTLV-1c) endemic region and has the highest incidence of chronic kidney disease (CKD) in Australia. The factors associated with HTLV-1 seropositivity among Aboriginal Australian adults with CKD receiving hemodialysis (HD) were determined. A retrospective observational study of Aboriginal adults (≥ 18 years) who were receiving regular HD at the two main dialysis units in Alice Springs, December 1, 2010 to December 31, 2015. Demographic and clinical data before commencing HD were extracted from hospital records from the first presentation to Alice Springs Hospital (ASH) to HD commencement and associations were determined using logistic regression. Among 373 patients receiving HD, 133 (35.9%) were HTLV-1 infected. Identifiable factors associated with HTLV-1 status included increasing age, male gender, and diabetes before HD. The odds of diabetes mellitus were significantly higher among patients with HTLV-1 (adjusted odds ratio [aOR]: 2.76, 95% confidence interval [CI]: 1.19, 6.39; p = 0.017). More than one-fifth of participants had an acute kidney injury, the risk of which was increased among those with a previous blood stream infection (aOR: 3.02, 95% CI: 1.71, 5.34, p < 0.001). Men with a high HTLV-1 proviral load (≥500 copies per 105 peripheral blood leukocytes) had an increased risk of urinary tract infection (UTI) before HD (aOR: 5.15, 95% CI: 1.62, 16.40; p = 0.006). A strong association between HTLV-1 and diabetes, and an increased risk of UTI among men with a high HTLV-1 PVL, suggest that interactions between HTLV-1 infection and conventional risk factors may increase the risk for CKD in this population.

Evaluating antimicrobial prescribing practice in Australian remote primary healthcare clinics.

BACKGROUND: Inappropriate antimicrobial prescribing contributes to the emergence of antimicrobial resistance. Gaps exist in the understanding of antimicrobial prescribing in the remote setting. We aimed to assess adherence to guidelines and appropriateness of antimicrobial prescribing in Central Australia. METHODS: A retrospective study assessing antimicrobial prescriptions in ten Aboriginal clinics (three in remote communities and seven in regional centre) using a validated evaluation tool. Antimicrobials prescribed between 1 January-31 December 2018 were randomly selected for inclusion into the study. The main outcome measures were the rates of guideline adherence and inappropriate prescribing. RESULTS: A total of 180 prescriptions were included (96.1% Aboriginal, 32.2% male). Ninety-nine (55.0%) prescriptions were written by general practitioners (GPs), 57 (31.7%) by nurses and 24 (13.3%) by others. Forty-three (25.7%) assessable prescriptions were deemed inappropriate and 75 (44.4%) did not adhere to guidelines. Prescriptions written by GPs were less likely to adhere to guidelines, particularly GPs located in remote communities. The most common reasons for inappropriate prescribing were incorrect dosage/frequency and antimicrobial not indicated. Skin and soft-tissue infection was the commonest indication, with 29 of 41 (70.7%) prescriptions deemed appropriate. Prescriptions for lower respiratory-tract infection had the lowest rate of appropriateness, with one of seven prescriptions deemed appropriate (14.3%). Antimicrobials with the lowest rate of appropriateness were ciprofloxacin, amoxicillin-clavulanate and cefalexin, at 50%, 56%, and 62%, respectively. CONCLUSION: A quarter of antimicrobial prescriptions written in select remote central Australian Aboriginal primary healthcare clinics were deemed inappropriate. The implementation of a comprehensive antimicrobial stewardship program is recommended.

Human T-cell leukaemia virus type 1 associated pulmonary disease: clinical and pathological features of an under-recognised complication of HTLV-1 infection.

The lung is one of several organs that can be affected by HTLV-1 mediated inflammation. Pulmonary inflammation associated with HTLV-1 infection involves the interstitium, airways and alveoli, resulting in several clinical entities including interstitial pneumonias, bronchiolitis and alveolitis, depending on which structures are most affected. Augmentation of the inflammatory effects of HTLV-1 infected lymphocytes by recruitment of other inflammatory cells in a positive feedback loop is likely to underlie the pathogenesis of HTLV-1 associated pulmonary disease, as has been proposed for HTLV-1 associated myelopathy. In contrast to the conclusions of early case series, HTLV-1 associated pulmonary disease can be associated with significant parenchymal damage, which may progress to bronchiectasis where this involves the airways. Based on our current understanding of HTLV-1 associated pulmonary disease, diagnostic criteria are proposed.

Pulmonary Disease Is Associated With Human T-Cell Leukemia Virus Type 1c Infection: A Cross-sectional Survey in Remote Aboriginal Communities.

BACKGROUND: The human T-cell leukemia virus type 1 (HTLV-1) subtype c is endemic to central Australia. We report the first large-scale, community-based, health survey of HTLV-1 and its disease associations in this setting. METHODS: Aboriginal community residents aged >2 years in 7 remote communities were invited to do a health survey that included a questionnaire, spirometry, and clinical examination by a physician blinded to HTLV-1 status, clinical records, and spirometry results. Blood was drawn for HTLV-1 serology and proviral load (PVL). Pulmonary disease was assessed clinically and spirometrically and, where records were available, radiologically after the clinical assessment. Associations between specific diseases and HTLV-1 status were determined using logistic regression, adjusting for available confounders. RESULTS: Overall, 579 residents (164 children aged 3-17 years; 415 adults) were examined (37.7% of the estimated resident population). HTLV-1 prevalences for children and adults were 6.1% and 39.3%, respectively. No associations were found between HTLV-1 and any assessed clinical condition among children. Chronic pulmonary disease and gait abnormalities were more common among adults with HTLV-1 infection. Adjusted odds ratios among participants with PVL ≥1000 per 105 peripheral blood leukocytes were 7.08 (95% confidence interval [CI], 2.67-18.74; P < .001), 9.81 (95% CI, 3.52-27.35; P < .001), and 14.4 (95% CI, 4.99-41.69; P < .001) for clinically defined chronic pulmonary disease, moderate-severe expiratory airflow limitation, and radiologically determined bronchiectasis/bronchiolitis, respectively, and 5.21 (95% CI, 1.50-18.07; P = .009) for gait abnormalities. CONCLUSIONS: In the first study of HTLV-1 disease associations based on community recruitment and blinded assessment, HTLV-1 infection was strongly associated with pulmonary disease and gait abnormalities.

HTLV-1c associated bronchiolitis in an Aboriginal man from central Australia.

We describe the first case of HTLV associated bronchiolitis to be associated with HTLV-1c subtype infection. An Aboriginal man with HTLV-1 infection was repeatedly admitted to Alice Springs Hospital, central Australia, with hypercapnic respiratory failure from the age of 28 years. High resolution CT chest findings were consistent with bronchiolitis and large numbers of lymphocytes were found in bronchoalveolar lavage fluid (BALF). After extensive investigations failed to find a cause, he was tested for HTLV-1 and found to have a high HTLV-1c proviral load (6.8 %) in peripheral blood leukocytes and in BALF (4.7 %). The administration of systemic corticosteroids resulted in a rapid clinical response; however, he did not continue treatment after discharge and died due to respiratory failure in the community.

Association between HTLV-1 infection and adverse health outcomes: a systematic review and meta-analysis of epidemiological studies.

BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that causes a lifelong infection. Several diseases, including an aggressive form of leukaemia, have been designated as associated with HTLV-1, whereby having HTLV-1 is a necessary condition for diagnosis. Beyond these diseases, there is uncertainty about other health effects of HTLV-1. We aimed to synthesise evidence from epidemiological studies on associations between health outcomes and HTLV-1. METHODS: For this systematic review and meta-analysis, we searched Embase, MEDLINE, MEDLINE In-Process, and Global Health for publications from their inception to July, 2018. We included cohort, case-control, and controlled cross-sectional studies that compared mortality or morbidity between people with and without HTLV-1. We excluded studies of psychiatric conditions, of symptoms or clinical findings only, of people who had undergone blood transfusion or organ transplant, and of population groups defined by a behavioural characteristic putting them at increased risk of co-infection with another virus. We extracted the risk estimates (relative risks [RRs] or odds ratios [ORs]) that reflected the greatest degree of control for potential confounders. We did a random-effects meta-analysis for groups of effect estimates where case ascertainment methods, age groups, and confounders were similar, presenting pooled estimates with 95% CIs and prediction intervals. FINDINGS: Of the 3318 identified studies, 39 met the inclusion criteria, examining 42 clinical conditions between them. The adjusted risk of death due to any cause was higher in people with HTLV-1 when compared with HTLV-1-negative counterparts (RR 1·57, 95% CI 1·37-1·80). From meta-analysis, HTLV-1 was associated with increased odds of seborrheic dermatitis (OR 3·95, 95% CI 1·99-7·81), Sjogren's syndrome (3·25, 1·85-5·70), and, inversely, with lower relative risk of gastric cancer (RR 0·45, 0·28-0·71). There were a further 14 diseases with significant associations or substantially elevated risk with HTLV-1 from single studies (eczema [children]; bronchiectasis, bronchitis and bronchiolitis [analysed together]; asthma [males]; fibromyalgia; rheumatoid arthritis; arthritis; tuberculosis; kidney and bladder infections; dermatophytosis; community acquired pneumonia; strongyloides hyperinfection syndrome; liver cancer; lymphoma other than adult T-cell leukaemia-lymphoma; and cervical cancer). INTERPRETATION: There is a broad range of diseases studied in association with HTLV-1. However, the elevated risk for death among people with HTLV-1 is not explained by available studies of morbidity. Many of the diseases shown to be associated with HTLV-1 are not fatal, and those that are (eg, leukaemia) occur too rarely to account for the observed mortality effect. There are substantial research gaps in relation to HTLV-1 and cardiovascular, cerebrovascular, and metabolic disease. The burden of disease associated with the virus might be broader than generally recognised. FUNDING: Commonwealth Department of Health, Australia.

Higher human T-cell leukaemia virus type 1 (HTLV-1) proviral load is associated with end-stage kidney disease in Indigenous Australians: Results of a case-control study in central Australia.

Case series suggest that human T-cell leukaemia virus type 1 (HTLV-1) is associated with kidney disease; however, little is known about the impact of proviral load (PVL). The present study was commenced to determine whether higher HTLV-1 PVL is associated with end stage kidney disease (ESKD) in Indigenous Australians. A case-control study was conducted in Alice Springs Hospital (ASH), 1 July 2007 to 30 November 2015. Cases included all 80 Indigenous adults (>17 years) with HTLV-1c and ESKD, matched 1:1 by sex to controls with HTLV-1 who had no renal disease or other recognised disease associations of HTLV-1, and were recruited during the same period. The association between PVL and ESKD was assessed using logistic regression. Median (IQR) HTLV-1c PVL for subjects with ESKD (6.86, IQR (3.35, 8.23) log copies per 105 peripheral blood leukocytes (PBL) (ie, 0.95; IQR, 0.03; 3.70% PBL) was significantly higher than that of the asymptomatic group (3.47; IQR (-0.04, 6.61) log copies per 10 5 PBL (ie, 0.01; IQR, 0.00; 0.52% PBL) (asymptomatic vs ESKD, P (ranksum) < .001). Major factors associated with ESKD were diabetes (adjusted odds ratio [aOR], 21.80; 95% CI, 4.84, 98.22; P < .001), hypertension (aOR, 4.16; 1.11, 15.64; P = .03), remote residence (aOR, 5.34; 95% CI, 1.17, 27.29; P = .03) and HTLV-1c PVL greater than or equal to 100 copies per 10 5 PBL (aOR, 3.67; 95% CI, 1.36, 9.92; P = .01). Higher HTLV-1c PVL are strongly associated with inflammatory diseases. The high HTLV-1c PVL reported here may have clinical implications for people with HTLV-1 who require haemodialysis. Longitudinal studies are required to determine whether this association is causal.

Predictors of non-cystic fibrosis bronchiectasis in Indigenous adult residents of central Australia: results of a case-control study.

The human T-cell leukaemia virus type 1 (HTLV-1) is associated with pulmonary inflammation. Indigenous Australians in central Australia have a very high prevalence of HTLV-1 infection and we hypothesised that this might contribute to high rates of bronchiectasis in this population. 80 Indigenous adults with confirmed bronchiectasis, each matched by age, sex and language to two controls without bronchiectasis, were recruited. Case notes and chest imaging were reviewed, HTLV-1 serology and the number of peripheral blood leukocytes (PBLs) infected with HTLV-1 (pro-viral load (PVL)) were determined, and radiological abnormality scores were calculated. Participants were followed for a mean±sd of 1.14±0.86 years and causes of death were determined. Median (interquartile range) HTLV-1 PVL for cases was 8-fold higher than controls (cases 213.8 (19.7-3776.3) copies per 105 PBLs versus controls 26.6 (0.9-361) copies per 105 PBLs; p=0.002). Radiological abnormality scores were higher for cases with HTLV-1 PVL ≥1000 copies per 105 PBLs and no cause of bronchiectasis other than HTLV-1 infection. Major predictors of bronchiectasis were prior severe lower respiratory tract infection (adjusted OR (aOR) 17.83, 95% CI 4.51-70.49; p<0.001) and an HTLV-1 PVL ≥1000 copies per 105 PBLs (aOR 12.41, 95% CI 3.84-40.15; p<0.001). Bronchiectasis (aOR 4.27, 95% CI 2.04-8.94; p<0.001) and HTLV-1 PVL ≥1000 copies per 105 PBLs (aOR 3.69, 95% CI 1.11-12.27; p=0.033) predicted death. High HTLV-1 PVLs are associated with bronchiectasis and with more extensive radiological abnormalities, which may result from HTLV-1-mediated airway inflammation.

Impact of Hepatitis B Virus Coinfection on Human T-Lymphotropic Virus Type 1 Clonality in an Indigenous Population of Central Australia.

The prevalence of human T-cell lymphotropic virus type 1 (HTLV-1) and hepatitis B virus (HBV) coinfection is high in certain Indigenous Australian populations, but its impact on HTLV-1 has not been described. We compared 2 groups of Indigenous adults infected with HTLV-1, either alone or coinfected with HBV. The 2 groups had a similar HTLV-1 proviral load, but there was a significant increase in clonal expansion of HTLV-1-infected lymphocytes in coinfected asymptomatic individuals. The degree of clonal expansion was correlated with the titer of HBV surface antigen. We conclude that HTLV-1/HBV coinfection may predispose to HTLV-1-associated malignant disease.

Multiplex Droplet Digital PCR Assay for Quantification of Human T-Cell Leukemia Virus Type 1 Subtype c DNA Proviral Load and T Cells from Blood and Respiratory Exudates Sampled in a Remote Setting.

During human T-cell leukemia virus type 1 (HTLV-1) infection, the frequency of cells harboring an integrated copy of viral cDNA, the proviral load (PVL), is the main risk factor for progression of HTLV-1-associated diseases. Accurate quantification of provirus by droplet digital PCR (ddPCR) is a powerful diagnostic tool with emerging uses for monitoring viral expression. Current ddPCR techniques quantify HTLV-1 PVL in terms of whole genomic cellular material, while the main targets of HTLV-1 infection are CD4+ and CD8+ T cells. Our understanding of HTLV-1 proliferation and the amount of viral burden present in different compartments is limited. Recently a sensitive ddPCR assay was applied to quantifying T cells by measuring loss of germ line T-cell receptor genes as method of distinguishing non-T-cell from recombined T-cell DNA. In this study, we demonstrated and validated novel applications of the duplex ddPCR assay to quantify T cells from various sources of human genomic DNA (gDNA) extracted from frozen material (peripheral blood mononuclear cells [PBMCs], bronchoalveolar lavage fluid, and induced sputum) from a cohort of remote Indigenous Australians and then compared the T-cell measurements by ddPCR to the prevailing standard method of flow cytometry. The HTLV-1 subtype c (HTLV-1c) PVL was then calculated in terms of extracted T-cell gDNA from various compartments. Because HTLV-1c preferentially infects CD4+ T cells, and the amount of viral burden correlates with HTLV-1c disease pathogenesis, application of this ddPCR assay to accurately measure HTLV-1c-infected T cells can be of greater importance for clinical diagnostics and prognostics as well as monitoring therapeutic applications.

Human T-Lymphotropic Virus type 1c subtype proviral loads, chronic lung disease and survival in a prospective cohort of Indigenous Australians.

BACKGROUND: The Human T-Lymphotropic Virus type 1c subtype (HTLV-1c) is highly endemic to central Australia where the most frequent complication of HTLV-1 infection in Indigenous Australians is bronchiectasis. We carried out a prospective study to quantify the prognosis of HTLV-1c infection and chronic lung disease and the risk of death according to the HTLV-1c proviral load (pVL). METHODOLOGY/PRINCIPAL FINDINGS: 840 Indigenous adults (discharge diagnosis of bronchiectasis, 154) were recruited to a hospital-based prospective cohort. Baseline HTLV-1c pVL were determined and the results of chest computed tomography and clinical details reviewed. The odds of an association between HTLV-1 infection and bronchiectasis or bronchitis/bronchiolitis were calculated, and the impact of HTLV-1c pVL on the risk of death was measured. Radiologically defined bronchiectasis and bronchitis/bronchiolitis were significantly more common among HTLV-1-infected subjects (adjusted odds ratio = 2.9; 95% CI, 2.0, 4.3). Median HTLV-1c pVL for subjects with airways inflammation was 16-fold higher than that of asymptomatic subjects. There were 151 deaths during 2,140 person-years of follow-up (maximum follow-up 8.13 years). Mortality rates were higher among subjects with HTLV-1c pVL ≥1000 copies per 105 peripheral blood leukocytes (log-rank χ2 (2df) = 6.63, p = 0.036) compared to those with lower HTLV-1c pVL or uninfected subjects. Excess mortality was largely due to bronchiectasis-related deaths (adjusted HR 4.31; 95% CI, 1.78, 10.42 versus uninfected). CONCLUSION/SIGNIFICANCE: Higher HTLV-1c pVL was strongly associated with radiologically defined airways inflammation and with death due to complications of bronchiectasis. An increased risk of death due to an HTLV-1 associated inflammatory disease has not been demonstrated previously. Our findings indicate that mortality associated with HTLV-1c infection may be higher than has been previously appreciated. Further prospective studies are needed to determine whether these results can be generalized to other HTLV-1 endemic areas.