Ecological divergence of wild birds drives avian influenza spillover and global spread.

The diversity of influenza A viruses (IAV) is primarily hosted by two highly divergent avian orders: Anseriformes (ducks, swans and geese) and Charadriiformes (gulls, terns and shorebirds). Studies of IAV have historically focused on Anseriformes, specifically dabbling ducks, overlooking the diversity of hosts in nature, including gull and goose species that have successfully adapted to human habitats. This study sought to address this imbalance by characterizing spillover dynamics and global transmission patterns of IAV over 10 years at greater taxonomic resolution than previously considered. Furthermore, the circulation of viral subtypes in birds that are either host-adapted (low pathogenic H13, H16) or host-generalist (highly pathogenic avian influenza-HPAI H5) provided a unique opportunity to test and extend models of viral evolution. Using Bayesian phylodynamic modelling we uncovered a complex transmission network that relied on ecologically divergent bird hosts. The generalist subtype, HPAI H5 was driven largely by wild geese and swans that acted as a source for wild ducks, gulls, land birds, and domestic geese. Gulls were responsible for moving HPAI H5 more rapidly than any other host, a finding that may reflect their long-distance, pelagic movements and their immuno-naïve status against this subtype. Wild ducks, long viewed as primary hosts for spillover, occupied an optimal space for viral transmission, contributing to geographic expansion and rapid dispersal of HPAI H5. Evidence of inter-hemispheric dispersal via both the Pacific and Atlantic Rims was detected, supporting surveillance at high latitudes along continental margins to achieve early detection. Both neutral (geographic expansion) and non-neutral (antigenic selection) evolutionary processes were found to shape subtype evolution which manifested as unique geographic hotspots for each subtype at the global scale. This study reveals how a diversity of avian hosts contribute to viral spread and spillover with the potential to improve surveillance in an era of rapid global change.

Host barriers to SARS-CoV-2 demonstrated by ferrets in a high-exposure domestic setting.

Ferrets (Mustela putorius furo) are mustelids of special relevance to laboratory studies of respiratory viruses and have been shown to be susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and onward transmission. Here, we report the results of a natural experiment where 29 ferrets in one home had prolonged, direct contact and constant environmental exposure to two humans with symptomatic disease, one of whom was confirmed positive for SARS-CoV-2. We observed no evidence of SARS-CoV-2 transmission from humans to ferrets based on viral and antibody assays. To better understand this discrepancy in experimental and natural infection in ferrets, we compared SARS-CoV-2 sequences from natural and experimental mustelid infections and identified two surface glycoprotein Spike (S) mutations associated with mustelids. While we found evidence that angiotensin-converting enzyme II provides a weak host barrier, one mutation only seen in ferrets is located in the novel S1/S2 cleavage site and is computationally predicted to decrease furin cleavage efficiency. These data support the idea that host factors interacting with the novel S1/S2 cleavage site may be a barrier in ferret SARS-CoV-2 susceptibility and that domestic ferrets are at low risk of natural infection from currently circulating SARS-CoV-2. We propose two mechanistically grounded hypotheses for mustelid host adaptation of SARS-CoV-2, with possible effects that require additional investigation.

Highly Pathogenic Avian Influenza A(H5N1) Virus Outbreak in New England Seals, United States.

We report the spillover of highly pathogenic avian influenza A(H5N1) into marine mammals in the northeastern United States, coincident with H5N1 in sympatric wild birds. Our data indicate monitoring both wild coastal birds and marine mammals will be critical to determine pandemic potential of influenza A viruses.

Age and season predict influenza A virus dynamics in urban gulls: consequences for natural hosts in unnatural landscapes.

Gulls are ubiquitous in urban areas due to a growing reliance on anthropogenic feeding sites, which has led to changes in their abundance, distribution, and migration ecology, with implications for disease transmission. Gulls offer a valuable model for testing hypotheses regarding the dynamics of influenza A virus (IAV) - for which gulls are a natural reservoir in urban areas. We sampled sympatric populations of Ring-billed (Larus delawarensis), Herring (L. argentatus), and Great Black-backed Gulls (L. marinus) along the densely populated Atlantic rim of North America to understand how IAV transmission is influenced by drivers such as annual cycle, host species, age, habitat type, and their interplay. We found that horizontal transmission, rather than vertical transmission, played an outsized role in the amplification of IAV due to the convergence of gulls from different breeding grounds and age classes. We detected overlapping effects of age and season in our prevalence model, identifying juveniles during autumn as the primary drivers of the seasonal epidemic in gulls. Gulls accumulated immunity over their lifespan, however short-term fluctuations in seroprevalence were observed, suggesting that migration may impose limits on the immune system to maintain circulating antibodies. We found that gulls in coastal urban habitats had higher viral prevalence than gulls captured inland, correlating with higher richness of waterbird species along the coast, a mechanism supported by our movement data. The peak in viral prevalence in newly fledged gulls that are capable of long-distance movement has important implications for the spread of pathogens to novel hosts during the migratory season as well as for human health as gulls increasingly utilize urban habitats.

Sequence Diversity and Differences at the Highly Duplicated MHC-I Gene Reflect Viral Susceptibility in Sympatric Pinniped Species.

Differences in disease susceptibility among species can result from rapid host-pathogen coevolution and differences in host species ecology that affect the strength and direction of natural selection. Among 2 sympatric pinniped species that differ in sociality and putative disease exposure, we investigate observed differences in susceptibility through an analysis of a highly variable, duplicated gene family involved in the vertebrate immune response. Using high-throughput amplicon sequencing, we characterize diversity at the 2 exons that encode the peptide binding region of the major histocompatibility complex class I (MHC-I) gene in harbor (N = 60) and gray (N = 90) seal populations from the Northwest Atlantic. Across species, we identified 106 full-length exon 2 and 103 exon 3 sequence variants and a minimum of 11 duplicated MHC-I loci. The sequence variants clustered in 15 supertypes defined by the physiochemical properties of the peptide binding region, including a putatively novel Northwest Atlantic MHC-I diversity sublineage. Trans-species polymorphisms, dN/dS ratios, and evidence of gene conversion among supertypes are consistent with balancing selection acting on this gene. High functional redundancy suggests particularly strong selection among gray seals at the novel Northwest Atlantic MHC-I diversity sublineage. At exon 2, harbor seals had a significantly greater number of variants per individual than gray seals, but fewer supertypes. Supertype richness and private supertypes are hypothesized to contribute to observed differences in disease resistance between species, as consistently, across the North Atlantic and many disease outbreaks, gray seals appear to be more resistant to respiratory viruses than harbor seals.

Emergence and radiation of distemper viruses in terrestrial and marine mammals.

Canine distemper virus (CDV) and phocine distemper virus (PDV) are major pathogens to terrestrial and marine mammals. Yet little is known about the timing and geographical origin of distemper viruses and to what extent it was influenced by environmental change and human activities. To address this, we (i) performed the first comprehensive time-calibrated phylogenetic analysis of the two distemper viruses, (ii) mapped distemper antibody and virus detection data from marine mammals collected between 1972 and 2018, and (iii) compiled historical reports on distemper dating back to the eighteenth century. We find that CDV and PDV diverged in the early seventeenth century. Modern CDV strains last shared a common ancestor in the nineteenth century with a marked radiation during the 1930s-1950s. Modern PDV strains are of more recent origin, diverging in the 1970s-1980s. Based on the compiled information on distemper distribution, the diverse host range of CDV and basal phylogenetic placement of terrestrial morbilliviruses, we hypothesize a terrestrial CDV-like ancestor giving rise to PDV in the North Atlantic. Moreover, given the estimated timing of distemper origin and radiation, we hypothesize a prominent role of environmental change such as the Little Ice Age, and human activities like globalization and war in distemper virus evolution.

Longitudinal analysis of pinnipeds in the northwest Atlantic provides insights on endemic circulation of phocine distemper virus.

Phocine distemper virus (PDV) is a morbillivirus that circulates within pinnipeds in the North Atlantic. PDV has caused two known unusual mortality events (UMEs) in western Europe (1988, 2002), and two UMEs in the northwest Atlantic (2006, 2018). Infrequent cross-species transmission and waning immunity are believed to contribute to periodic outbreaks with high mortality in western Europe. The viral ecology of PDV in the northwest Atlantic is less well defined and outbreaks have exhibited lower mortality than those in western Europe. This study sought to understand the molecular and ecological processes underlying PDV infection in eastern North America. We provide phylogenetic evidence that PDV was introduced into northwest Atlantic pinnipeds by a single lineage and is now endemic in local populations. Serological and viral screening of pinniped surveillance samples from 2006 onward suggest there is continued circulation of PDV outside of UMEs among multiple species with and without clinical signs. We report six full genome sequences and nine partial sequences derived from harbour and grey seals in the northwest Atlantic from 2011 through 2018, including a possible regional variant. Work presented here provides a framework towards greater understanding of how recovering populations and shifting species may impact disease transmission.

DURATION OF ANTIGEN SHEDDING AND DEVELOPMENT OF ANTIBODY TITERS IN MALAYAN TIGERS (PANTHERA TIGRIS JACKSONI) NATURALLY INFECTED WITH SARS-CoV-2.

Natural infection of three captive Malayan tigers (Panthera tigris jacksoni) with SARS-CoV-2 caused mild to moderate symptoms of lethargy, anorexia, and coughing. Each tiger was longitudinally sampled opportunistically via consciously obtained oral, nasal, and/or fecal samples during and after resolution of clinical signs, until 2 wk of negative results were obtained. Persistent shedding of SARS-CoV-2 genetic material was detected via reverse transcription-polymerase chain reaction in feces up to 29 d after initial onset of clinical signs, but not in nasal or oral samples. Tigers became resistant to behavioral training to obtain nasal samples but tolerated longitudinal oral sampling. Serum was obtained from two tigers, and antibody titers revealed a robust antibody response within 9 d of onset of clinical signs, which was sustained for at least 3 mon. The tigers were infected despite the use of masks and gloves by husbandry personnel. No known cause of the outbreak was identified, despite extensive investigational efforts by the regional health department. No forward cross-species transmission was observed in primates housed in nearby enclosures. The increasing regularity of reports of SARS-CoV-2 infection in nondomestic felids warrants further investigations into shedding and immunity.

Glycoprotein Mimics with Tunable Functionalization through Global Amino Acid Substitution and Copper Click Chemistry.

Glycoproteins and their mimics are challenging to produce because of their large number of polysaccharide side chains that form a densely grafted protein-polysaccharide brush architecture. Herein a new approach to protein bioconjugate synthesis is demonstrated that can approach the functionalization densities of natural glycoproteins through oligosaccharide grafting. Global amino acid substitution is used to replace the methionine residues in a methionine-enriched elastin-like polypeptide with homopropargylglycine (HPG); the substitution was found to replace 93% of the 41 methionines in the protein sequence as well as broaden and increase the thermoresponsive transition. A series of saccharides were conjugated to the recombinant protein backbones through copper(I)-catalyzed alkyne-azide cycloaddition to determine reactivity trends, with 83-100% glycosylation of HPGs. Only an acetyl-protected sialyllactose moiety showed a lower level of 42% HPG glycosylation that is attributed to steric hindrance. The recombinant glycoproteins reproduced the key biofunctional properties of their natural counterparts such as viral inhibition and lectin binding.

SERUM BIOCHEMICAL AND HEMATOLOGIC REFERENCE INTERVALS FOR WEANLING NORTHWEST ATLANTIC GRAY SEALS (HALICHOERUS GRYPUS).

Baseline health parameters are limited in the primary literature for gray seals (Halichoerus grypus) in the northwest Atlantic. Accurate normal physiologic reference ranges for both species and specific geographic populations are vital tools for assessing the health of individuals and understanding the health of the entire population. This study developed comprehensive reference intervals for biochemical and hematologic parameters of recently weaned gray seal pups on Cape Cod, Massachusetts from samples collected in 2013, 2016, and 2017. Reference ranges were developed using methodology outlined by the American Society of Clinical Veterinary Pathology. By establishing more comprehensive biochemical and hematologic reference ranges for this population based on a robust sample size, this study provides a new tool for clinicians, researchers, and rehabilitation organizations to improve individual patient care and population research.

Reassortment of Influenza A Viruses in Wild Birds in Alaska before H5 Clade 2.3.4.4 Outbreaks.

Sampling of mallards in Alaska during September 2014-April 2015 identified low pathogenic avian influenza A virus (subtypes H5N2 and H1N1) that shared ancestry with highly pathogenic reassortant H5N2 and H5N1 viruses. Molecular dating indicated reassortment soon after interhemispheric movement of H5N8 clade 2.3.4.4, suggesting genetic exchange in Alaska or surrounds before outbreaks.

Interferon-inducible mechanism of dendritic cell-mediated HIV-1 dissemination is dependent on Siglec-1/CD169.

Human immunodeficiency virus type 1 (HIV-1) interactions with myeloid dendritic cells (DCs) can result in virus dissemination to CD4⁺ T cells via a trans infection pathway dependent on virion incorporation of the host cell derived glycosphingolipid (GSL), GM3. The mechanism of DC-mediated trans infection is extremely efficacious and can result in infection of multiple CD4⁺ T cells as these cells make exploratory contacts on the DC surface. While it has long been appreciated that activation of DCs with ligands that induce type I IFN signaling pathway dramatically enhances DC-mediated T cell trans infection, the mechanism by which this occurs has remained unclear until now. Here, we demonstrate that the type I IFN-inducible Siglec-1, CD169, is the DC receptor that captures HIV in a GM3-dependent manner. Selective downregulation of CD169 expression, neutralizing CD169 function, or depletion of GSLs from virions, abrogated DC-mediated HIV-1 capture and trans infection, while exogenous expression of CD169 in receptor-naïve cells rescued GSL-dependent capture and trans infection. HIV-1 particles co-localized with CD169 on DC surface immediately following capture and subsequently within non-lysosomal compartments that redistributed to the DC--T cell infectious synapses upon initiation of T cell contact. Together, these findings describe a novel mechanism of pathogen parasitization of host encoded cellular recognition machinery (GM3--CD169 interaction) for DC-dependent HIV dissemination.

HIV-1 incorporation of host-cell-derived glycosphingolipid GM3 allows for capture by mature dendritic cells.

The interaction between HIV and dendritic cells (DCs) is an important early event in HIV-1 pathogenesis that leads to efficient viral dissemination. Here we demonstrate a HIV gp120-independent DC capture mechanism that uses virion-incorporated host-derived gangliosides with terminal α2-3-linked sialic acid linkages. Using exogenously enriched virus and artificial liposome particles, we demonstrate that both α2-3 gangliosides GM1 and GM3 are capable of mediating this interaction when present in the particle at high levels. In the absence of overexpression, GM3 is the primary ligand responsible for this capture mechanism, because siRNA depletion of GM3 but not GM1 from the producer cell and hence virions, resulted in a dramatic decrease in DC capture. Furthermore, HIV-1 capture by DCs was competitively inhibited by targeting virion-associated GM3, but was unchanged by targeting GM1. Finally, virions were derived from monocytoid THP-1 cells that constitutively display low levels of GM1 and GM3, or from THP-1 cells induced to express high surface levels of GM1 and GM3 upon stimulation with the TLR2/1 ligand Pam3CSK4. Compared with untreated THP-1 cells, virus produced from Pam3CSK4-stimulated THP-1 cells incorporated higher levels of GM3, but not GM1, and showed enhanced DC capture and trans-infection. Our results identify a unique HIV-1 DC attachment mechanism that is dependent on a host-cell-derived ligand, GM3, and is a unique example of pathogen mimicry of host-cell recognition pathways that drive virus capture and dissemination in vivo.

High-pathogenicity avian influenza in wildlife: a changing disease dynamic that is expanding in wild birds and having an increasing impact on a growing number of mammals.

While diverse strains of low-pathogenicity avian influenza have circulated in wild birds for a long period of time, there has previously been little pathology in wild birds, ducks have been the primary and largely asymptomatic wild reservoir, and spillover into mammals has been limited and rare. In recent years, a high-pathogenicity avian influenza (HPAI) virus has emerged on the global scene and shifted the previously established dogmas for influenza infection. High-pathogenicity avian influenza has expanded into wildlife in unprecedented numbers and species diversity, with unmatched disease severity for influenza in wildlife. As the disease ecology of influenza has shifted with this new variant, significant efforts are underway to understand disease course, pathology, and species susceptibility. Here we focus primarily on the impact that HPAI has had in wild mammals while framing these novel spillovers within the context of significantly expanding disease in avian species and geography. The clinical and pathology presentations of HPAI in these atypical hosts are discussed, as well as prognosis and risk for continued spillover. The companion Currents in One Health by Runstadler and Puryear, AJVR, May 2024, provides further context on viral reservoirs and possible routes of direct or environmental transmission and risk assessment of viral variants that are emerging within wildlife.

The virus is out of the barn: the emergence of HPAI as a pathogen of avian and mammalian wildlife around the globe.

Highly pathogenic avian influenza (HPAI) has persisted as a One Health threat whose current circulation and impact are addressed in the companion Currents in One Health by Puryear and Runstadler, JAVMA, May 2024. Highly pathogenic avian influenza emerged as a by-product of agricultural practices and adapted to endemic circulation in wild bird species. Over more than 20 years, continued evolution in a complex ecology involving multiple hosts has produced a lineage that expanded globally over the last 2 years. Understanding the continued evolution and movement of HPAI relies on understanding how the virus is infecting different hosts in different contexts. This includes understanding the environmental factors and the natural ecology of viral transmission that impact host exposure and ultimately evolutionary trajectories. Particularly with the rapid host expansion, increased spillover to mammalian hosts, and novel clinical phenotypes in infected hosts, despite progress in understanding the impact of specific mutations to HPAI viruses that are associated with spillover potential, the threat to public health is poorly understood. Active research is focusing on new approaches to understanding the relationship of viral genotype to phenotype and the implementation of research and surveillance pipelines to make sense of the enormous potential for diverse HPAI viruses to emerge from wild reservoirs amid global circulation.

Unbiased, Cell-free Profiling of Single Influenza Genomes at High-throughput.

The segmented structure of the Influenza A virus (IAV) genome facilitates reassortment, segment exchange during co-infection. When divergent strains mix across human, agricultural, and wildlife reservoirs novel strains are generated, which has been the source of pandemics. Due to the limited throughput and infection-based assays, IAV reassortment studies has been limited to permissive reassortment. We have developed DE-flowSVP to achieve extremely high throughput, direct profiling of as many as 10 5 IAV particles in a single-day experiment and enabled quantitative profiling of reassortment propensity between divergent strains for the first time. By profiling reassortants between two naturally circulating low-pathogenicity avian IAVs, we confirmed that molecular incompatibility yields strong preference toward within-strain mixing. Surprisingly, we revealed that two-to-three particle aggregation contributed primarily to genome mixing (75-99%), suggesting that aggregation mediated by sialic acid binding by viral surface proteins provides a secondary pathway to genome mixing while avoiding the co-packaging fitness cost. We showed that genome mixing is sensitively dependent on co-infection timing, relative segment abundances, and viral surface-protein background. DE-flowSVP enables large-scale survey of reassortment potential among the broad diversity of IAV strains informing pandemic strain emergence.

Role of glycosphingolipids in dendritic cell-mediated HIV-1 trans-infection.

Glycosphingolipids (GSLs) are components of the cell membrane that comprise a membrane bound lipid, ceramide, coupled to an extracellular carbohydrate. GSLs impact numerous aspects of membrane biology, including membrane fluidity, curvature, and organization. The role of these molecules in both chronic inflammation and infectious disease and underlying pathogenic mechanisms are just starting to be recognized. As a component of the cell membrane, GSLs are also incorporated into lipid bilayers of diverse enveloped viruses as they bud out from the host cell and can go on to have a significant influence on viral pathogenesis. Dendritic cell (DC) subsets located in the peripheral mucosal tissues are proposed to be one of the earliest cell types that encounter transmitted viruses and help initiate adaptive immune responses against the invading pathogen by interacting with T cells. In turn, viruses, as obligatory intracellular parasites, rely on host cells for completing their replication cycle, and not surprisingly, HIV has evolved to exploit DC biology for the initial transmission event as well as for its dissemination and propagation within the infected host. In this review, we describe the mechanisms by which GSLs impact DC-mediated HIV trans-infection by either modulating virus infectivity, serving as a direct virus particle-associated host-derived ligand for specific interactions with DCs, or modulating the T cell membrane in such a way as to impact viral entry and thereby productive infection of CD4(+) T cells.

Characterization of SARS-CoV-2 Aerosols Dispersed During Noninvasive Respiratory Support of Patients With COVID-19.

BACKGROUND: In the midst of the COVID-19 pandemic, noninvasive respiratory support (NRS) therapies such as high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) were central to respiratory care. The extent to which these treatments increase the generation and dispersion of infectious respiratory aerosols is not fully understood. The objective of this study was to characterize SARS-CoV-2 aerosol dispersion from subjects with COVID-19 undergoing NRS therapy. METHODS: Several different aerosol sampling devices were used to collect air samples in the vicinity of 31 subjects with COVID-19, most of whom were receiving NRS therapy, primarily HFNC. Aerosols were collected onto filters and analyzed for the presence of SARS-CoV-2 RNA. Additional measurements were collected in an aerosol chamber with healthy adult subjects using respiratory therapy devices under controlled and reproducible conditions. RESULTS: Fifty aerosol samples were collected from subjects receiving HFNC or NIV therapy, whereas 6 samples were collected from subjects not receiving NRS. Only 4 of the 56 aerosol samples were positive for SARS-CoV-2 RNA, and all positive samples were collected using a high air flow scavenger mask collection device placed in close proximity to the subject. The chamber measurements with healthy subjects did not show any significant increase in aerosol dispersion caused by the respiratory therapy devices compared to baseline. CONCLUSIONS: Our findings demonstrate very limited detection of SARS-CoV-2-containing aerosols in the vicinity of subjects with COVID-19 receiving NRS therapies in the clinical setting. These results, combined with controlled chamber measurements showing that HFNC and NIV device usage was not associated with increased aerosol dispersion, suggest that NRS therapies do not result in increased dispersal of aerosols in the clinical setting.

Sequential immunization with a subtype B HIV-1 envelope quasispecies partially mimics the in vivo development of neutralizing antibodies.

A major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is the design of Envelope (Env)-based immunogens effective at eliciting heterologous or broad neutralizing antibodies (NAbs). We hypothesized that programming the B-cell response could be achieved by sequentially exposing the host to a collection of env variants representing the viral quasispecies members isolated from an individual that developed broad NAbs over time. This ordered vaccine approach (sequential) was compared to exposure to a cocktail of env clones (mixture) and to a single env variant (clonal). The three strategies induced comparable levels of the autologous and heterologous neutralization of tier 1 pseudoviruses. Sequential and mixture exposure to quasispecies led to epitope targeting similar to that observed in the simian-human immunodeficiency virus (SHIV)-infected animal from which the env variants were cloned, while clonal and sequential exposure led to greater antibody maturation than the mixture. Therefore, the sequential vaccine approach best replicated the features of the NAb response observed in that animal. This study is the first to explore the use of a collection of HIV-1 env quasispecies variants as immunogens and to present evidence that it is possible to educate the B-cell response by sequential exposure to native HIV-1 quasispecies env variants derived from an individual with a broadened NAb response.

PPARgamma and LXR signaling inhibit dendritic cell-mediated HIV-1 capture and trans-infection.

Dendritic cells (DCs) contribute to human immunodeficiency virus type 1 (HIV-1) transmission and dissemination by capturing and transporting infectious virus from the mucosa to draining lymph nodes, and transferring these virus particles to CD4+ T cells with high efficiency. Toll-like receptor (TLR)-induced maturation of DCs enhances their ability to mediate trans-infection of T cells and their ability to migrate from the site of infection. Because TLR-induced maturation can be inhibited by nuclear receptor (NR) signaling, we hypothesized that ligand-activated NRs could repress DC-mediated HIV-1 transmission and dissemination. Here, we show that ligands for peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor (LXR) prevented proinflammatory cytokine production by DCs and inhibited DC migration in response to the chemokine CCL21 by preventing the TLR-induced upregulation of CCR7. Importantly, PPARgamma and LXR signaling inhibited both immature and mature DC-mediated trans-infection by preventing the capture of HIV-1 by DCs independent of the viral envelope glycoprotein. PPARgamma and LXR signaling induced cholesterol efflux from DCs and led to a decrease in DC-associated cholesterol, which has previously been shown to be required for DC capture of HIV-1. Finally, both cholesterol repletion and the targeted knockdown of the cholesterol transport protein ATP-binding cassette A1 (ABCA1) restored the ability of NR ligand treated cells to capture HIV-1 and transfer it to T cells. Our results suggest that PPARgamma and LXR signaling up-regulate ABCA1-mediated cholesterol efflux from DCs and that this accounts for the decreased ability of DCs to capture HIV-1. The ability of NR ligands to repress DC mediated trans-infection, inflammation, and DC migration underscores their potential therapeutic value in inhibiting HIV-1 mucosal transmission.