Edward Laurence Murphy

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive demyelinating disease of the spinal cord due to chronic inflammation. Hallmarks of disease pathology include dysfunctional anti-viral responses and the infiltration of HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ T cells in the central nervous system. HAM/TSP individuals exhibit CD4+ and CD8+ T cells with elevated co-expression of multiple inhibitory immune checkpoint proteins (ICPs), but ICP blockade strategies can only partially restore CD8+ T-cell effector function. Exosomes, small extracellular vesicles, can enhance the spread of viral infections and blunt anti-viral responses. Here, we evaluated the impact of exosomes isolated from HTLV-1-infected cells and HAM/TSP patient sera on dendritic cell (DC) and T-cell phenotypes and function. We observed that exosomes derived from HTLV-infected cell lines (OSP2) elicit proinflammatory cytokine responses in DCs, promote helper CD4+ T-cell polarization, and suppress CD8+ T-cell effector function. Furthermore, exosomes from individuals with HAM/TSP stimulate CD4+ T-cell polarization, marked by increased Th1 and regulatory T-cell differentiation. We conclude that exosomes in the setting of HAM/TSP are detrimental to DC and T-cell function and may contribute to the progression of pathology with HTLV-1 infection.

Blood donations in South Africa are tested for HIV RNA using individual donation NAT (ID-NAT), allowing detection and rapid antiretroviral therapy (ART) of acute HIV infections. We enrolled a cohort of acute and recent HIV-infected blood donation candidates in South Africa in 2015–2018, measured HIV antibody, ID-NAT, and recency of infection <195 days (Sedia LAg) at enrollment and initiated early ART. A small cohort of HIV elite controllers was followed without treatment. HIV reservoir measurements included ultrasensitive plasma RNA, cell-associated HIV RNA, and total DNA. Enrollment of 18 Fiebig I–III and 45 Fiebig IV–VI HIV clade C subjects occurred a median of 18 days after index blood donation. ART was administered successfully and compliance with follow-up visits was excellent. There were only minimal differences in HIV reservoir between ART initiation in Fiebig stages I–III vs. IV–VI, but ART noncompliance increased HIV reservoir. In 11 untreated HIV elite controllers, HIV reservoir levels were similar to or higher than those seen in our early treated cohort. National blood services can identify acute HIV cohorts for subsequent HIV cure research studies. Among HIV clade C-infected donors, HIV reservoir differed little by Fiebig stage at treatment initiation, but was smaller than in chronically treated HIV and those with ART noncompliance.

Objective: Antenatal anaemia is associated with increased peripartum transfusion requirement in South Africa. We studied whether HIV was associated with the response to treatment of iron‐deficiency anaemia.Design: Prospective cohort study.Setting: Hospital‐based antenatal anaemia clinic in South Africa.Sample: Equal‐sized cohorts of pregnant women testing positive for HIV (HIV+) and testing negative for HIV (HIV−) with iron‐deficiency anaemia.Methods: Haemoglobin trajectories of women with confirmed iron‐deficiency anaemia (ferritin < 50 ng/ml) were estimated from the initiation of iron supplementation using mixed‐effects modelling, adjusted for baseline HIV status, ferritin level, maternal and gestational ages and time‐varying iron supplementation.Main outcome measures: Haemoglobin trajectories.Results: Of 469 women enrolled, 51% were HIV+, 90% of whom were on antiretroviral therapy (with a mean CD4+ lymphocyte count of 403 cells/mm³). Anaemia diagnoses did not differ by HIV status. A total of 400 women with iron‐deficiency anaemia were followed during treatment with oral or intravenous (6%) iron therapy. In multivariable analysis, haemoglobin recovery was 0.10 g/dl per week slower on average in women who were HIV+ versus women who were HIV− (P = 0.001), 0.01 g/dl per week slower in women with higher baseline ferritin (P < 0.001) and 0.06 g/dl per week faster in women who were compliant with oral iron therapy (P = 0.002).Conclusions: Compared with women who were HIV−, women who were HIV+ with iron‐deficiency anaemia had slower but successful haemoglobin recovery with iron therapy. Earlier effective management of iron deficiency could reduce the incidence of peripartum blood transfusion.Tweetable Among pregnant women with iron‐deficiency anaemia in South Africa, HIV slows haemoglobin recovery in response to oral iron therapy.

Among 397,640 first-time blood donors screened in South Africa during 2012–2015, HIV prevalence was 1.13%, hepatitis B virus prevalence 0.66%, and hepatitis C virus prevalence 0.03%. Findings of note were a high HIV prevalence in Mpumalanga Province and the near absence of hepatitis C virus nationwide.

Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL) in human T-cell lymphotropic virus (HTLV) infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1), 45 human T-cell lymphotropic virus type 2 (HTLV-2), and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST) cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S) ratio (a measure of TL) and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs) using quantitative PCR (qPCR). Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322). TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection.