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Background We report outcomes and novel characterization of a unique cohort of 42 individuals with persistently indeterminate human immunodeficiency virus (HIV) status, the majority of whom are HIV viral controllers. Methods Eligible individuals had indeterminate or positive HIV serology, but persistently undetectable HIV ribonucleic acid (RNA) by commercial assays and were not taking antiretroviral therapy (ART). Routine investigations included HIV Western blot, HIV viral load, qualitative HIV-1 deoxyribonucleic acid (DNA), coinfection screen, and T-cell quantification. Research assays included T-cell activation, ART measurement, single-copy assays detecting HIV-1 RNA and DNA, and plasma cytokine quantification. Human immunodeficiency virus seropositivity was defined as ≥3 bands on Western blot; molecular positivity was defined as detection of HIV RNA or DNA. Results Human immunodeficiency virus infection was excluded in 10 of 42 referrals, remained unconfirmed in 2 of 42, and was confirmed in 30 of 42, who were identified as HIV elite controllers (ECs), normal CD4 T-cell counts (median 820/mL, range 805–1336), and normal CD4/CD8 ratio (median 1.8, range 1.2–1.9). Elite controllers had a median duration of elite control of 6 years (interquartile range = 4–14). Antiretroviral therapy was undetected in all 23 subjects tested. Two distinct categories of ECs were identified: molecular positive (n = 20) and molecular negative (n = 10). Conclusions Human immunodeficiency virus status was resolved for 95% of referrals with the majority diagnosed as EC. The clinical significance of the 2 molecular categories among ECs requires further investigation.

Background and ObjectivesTo evaluate the usefulness of CSF and plasma neurofilament light (Nf-L) as a biomarker for human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM).MethodsNf-L, CXCL10, and neopterin were measured by ELISA in 83 CSF samples obtained from 49 individuals living with HTLV-1/2. Plasma Nf-L was also measured by single molecule array. Results were correlated with duration of disease, age, mobility, CSF cell counts, CSF protein, and HTLV-1 proviral load.ResultsNf-L was detected in all CSF samples (median [range] = 575 [791.8–2,349] pg/mL) and positively correlated with markers of inflammation (CXCL10 (r = 0.733), neopterin (r = 0.499), cell count (r = 0.403), and protein levels (r = 0.693) in CSF; p < 0.0015). There was an inverse correlation between Nf-L and duration of disease (r = −0.584, p < 0.0001). Wheelchair-dependent patients had high concentrations of markers of inflammation and neuronal damage. Concentrations of CXCL10, neopterin, and Nf-L remained elevated in follow-up samples (mean follow-up 5.2 years). Nf-L in plasma correlated with concentration of Nf-L, neopterin, CXCL10, and protein in CSF.ConclusionsNf-L in plasma and CSF has potential to be used as a biomarker of disease activity in HAM. Neuronal damage seems to be more intense early in disease but persists long term. Wheelchair-dependent patients have ongoing neuroinflammation.

Adult T cell leukaemia/lymphoma (ATL) arises from clonally expanded T cells that are infected with human T cell leukaemia virus type-1 (HTLV-1). Here, we show that ATL can be detected early in HTLV-1-carriers through quantification of T-cell receptor (TCR)Vβ subunit diversity on T-cells infected with HTLV-1 (CD3+ CCR4+ CD26− T-cells) using an ‘oligoclonality index’ (OCI-flow). We established a reference range for OCI-flow by analysing peripheral blood mononuclear cells (PBMCs) from HTLV-1-carriers who had not developed ATL in a median of 10.5 years follow up (n = 38) and patients with ATL (n = 30). In the third cohort of HTLV-1-carriers with no history or clinical evidence of ATL (n = 106), 19% of high proviral load (PVL, ≥4 copies of HTLV-1/100 PBMCs) carriers had an OCI-flow in the ATL range, >0.770. Carriers with an OCI-flow >0.770 (n = 14) had higher lymphocyte counts and PVLs and were more likely to have a family history of ATL than carriers with OCI-flow ≤0.770. ATL subsequently developed in two of these 14 carriers but no carriers with OCI-flow ≤0.770 (p = 0.03, cumulative follow-up 129 person-years). This method can be used to identify a subset of high-PVL HTLV-1-carriers at increased risk of developing ATL who may benefit from intervention therapy, prior to the detection of disease.

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Human T-cell Lymphotropic virus (HTLV) prevalence is low in the UK, but higher in individuals originating from endemic countries. Anti-HTLV screening of all blood donations was introduced in 2002 to reduce the risk of transfusion transmission. The UK HTLV Cohort (UHC) was established for longterm follow up of people affected by HTLV. Recruitment by clinicians at blood centres and specialist clinics began in July 2003. Participants are asked to complete a baseline self completion questionnaire (SCQ) about their health and HTLV risk factors, flagged in central registries for cancer or death, and followed up about their health and well being every 2-3 years. Recruiting clinicians report participant’s clinical state at diagnosis. By March 2013, a total of 161 HTLV positive individuals had consented to take part: 89 of these were blood donors. Most were female (77%), of non-white ethnicity (64%) with a mean age of 49 years. Most (83%) positive participants were asymptomatic for HTLV at registration and eight (4%) participants died during follow-up. Baseline questionnaires were received from 160 (85%). Follow up was done in 2003, 2007 and 2010, the fourth is underway. Once complete, approximately 1,000 person years of follow up will be analyzed, factors associated with symptoms will be investigated and an assessment of the progression of HTLV related disease among the UHC will be presented. Information from the UHC, obtained from a decade of follow up, will provide a unique perspective since it is the only cohort of its kind in Europe.

The efficacy of treatments used for patients with HTLV-1 associated myelopathy/tropical spastic paraperesis (HAM/TSP) is uncertain although corticosteroids are widely prescribed. The effect of pulsed IV methylprednisolone was retrospectively analysed in an open cohort of 26 patients. 1g IV methylprednisolone was infused on three consecutive days. The outcomes were pain, gait, urinary frequency and nocturia, a range of inflammatory markers and HTLV-1 proviral load. A plasma cytokine profile was conducted in nine patients and correlated to gait and pain. Significant improvements in pain and 10m timed walk were observed immediately after the 3rd infusion and maintained, for pain, for up to six months. A shorter duration of disease was strongly correlated with improvement in the 10m timed walk (p=0.05) but not with the reduction in pain. Although baseline cytokine concentrations did not correlate to baseline pain or gait impairment a decrease in tumour necrosis factor-alpha (TNF-α) concentration after pulsed methylprednisolone was associated with improvements in both. Pulsed IV methylprednisolone significantly reduced pain in patients with HAM/TSP and was associated with a transient improvement in gait that may be related to a reduction in TNF-α concentration.

Adult T-cell lymphoma/leukaemia (ATLL) is known to be associated with poor immune response. Currently, it is not clear whether this is contributory to, or the consequence of the development of ATLL. In the National Centre for Human Retrovirology (NCHR) in London, we measured CD8/DR expression (a marker of T-cell activation) at ATLL presentation in our cohort of patients and compared these findings with a control population of aged-matched patients with myelopathy (HAM) and asymptomatic carriers (AC). The normal range for CD3+ CD8+ HLA-DR in HTLV-1 uninfected adults is 5.7% – 38.2%. The median overall survival status in our cohort of patients with ATLL (n = 53) is 9 months for acute subtype (range 3-22 months), lymphoma subtype 13.9 months (range 1-135 months), chronic subtype 64 months (range 8-144 months) and smouldering subtype 115 months. The median CD3+ CD8+ HLA-DR for AC was 25% (range 11-76%, n=20), 44% HAM (range 19-80%, n=20) and 45% for all ATLL subtypes (range 9-87%, n=26). By ATLL subtype: acute 58% (range 22-72%, n=5), lymphoma 43.5% (range 11-80%, n=10), chronic subtype 41% (range 23-60%, n=9), cutaneous 50% (n=1), smouldering subtype 46% (n=1). These data show that there is a significant increase in CD3+CD8+ HLA-DR expression in all ATLL subtype compared with AC and similar to that observed in patients with HAM. CD3+CD8+ HLA-DR expression is most marked in the acute subtype which is also associated with shortest survival. Despite evidence of CD8 T-cell activation this does not appear to be protective or associated with improved survival.

The lifetime risk of developing HTLV-1 associated myelopathy (HAM) is 0.25-3%. The main pathological feature is an immune-mediated response leading to chronic inflammation of the spinal cord. The optimal long term treatment has yet to be determined although clinical improvement with ciclosporin has been shown in a pilot study. Methotrexate, commonly used for autoimmune diseases, was introduced for the treatment of HAM at the National Centre for Human Retrovirology, London, UK as an alternative to ciclosporin.