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Journal articleAlagaratnam J, Kelly N, Dustan S, et al., 2025,
Proviral HIV DNA sequencing to inform suitability for long-acting injectable cabotegravir/rilpivirine
, AIDS, Vol: 39, Pages: 95-98, ISSN: 0269-9370Increasingly, people attending HIV services are requesting long-acting injectable (LAI) antiretroviral treatment (ART). However, without HIV RNA resistance-associated mutation results, individuals are considered unsuitable for LAI ART. We present our experience of sequencing proviral HIV DNA in 30 individuals to inform suitability for LAI ART, of whom 23 were considered suitable. In conclusion, optimization of diagnostic tools such as proviral HIV DNA sequencing to confirm suitability for LAI ART would be a welcome addition.
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Journal articleWang T, Campbell C, Stockdale AJ, et al., 2025,
Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy.
, JHEP Rep, Vol: 7BACKGROUND & AIMS: The dynamics of HBV viral load (VL) in patients with chronic hepatitis B (CHB) on nucleos(t)ide analogue (NA) treatment and its relationship with liver disease are poorly understood. We aimed to study longitudinal VL patterns and their associations with CHB clinical outcomes. METHODS: Utilising large scale, routinely collected electronic health records from six centres in England, collated by the National Institute for Health and Care Research Health Informatics Collaborative (NIHR HIC), we applied latent class mixed models to investigate VL trajectory patterns in adults receiving NA treatment. We assessed associations of VL trajectory with alanine transaminase, and with liver fibrosis/cirrhosis. RESULTS: We retrieved data from 1,885 adults on NA treatment (median follow-up 6.2 years, IQR 3.7-9.3 years), with 21,691 VL measurements (median 10 per patient, IQR 5-17). Five VL classes were identified from the derivation cohort (n = 1,367, discrimination: 0.93, entropy: 0.90): class 1 'long term suppression' (n = 827, 60.5%), class 2 'timely virological suppression' (n = 254, 18.6%), class 3 'persistent moderate viraemia' (n = 140, 10.2%), class 4 'persistent high-level viraemia' (n = 44, 3.2%), and class 5 'slow virological suppression' (n = 102, 7.5%). The model demonstrated a discrimination of 0.93 and entropy of 0.88 for the validation cohort (n = 518). Alanine transaminase decreased variably over time in VL-suppressed groups (classes 1, 2, 5; all p <0.001), but did not significantly improve in those with persistent viraemia (classes 3, 4). Patients in class 5 had twofold increased hazards of fibrosis/cirrhosis compared with class 1 (adjusted hazard ratio, 2.00; 95% CI, 1.33-3.02). CONCLUSIONS: Heterogeneity exists in virological response to NA therapy in CHB patients, with over 20% showing potentially suboptimal responses. Slow virological suppression is associated with liver disease progression. IMPACT A
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Journal articleCallaby H, Olver J, Emery K, et al., 2025,
Monkeypox virus isolation from longitudinal samples in 11 hospitalised patients.
, Lancet Infect Dis, Vol: 25, Pages: e4-e5 -
Journal articleOkhai H, Winston A, Post F, et al., 2024,
Exploring the cascade of mental healthcare among people with HIV experiencing depressive symptoms in the UK and Ireland: The POPPY study
, HIV MEDICINE, ISSN: 1464-2662 -
Journal articleFenn J, Madon K, Conibear E, et al., 2024,
An ultra-early, transient interferon-associated innate immune response associates with protection from SARS-CoV-2 infection despite exposure.
, EBioMedicine, Vol: 111BACKGROUND: A proportion of individuals exposed to respiratory viruses avoid contracting detectable infection. We tested the hypothesis that early innate immune responses associate with resistance to detectable infection in close contacts of COVID-19 cases. METHODS: 48 recently-exposed household contacts of symptomatic COVID-19 cases were recruited in London, UK between May 2020 and March 2021 through a prospective, longitudinal observational study. Blood and nose and throat swabs were collected during the acute period of index case viral shedding and longitudinally thereafter. Magnitude of SARS-CoV-2 exposure was quantified, and serial PCR and serological assays used to determine infection status of contacts. Whole-blood RNA-seq was performed and analysed to identify transcriptomic signatures of early infection and resistance to infection. FINDINGS: 24 highly-exposed household contacts became PCR-positive and seropositive whilst 24 remained persistently PCR-negative and seronegative. A 96-gene transcriptomic signature of early SARS-CoV-2 infection was identified using RNA-seq of longitudinal blood samples from PCR-positive contacts. This signature was dominated by interferon-associated genes and expression correlated positively with viral load. Elevated expression of this 96-gene signature was also observed during exposure in 25% (6/24) of persistently PCR-negative, seronegative contacts. PCR-negative contacts with elevated signature expression had higher-magnitude SARS-CoV-2 exposure compared to those with low signature expression. We validated this signature in SARS-CoV-2-infected individuals in two independent cohorts. In naturally-exposed healthcare workers (HCWs) we found that 7/58 (12%) PCR-negative HCWs exhibited elevated signature expression. Comparing gene-signature expression in SARS-CoV-2 Controlled Human Infection Model (CHIM) volunteers pre- and post-inoculation, we observed that 14 signature genes were transiently upregulated as soon as 6 hr post
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Journal articleSun W, Gao C, Gladkov GT, et al., 2024,
Footprints of innate immune activity during HIV-1 reservoir cell evolution in early-treated infection
, Journal of Experimental Medicine, Vol: 221, ISSN: 0022-1007Antiretroviral treatment (ART) initiation during the early stages of HIV-1 infection is associated with a higher probability of maintaining drug-free viral control during subsequent treatment interruptions, for reasons that remain unclear. Using samples from a randomized-controlled human clinical trial evaluating therapeutic HIV-1 vaccines, we here show that early ART commencement is frequently associated with accelerated and efficient selection of genome-intact HIV-1 proviruses in repressive chromatin locations during the first year after treatment initiation. This selection process was unaffected by vaccine-induced HIV-1-specific T cell responses. Single-cell proteogenomic profiling demonstrated that cells harboring intact HIV-1 displayed a discrete phenotypic signature of immune selection by innate immune responses, characterized by a slight but significant upregulation of HLA-C, HLA-G, the IL-10 receptor, and other markers involved in innate immune regulation. Together, these results suggest an accelerated immune selection of viral reservoir cells during early-treated HIV-1 infection that seems at least partially driven by innate immune responses.
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Journal articleCockbain B, Fidler S, Lyall H, 2024,
Preventing perinatal HIV acquisition; current gaps and future perspectives.
, Curr Opin HIV AIDS, Vol: 19, Pages: 293-304PURPOSE OF REVIEW: Although current treatment could eradicate vertical transmission, in 2022, 130 000 infants acquired HIV globally. HIV suppression with antiretroviral therapy (ART) transforms survival for people living with HIV (PLWH), and prevents transmission, including vertical. International guidelines recommend lifelong ART for PLWH, consequently perinatal HIV acquisition reflects implementation gaps in the HIV care cascade. We summarize these gaps, exploring potential novel approaches and therapeutic innovations towards eliminating vertical HIV transmission. RECENT FINDINGS: Multifactorial challenges continue to underpin gaps in the HIV care cascade, including accessibility, availability and sustainability of HIV testing, prevention and treatment, alongside stigma, gender-based violence and poverty. Long-acting ART may be important in preventing perinatal HIV acquisition, with early data demonstrating tolerability and efficacy of injectable ART throughout pregnancy, both as HIV treatment and prevention. Carefully selected long-acting broadly neutralizing antibodies (bNAbs) matching circulating, exposing viral envelope sequences have demonstrated safety, clinical trials are ongoing to demonstrate efficacy. SUMMARY: Emerging clinical studies should prioritize pregnant/lactating people and infants to ensure such therapies are well tolerated and efficacious. Alongside therapeutic innovation, programmatic strategies must address social and economic challenges, ensuring sustainable HIV treatment/prevention programmes and facilitating global elimination of blood-borne viruses.
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Journal articleTipoe T, Ogbe A, Lee M, et al., 2024,
Impact of antiretroviral therapy during primary HIV infection on T-cell immunity after treatment interruption.
, Eur J Immunol, Vol: 54This study aims to understand the impact of early antiretroviral therapy (ART) on HIV-specific T-cell responses measured after treatment interruption, which may inform strategies to deliver ART-free immune-mediated viral suppression. HIV-specific T-cell immunity was analysed using gamma interferon enzyme-linked immunospot assays in two studies. SPARTAC included individuals with primary HIV infection randomised to 48 weeks of ART (n = 24) or no immediate therapy (n = 37). The PITCH (n = 7) cohort started antiretroviral therapy in primary infection for at least one year, followed by TI. In SPARTAC, participants treated in PHI for 48 weeks followed by TI for 12 weeks, and those who remained untreated for 60 weeks made similar HIV Gag-directed responses (both magnitude and breadth) at week 60. However, the treated group made a greater proportion of novel HIV Gag-directed responses by Week 60, suggestive of a greater reserve to produce new potentially protective responses. In the more intensively followed PITCH study, 6/7 participants showed dominant Gag and/or Pol-specific responses post-TI compared with pre-TI. Although early ART in PHI was not associated with major differences in HIV-specific immunity following TI compared with untreated participants, the potential to make more new Gag-directed responses warrants further investigation as this may inform strategies to achieve ART-free control.
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Journal articleWinston A, Henderson M, 2024,
Our evolving understanding of the impact of primary HIV infection on brain health
, BRAIN, Vol: 147, Pages: 3643-3644, ISSN: 0006-8950 -
Journal articleMahdifar M, Boostani R, Taylor GP, et al., 2024,
Comprehensive insight into the functional roles of NK and NKT cells in HTLV-1-associated diseases and asymptomatic carriers
, Molecular Neurobiology, Vol: 61, Pages: 7877-7889, ISSN: 0893-7648Human 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.
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