Sarah Rowland-Jones

Background: Human immunodeficiency virus (HIV-1) infection leads to reduced telomere length (TL), a biomarker of immune aging. We investigated relationships between HIV viral load (VL) and CD4 count with TL and its rate of attrition in children with HIV from Zambia and Zimbabwe. Methods: Buffy coat was obtained at baseline and 48 weeks from children aged 11–19 years with perinatally acquired HIV taking combination antiretroviral therapy (cART) for >6 months recruited into the VITALITY trial. Relative TL was measured using monochrome multiplex quantitative polymerase chain reaction, standardizing units for analysis. Cross-sectional analyses used multivariable linear regression adjusting for age, sex, and study site; longitudinal analysis additionally adjusted for baseline TL. Results: Among participants at baseline (N = 842; mean ± SD age, 15.5 ± 2.6 years; 53.2% female), 678 (80.5%) had HIV VL 1000 copies/mL. The mean CD4 count was 584 ± 243 cells/μL. Compared to participants with VL 1000 copies/mL had shorter TL (β = −.239 [95% confidence interval {CI}, −.451 to −.026]; P = .028), whereas those with 60–1000 copies/mL did not (P = .836). Lower CD4 cell count was associated with shorter TL (β = −.038 [95% CI, −.009 to −.066] per 100 CD4 cells/μL; P = .009). In longitudinal analysis (n = 783) after mean 336 ± 6 days, those with HIV VL >1000 copies/mL at both timepoints had an accelerated telomere attrition rate (β = −.276 [95% CI, −.546 to −.005]; P = .046) compared with participants with VL 1000 copies/mL among children with HIV on cART in Africa is associated with a degradation of immune age within 1 year, which may increase risk of comorbidities later in life. Clinical Trials Registration: PACTR202009897660297.

A better understanding of the immune responses associated with future viral control in humans during acute HIV-1 infection (AHI) is critical to inform vaccines and immune-based therapeutics. Natural killer (NK) cells and CD8 ⁺ T-cells are pivotal in antiviral defence, yet the dynamics and complementary roles of these effector subsets during AHI with different HIV-1 subtypes remain poorly understood. Access to a unique patient cohort recruited during and post-peak HIV-1 viral load with different HIV-1 subtypes and followed up longitudinally in the absence of antiretroviral therapy up to six years post estimated date of infection (EDI) provided a rare opportunity to fill this knowledge gap. Our data show an early expansion of FcεRγ ⁻ CD57 ⁺ NK cells with classical adaptive traits concomitant with an enhanced capacity for antibody-dependent cellular cytotoxicity (ADCC) and reactivity against HIV-1 antigens. This distinctive NK cell profile was more abundant in donors with subtype A infection compared to non-subtype A, partially driven by elevated pro-inflammatory cytokine levels and changes in the epigenetic landscape. The accumulation of adaptive NK cells during the first month of infection contributed to the optimal activation of CD8 ⁺ T-cells, promoting virus-specific responses. Notably, individuals with higher levels of FcεRγ ⁻ CD57 ⁺ adaptive NK cells during the first month of infection were more likely to exhibit long-term viral control in the absence of ART. These findings underscore the critical role of early, high-magnitude adaptive NK cell responses in CD8 ⁺ T-cell activation and subsequent immune control. This work provides novel insights into the correlates of protective immunity against HIV-1 infection, with implications for preventative or therapeutic vaccine strategies aimed at promoting adaptive NK cell responses. One Sentence Summary: Early expansion of adaptive NK cells during acute HIV-1 infection promotes long-term viral control.

The complex dynamics of protein expression in plasma during hyperacute HIV-1 infection and its relation to acute retroviral syndrome, viral control, and disease progression are largely unknown. Here, we quantify 1293 blood plasma proteins from 157 longitudinally linked plasma samples collected before, during, and after hyperacute HIV-1 infection of 54 participants from four sub-Saharan African countries. Six distinct longitudinal expression profiles are identified, of which four demonstrate a consistent decrease in protein levels following HIV-1 infection. Proteins involved in inflammatory responses, immune regulation, and cell motility are significantly altered during the transition from pre-infection to one month post-infection. Specifically, decreased ZYX and SCGB1A1 levels, and increased LILRA3 levels are associated with increased risk of acute retroviral syndrome; increased NAPA and RAN levels, and decreased ITIH4 levels with viral control; and increased HPN, PRKCB, and ITGB3 levels with increased risk of disease progression. Overall, this study provides insight into early host responses in hyperacute HIV-1 infection, and present potential biomarkers and mechanisms linked to HIV-1 disease progression and viral load.

Stunting and pubertal delay are common among children growing up with human immunodeficiency virus (HIV) and are associated with bone and muscle impairments. We investigated factors associated with bone density and muscle function in adolescents living with HIV (ALWH). The VITALITY trial (PACTR202009897660297) investigated whether vitamin D and calcium supplementation improves musculoskeletal health among ALWH. A total of 842 ALWH aged 11–19 years, established on antiretroviral therapy (ART) for ≥6 months, were enrolled from HIV clinics in Zambia and Zimbabwe. Clinical history and examination were undertaken, and serum 25-hydroxyvitamin D₃ (25[OH]D₃) was measured. Dual-energy X-ray absorptiometry measured total-body-less-head bone mineral density adjusted for height (TBLH-BMD^HT), and lumbar spine bone mineral apparent density (LS-BMAD) z scores. The association between a priori–defined covariates and musculoskeletal outcomes were investigated using baseline enrollment data and multivariable logistic regression. TBLH-BMD^HT z scores were impaired (mean, −1.42 for male and −0.63 female participants), as were LS-BMAD z scores (mean −1.15 for male and −0.47 for female participants). In bivariate analysis, early pubertal stage, less physical activity, and older age at ART initiation were associated with lower TBLH-BMD^HT z scores. Younger age, early pubertal stage, and low socioeconomic status were associated with lower LS-BMAD z scores. Grip-strength-for-height and jump-power-for-height z scores were associated with lower TBLH-BMD^HT and LS-BMAD z scores. Low dietary vitamin D and calcium were associated with lower adjusted TBLH-BMD^HT z scores. Lower 25(OH)D₃ was associated with lower adjusted TBLH-BMD^HT and LS-BMAD z scores. Deficits in bone density are common in ALWH. Vitamin D and calcium supplementation and promotion of exercise may improve musculoskeletal health among perinatally infected ALWH.

Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly influence immune cell function and differentiation, including NK cell responses. Persistent HIV-1 infection leads to a state of chronic immune activation, NK cell subset redistribution, and progressive NK cell dysregulation. In this study, we examined the metabolic processes that characterize NK cell subsets in HIV-1 infection, including adaptive NK cell subpopulations expressing the activating receptor NKG2C, which expand during chronic infection. These adaptive NK cells exhibit an enhanced metabolic profile in HIV-1 ^– individuals infected with human cytomegalovirus (HCMV). However, the bioenergetic advantage of adaptive CD57 ⁺ NKG2C ⁺ NK cells is diminished during chronic HIV-1 infection, where NK cells uniformly display reduced oxidative phosphorylation (OXPHOS). Defective OXPHOS was accompanied by increased mitochondrial depolarization, structural alterations, and increased DRP-1 levels promoting fission, suggesting that mitochondrial defects are restricting the metabolic plasticity of NK cell subsets in HIV-1 infection. The metabolic requirement for the NK cell response to receptor stimulation was alleviated upon IL-15 pretreatment, which enhanced mammalian target of rapamycin complex 1 (mTORC1) activity. IL-15 priming enhanced NK cell functionality to anti-CD16 stimulation in HIV-1 infection, representing an effective strategy for pharmacologically boosting NK cell responses.

Background Vitamin D3 (vit.D3) plays an important role in immune responses, and deficiency has been linked to inflammation and higher susceptibility to infections. In vitro studies using pure cell cultures demonstrated vit.D3’s contribution to microbial killing capacity of macrophages. However, the effect on neutrophils is poorly described. We assessed the effect of high dose vit.D3 in vitro on activation and microbial killing capacities of neutrophils and monocytes under near-physiological conditions using fresh whole blood from adult healthy donors. Methods Whole blood was exposed to Mycobacterium bovis Bacille Calmette-Guérin (BCG) and Lipopolysaccharide (LPS) post treatment with 100 nM vit.D3 for 2hr, 6hr, and 24hr. Cellular phenotyping by flow cytometry was performed to quantify expression of neutrophil (CD16bri14low) and monocyte (CD14bri16low) activation markers (CD11b, CD62L), bacterial phagocytic capacity, and reactive oxygen species (ROS) production. Interleukin 8 (IL-8) and myeloperoxidase serum levels were quantified using ELISA, and correlated with intracellular killing capacities by performing colony forming unit (CFU) analysis. Results Vit. D3 had no significant direct effect on CD11b/62L expression, phagocytic capacity, ROS production, inflammatory marker expression (IL-8, MPO) and killing efficacy independent of the pre-treatment durations. This may reflect differences in vit.D3 concentrations used and kinetics of vit.D3 mediated response patterns in the cells studied when compared to previous reports. Although these results cannot be extrapolated onto in vivo conditions as vit.D3 effects under physiological conditions can be more complex, the whole blood assay proves a valuable tool to analyse host responses ex vivo in patient cohorts. This assay is employed in our ongoing EDCTP funded 96-week randomized placebo-controlled clinical trial (VITALITY) involving high-dose vit.D3 supplementation (20,000 IU/week) in HIV positive adolescents to assess effects on neutrophil and monocyte antimicrobial responses. Conclusion An interplay of background effects of HIV and other comorbidities need to be considered as they may influence overall benefits of vit.D3 in this population.

Pronounced immune escape by the SARS-CoV-2 Omicron variant has resulted in large numbers of individuals with hybrid immunity, generated through a combination of vaccination and infection. Based primarily on circulating neutralizing antibody (NAb) data, concerns have been raised that omicron breakthrough infections in triple-vaccinated individuals result in poor induction of omicron-specific immunity, and that a history of prior SARS-CoV-2 in particular is associated with profound immune dampening. Taking a broader and comprehensive approach, we characterized mucosal and blood immunity to both spike and non-spike antigens following BA.1/BA.2 infections in triple mRNA-vaccinated individuals, with and without a history of previous SARS-CoV-2 infection. We find that the majority of individuals increase BA.1/BA.2/BA.5-specific NAb following infection, but confirm that the magnitude of increase and post-omicron titres are indeed higher in those who were infection-naive. In contrast, significant increases in nasal antibody responses are seen regardless of prior infection history, including neutralizing activity against BA.5 spike. Spike-specific T cells increase only in infection-naive vaccinees; however, post-omicron T cell responses are still significantly higher in previously-infected individuals, who appear to have maximally induced responses with a CD8+ phenotype of high cytotoxic potential after their 3 ^rd mRNA vaccine dose. Antibody and T cell responses to non-spike antigens also increase significantly regardless of prior infection status, with a boost seen in previously-infected individuals to immunity primed by their first infection. These findings suggest that hybrid immunity induced by omicron breakthrough infections is highly dynamic, complex, and compartmentalised, with significant immune enhancement that can help protect against COVID-19 caused by future omicron variants.

HLA class I (HLA-I) allotypes vary widely in their dependence on tapasin (TAPBP), an integral component of the peptide-loading complex, to present peptides on the cell surface. We identified two single-nucleotide polymorphisms that regulateTAPBPmessenger RNA (mRNA) expression in Africans,rs111686073(G/C) andrs59097151 (A/G), located in an AP-2α transcription factor binding site and a microRNA (miR)-4486 binding site, respectively.rs111686073Gandrs59097151Ainduced significantly higherTAPBPmRNA expression relative to the alternative alleles due to higher affinity for AP-2α and abrogation of miR-4486 binding, respectively. These variants associated with lowerPlasmodium falciparumparasite prevalence and lower incidence of clinical malaria specifically among individuals carrying tapasin-dependent HLA-I allotypes, presumably by augmenting peptide loading, whereas tapasin-independent allotypes associated with relative protection, regardless of imputedTAPBPmRNA expression levels. Thus, an attenuated course of malaria may occur through enhanced breadth and/or magnitude of antigen presentation, an important consideration when evaluating vaccine efficacy.