Developing safe and effective treatments against emerging RNA viruses is an important goal in pandemic preparedness efforts. 4'-fluorouridine (4'-FlU) is a broad-spectrum antiviral that was shown to inhibit viral RNA-dependent RNA polymerases (RdRps). Given its notable range of antiviral activity, this class of nucleoside analogs warrants further investigation. Here, we studied the antiviral activity and underlying mechanism of inhibition of 4'-fluoroadenosine (4'-FlA). Like 4'-FlU, 4'-FlA demonstrates a broad-spectrum of antiviral activity against eight prototypic viruses representing diverse families. Enzyme kinetics show that the triphosphate (4'-FlA-TP) is efficiently incorporated by viral RdRps. A cryo-EM structure of the RdRp of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in complex with double-stranded RNA and the incorporated monophosphate (4'-FlA-MP) characterizes interactions at the active site. The incorporated analog elicits heterogeneous inhibition patterns in primer extension reactions. In contrast, templates with embedded 4'-FlA-MP inhibit incorporation of complementary UTP across the viral RdRps. However, incorporation of 4'-FIA-TP is not limited to viral polymerases and likewise includes human mitochondrial RNA polymerase. These results demonstrate the general potential for 4'-fluorinated nucleotides as antiviral drugs and guide the development of more selective derivatives for medical use in appropriate settings.
Neurodegenerative diseases and neurocognitive disorders increasingly appear to share a common and underappreciated contributor: the viral-immune axis in the brain. This review presents current evidence linking neurotropic viruses and host antiviral immunity to the onset and progression of neurodegeneration and neurocognitive dysfunction. We explore how viral infections, particularly by Herpesviruses, Severe Acute Respiratory Syndrome Coronavirus 2, and Human Immunodeficiency Virus, disrupt neural homeostasis through neuroinflammation, amyloidosis, tauopathy, and autophagy dysregulation in neurodegeneration including Alzheimer's disease (AD). Simultaneously, host antiviral mechanisms, including type I interferons and interferon regulatory factors, often amplify neuronal damage when dysregulated. By examining viral and immune interactions within the neurodegenerative diseases, this review aims to broaden our understanding of the viral-immune axis in the brain and inspire novel approaches to prevention and treatment.
Respiratory viruses such as influenza A virus (IAV), respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) impose a persistent global health burden, yet current antivirals are often limited by toxicity and side effects. This highlights the urgent need for broad-spectrum antiviral agents that can safely block viral infections. Carbon dots (cDots) provide an ideal scaffold for this strategy due to their ultra-small size, tuneable surface chemistry, and inherent biocompatibility. Notably, we previously demonstrated that 2-aminophenylboronic acid (APBA)-derived cDots have virus-binding capabilities by inhibiting human immunodeficiency virus (HIV)-1 entry. Herein, we synthesize APBA-functionalized cDots via pyrolysis, yielding cDots densely decorated with boronic acid and boroxine groups. These non-toxic APBA-cDots demonstrate potent antiviral activity against RSV, IAV, and hMPV in vitro. Competitive inhibition by N-acetylglucosamine and molecular docking analyses are consistent with a proposed boronic acid-mediated interaction with glycan-rich viral surfaces, although this mechanism has not yet been definitively proven by direct loss-of-function chemistry. Overall, these findings identify APBA-cDots as a promising antiviral nanoplatform and provide preliminary support for a glycan-targeting mechanism that warrants further validation.
Exhaustion of antiviral immunity driven by inhibitory signals is one hallmark of persistent viral infection. Notably, PD-1 and IL-10 are two major contributors to CD8+ T cell dysfunction. How these molecules are specifically induced during chronic viral infection remains mainly unknown. Using the lymphocytic choriomeningitis virus model, we show that the apoptotic-cell accumulation and expression of tyrosine kinase Mertk are linked to the outcome of chronic viral infection. Early CD8+ T cell activation correlated with increased dead-cell deposition, rapid induction of IL-10 and TGF-β in macrophages and dendritic cells (DCs), and a pronounced upregulation of PD-1 on CD8+ T cells and its ligand PD-L1. In TCR-β-deficient mice lacking CD8+ T cells, dead-cell generation and expression of IL-10, TGF-β, PD-1, and PD-L1 were markedly restricted. Our findings suggest that CD8+ T cell-mediated killing of infected targets generates large quantities of apoptotic cells, which activate the phosphatidylserine-binding kinase Mertk on macrophages and DCs. This signalling cascade subsequently promotes expression of IL-10, TGF-β, PD-1, and partially PD-L1. Consistent with this model, loss of Mertk in Mertk-/- mice reduced inhibitory cytokines and PD-1 expression, accelerated antiviral CD8+ T cell responses, and improved viral control. Collectively, our study provides important insight into cellular basis of T cell regulation identifying apoptotic cells and Mertk activation as key mechanisms initiating the suppression of CD8+ T cell immunity during chronic viral infection.
Japanese encephalitis virus (JEV), a neurotropic flavivirus and a major cause of viral encephalitis, poses a significant global health threat due to its neuroinvasive potential. Host innate immune responses, particularly those mediated by pattern-recognition receptors such as Toll-like receptors (TLRs) and RIG-I-like receptors, play critical roles in detecting JEV infection in neurons and glial cells, triggering antiviral defenses through induction of type I interferons (IFNs), inflammatory cytokines, and interferon-stimulated genes. However, dysregulated inflammatory responses may contribute to neurodegeneration and disease severity. JEV has evolved multiple immune evasion strategies, including suppression of IFN signaling, modulation of host microRNAs, and exploitation of cellular pathways such as autophagy to facilitate viral replication and persistence. This review summarizes current knowledge regarding TLR and other PRRs-mediated innate immune sensing during JEV infection, highlights the molecular mechanisms underlying viral immune evasion, and discusses the potential of TLR agonists as antiviral immunomodulators and vaccine adjuvants.
JQKD82 is an epigenetic modulator that inhibits lysine-specific demethylase 5 (KDM5), a host factor implicated in HIV latency and cell survival. Although JQKD82 has been studied in latent HIV infection of T cell models, its effects on HIV infection in macrophages remain unclear. Here, we investigated the impact of JQKD82 on HIV infection of primary human monocyte-derived macrophages (MDMs). We observed that treatment of MDMs with non-cytotoxic concentrations of JQKD82 dose-dependently inhibited HIV replication, as evidenced by reduced virus-induced syncytium formation, decreased viral Gag mRNA expression, and lower p24 protein levels. Pretreatment of cells with JQKD82 was more effective than post-infection treatment, suggesting inhibition at the viral entry stage, which was confirmed using pseudotyped HIV NL4-3-ΔEnv-eGFP-Bal. Mechanistically, JQKD82 downregulated CD4 and CCR5 expression while inducing the CCR5 ligand RANTES in MDMs. In addition, JQKD82 enhanced interferon-stimulated gene (ISG) expression in HIV-infected macrophages. Together, these findings demonstrate that JQKD82 inhibits HIV infection through dual mechanisms-blocking viral entry and enhancing antiviral ISG responses-supporting further evaluation of KDM5 inhibition as a potential therapeutic strategy against HIV.
Intrinsic cellular factors that inhibit herpesvirus infection remain incompletely defined. Here, we identify TRIM5α as a restriction factor for herpes simplex virus type 1 (HSV-1). TRIM5α-mediated restriction requires its ubiquitin ligase activity, PRY-SPRY domain, and the ability to oligomerize. Mechanistically, we show that TRIM5α directly engages capsid protein VP19C and promotes the stability of the VP19C-VP23 complex and its nuclear accumulation. VP19C also activates NF-κB synergistically with TRIM5α and independently. HSV-1 counteracts this host defense by triggering proteasome-dependent TRIM5α degradation. In addition, we show that Cyclophilin A (CypA), which is incorporated into HSV-1 virions, also binds to VP19C, but enhances infection. As with HIV-1 and orthopoxviruses, the proviral activity of CypA is disrupted by cyclosporin A (CsA), but unlike the situation with these other viruses, the proviral activity of CypA is independent of TRIM5α. Notably, CsA and its non-immunosuppressive derivatives also exhibit anti-HSV-1 activity in neuronal cell lines, suggesting a potential therapy for HSV-1 encephalitis. TRIM5α and CypA also interact with orthologs of VP19C in other alpha, beta and gamma human herpesviruses. These findings reveal two distinct host pathways acting on the herpesvirus capsid and provide a foundation for comparing how TRIM5α and CypA modulate infection of unrelated virus families, offering new directions to identify shared principles of host recognition and viral evasion.
Japanese encephalitis virus (JEV) is an important neurotropic orthoflavivirus that poses a threat to both human and animal health. However, the mechanism underlying its rapid replication in the central nervous system (CNS) remains poorly understood. In this study, we conducted metabolomic profiling of JEV-infected mouse brains and neurons, revealing a profound reprogramming of central carbon metabolism, particularly an enhancement in nucleotide synthesis. Integrated multi-omics analyses confirmed that JEV infection transcriptionally upregulates key enzymes involved in de novo purine biosynthesis (DNPB), one-carbon (1C) metabolism, and the pentose phosphate pathway (PPP) in neurons. Pharmacological inhibition of the core DNPB enzymes potently suppressed JEV replication in neurons and reduced both viral loads and neuroinflammation in JEV-infected mice, suggesting the essential role of DNPB in JEV replication within CNS. Mechanistically, we delineated the critical functions of both the non-oxidative PPP and MTHFD2-mediated 1C metabolism, which jointly supply essential precursors, such as ribose-5-phosphate and formyl groups, for the de novo biosynthesis of purines required for viral RNA replication. These findings unveil a strategy by which JEV co-opts the host's purine biosynthetic machinery to fulfill the nucleotide demands for its genomic replication, establishing DNPB and its supporting pathways as promising therapeutic targets for infections caused by JEV and other neurotropic viruses.
To discuss neurocognition measurement in view of current controversies in HIV-associated neurocognitive disorders (HAND). The HAND criteria have been criticised for several reasons with some proposing alternative criteria and terminology, HIV-associated brain injury (HABI). The following concerns have been raised: the legacy effect from past ineffective therapy is not included, the adoption of an asymptomatic neurocognitive impairment (ANI) stage, including liberal neuropsychological test cut-offs overestimate neurocognitive impairment (NCI), and that NCI with viral suppression is still related to HIV rather than the effect of either legacy and/or comorbidities. However, the legacy effect cannot be easily identified, the HAND criteria have been inappropriately used, and there is increasing evidence that low level HIV replication is important in virally suppressed HAND, though likely mitigated in some by resilience factors. Potential solutions to addressing these within the HAND framework will be proposed. The HAND framework is still useful but it must be put in clinical context. ANI should be considered a research category pending further clarification of its clinical utility. Further work is needed to identify and quantify the legacy effect/ongoing NCI, as well as the nature of resilience.
Endolysosomal compartments act as critical sorting hubs for viral entry, trafficking, and uncoating, yet the contribution of lipid-modifying enzymes to these processes remains incompletely understood. Acid sphingomyelinase (ASM), a key regulator of endolysosomal membrane composition, has been implicated in host-pathogen interactions, and is actively engaged in human adenovirus (HAdV) infection. Here, we confirm ASM activity as an essential host determinant of efficient HAdV infection and demonstrate that its pharmacological inhibition synergizes with direct-acting antiviral therapy. Analysis of publicly available human datasets revealed age-associated changes in expression of host cell determinants for HAdV entry like ASM expression in respiratory epithelial tissues and colonic tissue, suggesting that ASM-dependent endolysosomal functions are modulated across the human lifespan. Using epithelial cell models of HAdV infection, we show that viral entry and replication critically depend on ASM activity. Pharmacological inhibition of ASM by functional inhibitors such as fluoxetine resulted in a dose-dependent suppression of viral replication and significantly reduced infection rates in single-cycle infection assays, indicating disruption of early stages of the viral life cycle. Mechanistically, ASM inhibition impaired HAdV uptake and trafficking by reducing viral internalization and co-localization with early endosomes. Importantly, combined treatment with fluoxetine and the viral DNA polymerase inhibitor brincidofovir acts synergistically in reducing HAdV titer. These findings demonstrate that targeting host-controlled endosomal entry pathways can potentiate the antiviral efficacy of direct-acting agents. Together, our study validates ASM as a central regulator of HAdV entry and identifies combined host- and virus-directed therapy as a promising strategy to suppress HAdV infection.
Extracellular vesicles (EVs) are important mediators of intercellular communication in hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. EVs released from infected hepatocytes can carry viral nucleic acids, proteins, and regulatory non-coding RNAs to immune and nonimmune cells, thereby influencing viral dissemination, immune regulation, and disease progression. In particular, EV-associated cargos modulate antiviral immunity by affecting interferon signaling, natural killer cell function, cytokine production, immune checkpoint pathways, and T-cell exhaustion. These effects may promote viral persistence and immune evasion, although some EV populations can also enhance innate antiviral responses, indicating context-dependent dual roles. EVs also contribute to fibrosis and hepatocarcinogenesis by regulating hepatic stellate cell activation, inflammatory signaling, and tumor microenvironment remodeling. In addition, EV-derived RNAs and proteins show potential as noninvasive biomarkers and therapeutic targets. This review summarizes current evidence on EVs in HBV and HCV infection, with emphasis on immune regulation, viral persistence, disease progression, and translational prospects, while also discussing key challenges such as EV heterogeneity and co-isolation with viral particles.
TRIpartite Motif (TRIM) protein 5 alpha (TRIM5α) is a well-characterized cellular inhibitor of lentivirus replication that limits transmission of related viruses between primates. We previously reported that TRIM5α derived from humans and rhesus macaques inhibits replication of orthoflaviviruses belonging to the tick-borne encephalitis virus (TBEV) serocomplex, including TBEV, Kyasanur forest disease virus and Langat virus (LGTV), but interestingly not the tick-borne Powassan virus (POWV). To further characterize the primate TRIM5α and orthoflavivirus interface, we screened TRIM5α variants from representative old- and new-world primates for restriction capacity. TRIM5α from old-world African green monkey, De Brazza's monkey and chimpanzee demonstrated virus-specific restriction of tick-borne orthoflaviviruses. Efforts to determine why TRIM5α fails to inhibit POWV revealed that our lab stock had acquired a non-synonymous mutation in NS3 that, when introduced into a POWV molecular clone, facilitated virus replication in the presence of all inhibitory primate TRIM5α proteins. Infection of human dendritic cells with TRIM5α-resistant POWV resulted in high early replication and strong induction of interferon responses that limited replication compared with the wild-type virus. Thus, primate TRIM5α functions as a potent cellular barrier to infection with tick-borne orthoflaviviruses that restrains replication to a level that may help avoid early innate immune recognition.
Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b, genotype D1.1, are responsible for widespread outbreaks in poultry and continue to cause sporadic, sometimes severe, human infections. Herein, we characterized a wild-type (WT) influenza A(H5N1) D1.1 isolate (BC-H5N1-WT) and its H275Y neuraminidase (NA) variant (BC-H5N1-H275Y), both of which emerged on farms in British Columbia, Canada, during the fall 2024 outbreak. In vitro analysis assessed replication kinetics in MDCK cells, with supernatants collected at different days post-infection (p.i.) and titrated by TCID50 and qRT-PCR. Neuraminidase inhibitor (NAI) susceptibility was determined by NA inhibition assays, whereas susceptibility to baloxavir acid (BXA) was evaluated by plaque reduction assay. In vivo virulence was evaluated in BALB/c mice infected with serial 10-fold dilutions of each virus to monitor weight loss and mortality. Viral titers in lungs, brain, nose, kidney, spleen, and heart were quantified at day 4 p.i. The BC-H5N1-WT virus was susceptible to the four antivirals tested, whereas BC-H5N1-H275Y displayed resistance to oseltamivir and peramivir but remained susceptible to zanamivir and BXA. The BC-H5N1-WT exhibited significantly higher viral replication titers than BC-H5N1-H275Y at all tested time points and showed larger plaque sizes. In mice, BC-H5N1-WT was more virulent with LD50 values of 1.78 × 103 PFUs compared to 8.71 × 104 PFUs for BC-H5N1-H275Y, and produced higher viral titers in lungs and other organs. Despite the reduced fitness of the resistant H5N1 D1.1 variant, its emergence in the absence of viral selection pressure underscores the need for continued surveillance.
Immune modulation in the male genital tract during HIV infection is not well understood, despite its role in viral persistence and transmission. In a study using an SIV rhesus macaque model, we assessed viral RNA and 61 cytokines, chemokines, and growth factors in peripheral plasma (PP) and seminal plasma (SP). SIV RNA was found in both plasma samples, but the SP viral loads were more variable and decreased over time, independent of the systemic viremia. Baseline immune mediator profiles exhibited compartment-specific patterns, and principal component analysis demonstrated distinct clustering between PP and SP samples. Unlike the extensive systemic immune activation in PP, SIV infection in SP results in selective modulation involving CXCL1, IL-7, CCL4, and YKL-40, with these changes not correlating with the local viral loads. Our findings suggest that the seminal compartment is immunologically distinct, with selective inflammatory responses, highlighting the mechanisms that may influence viral persistence and transmission.
Arboviral infections are increasingly recognized as triggers of Guillain-Barré syndrome (GBS), yet the clinical spectrum, subtype distribution, and strength of association across different arboviruses remain incompletely characterized. This systematic review and meta-analysis evaluated the epidemiology, clinical features, and outcomes of arbovirus-associated GBS. PubMed, Scopus, Web of Science, and Google Scholar were searched through early 2025 following PRISMA 2020 guidelines. Observational studies were included in the quantitative meta-analysis, while case reports and case series were synthesized qualitatively. Random-effects models were used to estimate pooled prevalence, odds ratios, and clinical outcomes. One hundred studies were included, comprising 74 case reports/case series, 19 prevalence studies, and seven case-control studies. The pooled prevalence of GBS among individuals with arboviral infection was 1% (95% CI: 0.3%-3.3%), whereas 37% (95% CI: 22%-54%) of patients with GBS had laboratory evidence of recent arboviral infection. Arboviral co-infections occurred in 16% (95% CI: 8%-31%) of confirmed cases. Case-control studies demonstrated a significant association between Zika virus infection and GBS (OR = 8, 95% CI: 2-34). Qualitative synthesis showed frequent intensive care admission, mechanical ventilation, disability, and mortality. Demyelinating subtypes predominated in Zika virus-associated GBS, whereas axonal variants were more common following Japanese encephalitis virus infection. Multiple arboviruses are associated with GBS, with the strongest evidence for Zika virus. Arbovirus-associated GBS frequently results in severe neurological outcomes, highlighting the need for standardized diagnostics, enhanced surveillance, and prospective multicenter studies to improve understanding of disease mechanisms and optimize patient management.
Post-acute sequelae of SARS-CoV-2 (PASC) occurs in subsets of individuals, including those with pre-existing lung disease. To investigate PASC pathogenesis and therapeutics in a chronic bronchitis mouse model (Scnn1b-Tg), Scnn1b-Tg and WT mice were inoculated with a mouse adapted SARS-CoV-2 virus (SARS-CoV-2MA10) and followed for 60 days. Viral titer, histology, immunohistochemistry (IHC), single-cell RNA sequencing, RNA in situ hybridization, and spatial transcriptomic profiling characterized disease pathologies. Scnn1b-Tg mice inoculated with SARS-CoV-2MA10 exhibited lower viral titers and less weight loss than WT mice. Airway epithelia of Scnn1b-Tg mice were less infected than epithelia of WT mice, reflecting increased airway mucus and enhanced epithelial antiviral activities in Scnn1b-Tg mice. However, Scnn1b-Tg mice subsequently exhibited heterogeneous airway and parenchymal disease with elevated Il33 expression characteristic of human eosinophilic pneumonia. Cohorts of infected mice were administered a monoclonal antibody targeting the IL-33 receptor (ST2) or enteral prednisone. Administration of an anti-ST2 monoclonal antibody mitigated development of eosinophilic pneumonia while enteral prednisone suppressed IL33 expression and disease. The eosinophilic pneumonia in Scnn1b-Tg mice after SARS-CoV-2MA10 infection mimics reports of eosinophilic pneumonia in humans post-SARS-CoV-2, suggesting targeting of IL-33 may be beneficial in treating post-viral eosinophilic pneumonia in humans.
ObjectiveThis study explored the differences in intrapatient variability of tacrolimus between prolonged-release and immediate-release formulations and evaluated the association between tacrolimus intrapatient variability and reactivation of BK virus and cytomegalovirus in kidney transplant recipients.MethodsThis retrospective observational study included 270 kidney transplant recipients receiving either prolonged-release tacrolimus or immediate-release tacrolimus. Receiver operating characteristic curve analysis identified tacrolimus intrapatient variability cutoff values associated with viral reactivation. Logistic regression analyses identified predictors of BK virus and cytomegalovirus reactivation.ResultsThe prolonged-release tacrolimus group had significantly lower tacrolimus intrapatient variability than the immediate-release tacrolimus group (p < 0.001). No significant differences were observed in BK virus and cytomegalovirus reactivation rates. Receiver operating characteristic curve analysis identified tacrolimus intrapatient variability cutoffs of 0.268 for BK virus and 0.261 for cytomegalovirus. High tacrolimus intrapatient variability was significantly associated with increased BK virus and cytomegalovirus reactivation. Logistic regression showed that high tacrolimus intrapatient variability was significantly associated with BK virus and cytomegalovirus reactivation. Multivariate analysis confirmed an independent association between high tacrolimus intrapatient variability and cytomegalovirus reactivation.ConclusionsTacrolimus intrapatient variability may predict reactivation of latent viral infection after kidney transplantation. Although viral reactivation rates were similar between tacrolimus formulations, prolonged-release tacrolimus showed lower tacrolimus intrapatient variability levels, suggesting that fluctuations in tacrolimus exposure might increase the risk of viral reactivation.
More than four decades of HIV/AIDS studies reveal that generation of effective vaccines against HIV infection requires understanding of a host immunity that protects our DNA against the HIV infection. An effective vaccine can elicit the host immunity to stop HIV RNA expression despite the viral DNA integrated into the host DNA. Vaccination is one of the most successful public health interventions of all time. Recent studies show that humans have an intrinsic immunity against foreign nucleotide gene expression, and we have named this the epigenetic immunity. We propose that chromatin vaccine (cVacc), a foreign DNA in chromatin format, is capable of triggering the immunity of host DNA, the epigenetic immunity, to silence the viral gene expression at its RNA transcription level. We discuss these advances in the field of host - virus interaction, specifically host immunity against the retroviral infections by silencing its gene expression, ranging from nucleotide sensors that distinguish self-nonself to the chromatin features that constrict the HIV reservoir. Bolstered by the progress in the fields of virology, immunology and epigenetics, we propose to maneuver cutting edge technologies to develop next-generation vaccines like cVacc, not only silencing the foreign gene expression, but assimilating it to improve our DNA function as well.
Poxviruses, including variola and mpox virus (MPXV), are large dsDNA viruses that replicate their genomes in the host cytoplasm via virally encoded proteins. The single-stranded DNA-binding protein (SSB) I3L is an essential component of this replication machinery, yet its structural mechanism remains to be fully elucidated. Here, we determined the cryo-EM structure of MPXV I3L and constructed a structural model of its complex with ssDNA. Unlike canonical SSBs, I3L forms an architectural double-ring assembly. The individual I3L protomer adopts an OB-fold variant with specialized elements beyond the classic pattern. Furthermore, biochemical assays and structural modeling suggest an assembly-dependent ssDNA-engagement mode, while monomeric binding features remain conserved. These distinctive structural features suggest a specialized molecular mechanism for poxviral DNA replication. Our findings advance the mechanistic understanding of poxvirus genome maintenance and provide perspectives for antiviral development against MPXV.
In 1991 a statewide service for the management of pregnant women living with HIV (WLHIV) was established in Western Australia (WA). To review the maternal epidemiology and obstetric and neonatal outcomes for pregnancies in WLHIV under the care of this multidisciplinary management team since its inception. All ongoing pregnancies for WLHIV between 1991 and December 2022 were identified from interrogation of the state-wide multidisciplinary perinatal HIV management database. WLHIV with early pregnancy losses or who delivered outside of WA were excluded. Two hundred and thirty four viable pregnancies to 162 WLHIV occurred. Maternal ethnicity altered significantly; the rate of new cases of pregnancies in WLHIV for African and Southeast Asian women being 3.92 times (95% CI 1.22-12.60, p = 0.022) and 4.41 times higher (95% CI 1.37-14.25, p = 0.013) from 2007 to 2022, respectively, from those in 1998 to 2006. A significant decrease in HIV-exposed pregnancies occurred among Indigenous Australian women during these time periods (IRR 0.15, 95% CI 0.05 to 0.44, p = 0.001). Over time there was a significant reduction in the proportion of women with a detectable viral load at booking. Prior to 2007, 31 cases (72.1%) had a detectable viral load at booking compared with 68 (38.9%) from 2007 onwards (p < 0.001). Overall, an undetectable viral load at delivery was recorded for 88.3% (197/223). The vertical HIV transmission rate was very low, with one case (0.4%) reported. Most women formula fed their babies (94.5%). A state-wide multi-disciplinary service, combined with universal antenatal HIV screening, has been successful in preventing HIV MTCT in WA.