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Summary Regenerative medicine has great potential. The pace of scientific advance is exciting and the medical opportunities for regeneration and repair may be transformative. However, concerns continue to grow, relating to problems caused both by unscrupulous private clinics offering unregulated therapies based on little or no evidence and by premature regulatory approval on the basis of insufficient scientific rationale and clinical evidence. An initiative by the InterAcademy Partnership convened experts worldwide to identify opportunities and challenges, with a focus on stem cells. This was designed to be inclusive and consensus outputs reflected the diversity of the global research population. Among issues addressed for supporting research and innovation while protecting patients were ethical assessment; pre-clinical and clinical research; regulatory authorization and medicines access; and engagement with patients, policy makers, and the public. The InterAcademy Partnership (IAP) identified options for action for sharing good practice and building collaboration within the scientific community and with other stakeholders worldwide., Highlights • An inclusive IAP study examined global stem cell opportunities and challenges • Great potential leads to concerns for evidence base in unregulated clinics • Also concerns for premature regulatory approval without sufficient evidence • Recommendations for responsible research and innovation and collaborations, In this article, Fears and colleagues describe an inclusive global initiative by the InterAcademy Partnership examining stem cell opportunities and challenges. Great therapeutic potential brings concerns about the inadequate evidence base used by unregulated clinics. Concerns are also expressed about premature regulatory approval without sufficient evidence. Recommendations cover ethical assessment; pre-clinical and clinical research; regulatory authorization and medicines access; and engagement with patients, policy makers, and the public.

Robin Fears and co-authors discuss evidence-informed regional and global policy responses to health impacts of climate change.

The IAP FNSA project was funded by the German Federal Ministry of Education and Research (BMBF) .

COVID-19 has shown that international collaborations and global data sharing are essential for health research, but legal obstacles are preventing data sharing for non–pandemic-related research among public researchers across the world, with potentially damaging effects for citizens and patients.

While there is abounding literature on virus-induced pathology in general and coronavirus in particular, recent evidence accumulates showing distinct and deleterious brain affection. As the respiratory tract connects to the brain without protection of the blood–brain barrier, SARS-CoV-2 might in the early invasive phase attack the cardiorespiratory centres located in the medulla/pons areas, giving rise to disturbances of respiration and cardiac problems. Furthermore, brainstem regions are at risk to lose their functional integrity. Therefore, long-term neurological as well as psychiatric symptomatology and eventual respective disorders cannot be excluded as evidenced from influenza-A triggered post-encephalitic Parkinsonism and HIV-1 triggered AIDS–dementia complex. From the available evidences for coronavirus-induced brain pathology, this review concludes a number of unmet needs for further research strategies like human postmortem brain analyses. SARS-CoV-2 mirroring experimental animal brain studies, characterization of time-dependent and region-dependent spreading behaviours of coronaviruses, enlightening of pathological mechanisms after coronavirus infection using long-term animal models and clinical observations of patients having had COVID-19 infection are calling to develop both protective strategies and drug discoveries to avoid early and late coronavirus-induced functional brain disturbances, symptoms and eventually disorders. To fight SARS-CoV-2, it is an urgent need to enforce clinical, molecular biological, neurochemical and genetic research including brain-related studies on a worldwide harmonized basis.

The scientific advice needed to inform national and regional policies addressing the key challenges we face today must take account of disparate requirements. The complex nature of the problems addressed in this article—which encompass food and nutrition security, global health and climate change—and the multitude of their interconnections, calls for an integrated and multi-disciplinary approach that spans aspects related to the use of natural resources; the adoption of new technologies all the way to issues related to food demand and human behaviour. The scale is also important: national policies need to respond to a set of heterogeneous local conditions and requirements and should be particularly mindful of the effect on vulnerable groups of the population. At the same time, the global interconnectedness of food systems and shared natural resources also necessitates coordinated action at regional and global levels. The InterAcademy Partnership sought to develop an innovative model for integrating and analysing multidisciplinary scientific evidence to inform governments and regional policy bodies for policymaking on food and nutrition security. This approach relies on IAP’s membership of over 130 science academies grouped in four regional networks for Africa, America, Asia and Europe. Our article reviews the model, in particular with regards to interdisciplinarity, exploring examples relating to yield gap, plant breeding and food processing, and reflects on lessons learned during the project discussions and when engaging with policy-makers and other stakeholders. We propose that the framework developed can be applied to integrated assessment of other societal challenges where the scientific community can play a significant role in informing policy choices.

Robin Fears Volker ter Meulen Joachim von Braun Today, the number of hungry, undernourished people across the planet is increasing, with micronutrient deficiencies impairing the overall health of more than 2 billion people worldwide. Early child mortality and morbidity are unacceptably high, and problems related to unsafe food, food waste, and poorly managed agricultural systems continue, as do problems associated with overconsumption. The impacts of inadequately managed agricultural systems are damaging land, water, and atmospheric systems, which, together, are posing unprecedented threats to global food security. These problems are rooted in deficient and deeply intertwined policies and practices that need to be addressed on a global scale. These challenges—all related to food distribution, agricultural systems, and planetary health—lie squarely in the path of achieving global Sustainable Development Goals (SDGs) and equity in the distribution of resources across global populations. Although research related to crop cultivation has made great contributions to agricultural productivity, global leaders have begun to recognize the severity of problems rooted in inequity and the expanding demands of populations. In response, they have been increasing efforts to identify scientific endeavors to foster responsible innovation in food systems and, in tandem, shape necessary related local, national, and international policies. Such scientific leadership has recently …

While there is abounding literature on virus-induced pathology in general and coronavirus in particular, recent evidence accumulates showing distinct and deleterious brain affection. As the respiratory tract connects to the brain without protection of the blood-brain barrier, SARS-CoV-2 might in the early invasive phase attack the cardiorespiratory centres located in the medulla/pons areas, giving rise to disturbances of respiration and cardiac problems. Furthermore, brainstem regions are at risk to lose their functional integrity. Therefore, long-term neurological as well as psychiatric symptomatology and eventual respective disorders cannot be excluded as evidenced from influenza-A triggered post-encephalitic Parkinsonism and HIV-1 triggered AIDS-dementia complex. From the available evidences for coronavirus-induced brain pathology, this review concludes a number of unmet needs for further research strategies like human postmortem brain analyses. SARS-CoV-2 mirroring experimental animal brain studies, characterization of time-dependent and region-dependent spreading behaviours of coronaviruses, enlightening of pathological mechanisms after coronavirus infection using long-term animal models and clinical observations of patients having had COVID-19 infection are calling to develop both protective strategies and drug discoveries to avoid early and late coronavirus-induced functional brain disturbances, symptoms and eventually disorders. To fight SARS-CoV-2, it is an urgent need to enforce clinical, molecular biological, neurochemical and genetic research including brain-related studies on a worldwide harmonized basis.

An EASAC working group on genome editing recommends that regulators should focus on specific applications of these new techniques rather than attempting to regulate genome editing itself as a new technology.

Gain-of-function (GoF) studies to understand factors affecting transmissibility of potentially pandemic pathogens are controversial. The European Academies Science Advisory Council (EASAC) recently published consensus recommendations relating to GoF research review and management on self-regulation and harmonization; bioethical considerations; benefit-risk assessment; biosafety, and biosecurity advisory options; and publication of sensitive information. A layered approach to integration of responsibilities must include conforming to the stringent rules and guidance already existing. Further commitment is essential to extend the debate on issues worldwide.

N-methyl-D-aspartate (NMDA) receptor activation is involved in the pathogenetic cascades of neurodegenerative disorders including human immunodeficiency virus (HIV) dementia. Memantine, an uncompetitive NMDA receptor antagonist, which has been recently approved for the treatment of Alzheimer's disease, is being discussed as a potential adjunctive therapeutic substance for HIV dementia. We used simian immunodeficiency virus-infected rhesus macaques to assess the effects of memantine on brain dysfunction and brain pathology within 3-5 months after initial infection during early asymptomatic stage of disease. We had shown previously that within this time frame, marked changes were evident in the dopaminergic systems. Memantine was administered two weeks post infection, at peak viremia, in order to prevent early NMDA receptor activation due to immune mediators. We found that memantine prevented onset of dopamine deficits in the brains of SIV-infected macaques, without affecting early brain pathology or peripheral course of infection. Memantine specifically upregulated mRNA and protein expression of the neurotrophic factor brain-derived neurotrophic factor (BDNF), suggesting that the protective effect of memantine on dopamine function may be mechanistically remote from NMDA receptor antagonism. This novel pharmacological action of memantine may also be relevant for other neurodegenerative disorders and supports the involvement of neurotrophic factors in adult brain neuroprotection.

The objectives of this study is to clarify whether there are phases critical for the infection of the central nervous system (CNS) as defined by active viral replication in the cerebrospinal fluid (CSF) in human immunodeficiency virus (HIV) infection. One hundred and nine HIV-1-positive homo- and bisexual patients in early and late disease stages with or without highly active antiretroviral therapy (HAART) were included in the cross-sectional, diagnostic (phase I) multicenter study. No patients had any overt neurological deficits; all underwent venous and lumbar puncture as well as neuropsychological testing. In untreated early-stage patients, cerebrospinal fluid (CSF) viral load correlated with inflammatory parameters, but not significantly with neuropsychological abnormalities. CSF viral load and inflammatory reactions were suppressed in HAART-treated early-stage patients. In HAART-treated late-stage patients, there was a weak correlation between CSF viral load and CSF cell count as well as a moderate correlation with immune activation markers and with distinct cerebral deficits independent of CSF viral load. Seventeen of the 109 patients had higher CSF than plasma viral loads and marked inflammatory reactions and immune activation. In patients with greater plasma than CSF viral loads, the factors contributing to cerebral deficits still need to be identified. The results suggest not only that there is an early "set point" for CSF/central nervous system (CNS) infection, but also that there is a subgroup of patients in whom intrathecal viral replication correlates with cerebral deficits. Lumbar puncture should be performed in all positive patients to identify members of this subgroup and to ascertain what characteristic factors they have in common in order to improve therapy.

RESUME Les maladies infectieuses representent un probleme de sante majeur, tant pour les pays developpes, que pour les pays emergents. Envisagees a l’echelon mondial, les maladies infectieuses sont, en effet, a l’origine d’environ un tiers de tous les deces (46 %des causes de morts dans les pays en voie de developpement). D’importants appels ont ete lances travers le monde dans le but d’ameliorer les systemes de sante publique, compte tenu des dangers croissants que presentent les maladies infectieuses, du fait d’un ensemble de microbes d’apparition recente ou resurgents, tels le SRAS, la tuberculose, le sida, la legionellose, le microbe Ebola, l’encephalite du Nil, les infections nosocomiales opportunistes, les nouvelles varietes de grippe. Ces facteurs sont egalement associes a des problemes de securite microbiologiques des aliments et au role joue par le developpement des voyages internationaux, par la croissance du commerce mondial de l’agriculture, tous elements qui s’integrent dans les mailles du bioterrorisme. Les maladies infectieuses animales (aux consequences vitales) tels la grippe aviaire, le virus du singe, les maladies dues aux aliments, transmissibles ou non a l’homme, les maladies vegetales, posent, elles aussi, des problemes, et representent autant de cibles potentielles pour le bioterrorisme. Et, meme si nous disposons d’antibiotiques et de vaccins, les defis persistent dans la lutte contre les micro-organismes, car l’on assiste a une augmentation des resistances antibacteriennes et antivirales. Les strategies vaccinales, quant a elles, peuvent echouer du fait de leur cout trop eleve pour les pays en voie de developpement, voire de l’opposition rencontree dans certains pays de l’Union Europeenne, sans sous-estimer les variations antigeniques de certains microorganismes, et de certains virus. L’Academie Allemande des Sciences Leopoldina, en collaboration avec le Comite Consultatif de l’Academie Europeenne des Sciences, a precise quelles devaient etre les actions a entreprendre pour lutter contre les maladies infectieuses, et identifie les zones les plus exposees, autant de realites auxquelles les responsables politiques de l’union Europeenne devront faire face. Ces priorites seront exposees et discutees.

Movement disorders are a common neurological complication of immunodeficiency virus infection and are thought to result from dopaminergic dysfunction in the basal ganglia. We measured levels of dopamine, and its metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid, in the putamen of healthy and simian immunodeficiency virus (SIV)-infected rhesus monkeys from infection until the development of AIDS. Changes in expression levels of cAMP response element binding protein (CREB), a transcription factor involved in the signalling pathway of dopamine, were also examined. Furthermore, we isolated microglia from the same animals and investigated their activation status in order to explore whether neurochemical findings are associated with immune activation. Plasma and CSF viral RNA load, T-cell analysis and basal ganglia histopathology provided information about disease progression in the animals. Putamen dopamine content was significantly reduced within 3 months of SIV infection, due to decreased dopamine synthesis initially, followed by loss of tyrosine hydroxylase-positive cells in substantia nigra, and accompanied by a decrease in total CREB expression. Pharmacological manipulation of dopaminergic tone with L-DOPA and selegiline showed that the reduction in CREB expression was due to reduced levels of dopamine. These neurochemical changes were significantly correlated with microglia activation in the absence of gross histopathological lesions. Our data demonstrate that putamen dopaminergic function is impaired during SIV infection and indicate that microglia may trigger endogenous mechanisms involved in the dysfunction of dopaminergic systems.

Synthetic caspase inhibitors are known to block death receptor-induced apoptosis. We have reported previously that in addition to apoptosis inhibition, caspase inhibitors induce a switch from proapoptotic to proinflammatory signaling in T cells. This switch sensitizes TNF-R1 to trigger TNF-alpha-induced reactivation of HIV in latently infected T cells. Here we ponder the prospects of caspase inhibitors as a supplement in immune activation therapies (IAT) to achieve eradication of HIV from the latent virus reservoirs in HIV-infected patients.

Human immunodeficiency virus (HIV) infection leads to a decline of CD4+ T-cells in blood. Because blood represents only a small proportion of the total lymphocyte pool, it is important to investigate other lymphoid organs. So far, only relative proportions of lymphocyte subsets in single peripheral lymph node (LN) regions of HIV-infected patients and simian immunodeficiency virus (SIV)-infected macaques have been documented. We have therefore quantified the absolute numbers of lymphocyte subsets in blood and six different LN regions of 10 uninfected and 26 SIV-infected macaques. In addition, we have determined the expression of markers of activation and differentiation. Already, in uninfected monkeys, there were significant differences in the cellular composition of different LN regions. Infection with SIV resulted in drastic changes in the proportion as well as absolute numbers of different lymphocyte subsets. Moreover, the relative contribution of the single LN regions to the total lymphocyte pool was also altered.

After passive transfer of measles virus (MV)-specific antibodies, vaccine-induced seroconversion and subsequent protection is inhibited in cotton rats (Sigmodon hispidus). In this system, an attenuated, recombinant vesicular stomatitis virus expressing the MV haemagglutinin (VSV-H) was found previously to induce neutralizing antibodies and protection against MV challenge after intranasal (i.n.) immunization. Here it is demonstrated that, after i.n. immunization, VSV-H is found in both lung and brain tissue in the absence of clinical signs. Intratracheal inoculation, which does not lead to infection of the brain, proved that immunization via the lung mucosa is sufficient to protect. To reduce or eliminate infection of the brain after i.n. inoculation, stepwise-attenuated VSV-H mutants with truncated cytoplasmic tails of the G protein were tested in cotton rats. A mutant with 9 aa in the G cytoplasmic tail was found at much lower levels in the brain and was protective in the absence or presence of MV-specific antibodies. A more attenuated mutant containing only 1 aa in its tail was not found in brain tissue after inoculation, but it still induced protective antibody to measles in the absence of MV-specific antibody. However, its ability to induce MV-neutralizing antibodies in the presence of passively transferred MV-specific antibodies and its protective capacity was abolished unless higher-dose immunizations were used. This study demonstrates that a lower degree of attenuation is required to be able to immunize in the presence of MV-specific antibodies.

Impaired proliferative response of lymphocytes after mitogenic stimulation ex vivo is a key feature of the generalized immunosuppression induced by measles virus (MV). Compelling evidence suggests that negative signalling by the MV glycoprotein (gp) complex and the surface of uninfected lymphocytes is essential for this effect. So far, the inhibitory activity of this complex applied to all lymphocyte subpopulations irrespective of the mode of stimulation and could not be overcome by external stimulation. This study shows that the isopentenyl pyrophosphate (IPP)/IL-2-stimulated expansion of human gamma/delta T cell receptor (TCR) T cells from peripheral blood mononuclear cells (PBMCs) is inhibited efficiently when the MV gp complex is expressed on the surface of persistently MV-infected T or monocytic cells. In contrast, persistently infected B cells or infected human dendritic cells (DCs) do not interfere with expansion of gamma/delta TCR T cells from PBMCs. These particular two cell populations, however, efficiently inhibit IPP/IL-2-stimulated expansion of gamma/delta TCR T cells from purified T cells and this is reverted by resubstitution with monocytes. As revealed by filter experiments, cocultivation with B cells and DCs empower monocytes, at least partially by soluble mediators, to provide membrane contact-dependent costimulatory signals that neutralize the inhibitory effect of the MV gp complex. Thus, gamma/delta TCR T cells are sensitive to MV gp-mediated inhibition; however, this is overcome efficiently by signals delivered from monocytes conditioned by B cells and DCs.

Measles virus remains among the most potent global pathogens killing more than 1 million children annually. A profound suppression of general immune functions occurs during and for weeks after the acute disease, which favors secondary infections. In contrast, virus-specific immune responses are efficiently generated, mediate viral control and clearance and confer a long-lasting immunity. Because they sense pathogen-associated molecular patterns, and subsequently initiate and shape adaptive immune responses, professional antigen-presenting cells (APC) such as dendritic cells are likely to play a key role in the induction and quality of the virus-specific immune response. Key features of immune suppression associated with measles virus, however, are compatible with interference with APC maturation and function and subsequent qualitative and quantitative alterations of T cell activation.

As important determinants of measles virus (MV) pathogenicity, the MV glycoproteins play a key role in conferring the cellular tropism of this virus, but also in modulating the activity of immunocompetent cells. Whereas all MV strains are able to use CD150 (SLAM) for binding and entry into target cells, only certain, mainly vaccine, strains, can use both CD46 and CD150. Both molecules are down-regulated from the cell surface and this is brought about by both infection and contact with the MV H protein of strains that are able to interact with these molecules. Whereas down-regulation of CD46 could be linked to enhanced sensitivity to complement-mediated lysis, and may thus represent an attenuation marker for vaccine strains, pathogenetic consequences of CD150 down-regulation are unknown as yet. Although the role of CD150 is not entirely clear, viruses containing a wild-type strain-derived H protein revealed a particular tropism for human dendritic cells in vitro, and replicated well in secondary lymphatic tissues of cotton rats where they were also able to cause immunosuppression, as documented by an impaired proliferative response of lymphocytes ex vivo. Most likely, inhibition of T cell expansion by these cells is brought about by another activity of the MV glycoprotein complex, namely by disrupting a pathway important for S-phase entry of T cells, by a mere surface contact.

CD95 is a major apoptosis receptor that induces caspase activation and programmed cell death in susceptible cells. CD95-induced apoptosis can be blocked by peptidic caspase inhibitors such as benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone or Ile-Glu-Thr-Asp-fluoromethyl ketone. Here we show that stimulation of CD95 in the presence of these inhibitors induces necrosis and expression of various proinflammatory cytokines in primary T lymphocytes, such as TNF-alpha, IFN-gamma and granulocyte/macrophage colony-stimulating factor. In the absence of caspase inhibition CD95 stimulation did not result in cytokine expression, indicating that this proinflammatory signaling pathway is suppressed by active caspases. Further analysis with A3.01 T cells revealed that the proinflammatory signaling activity of CD95 was mediated by MEK/ERK, p38 and NF-kappaB signaling pathways. These findings point to a pivotal role of caspases not only as mediators of apoptosis but also as enzymes that prevent proinflammatory signaling during CD95-induced apoptosis. Moreover, our findings may be useful for the development of novel pharmacological strategies.

MEASLES VIRUS INDUCES a profound suppression of immune responses during and for weeks after the acute disease, and this favors the establishment and aggravates the course of secondary infections. Virus-specific immune responses are, however, efficiently generated and lead to viral clearance and a longlasting immunity. As the link the innate to the adaptive immune response, professional antigen-presenting cells (APC) such as monocytes and bone marrow–derived dendritic cells (DC) are crucial for inducing and shaping the virus-specific immune response. Key findings of immune suppression associated with measles are, however, also compatible with viral interference with APC maturation and function thereby qualitatively and quantitatively affecting T cell activation.

Stimulation of tumor necrosis factor receptor 1 (TNF-R1) triggers both caspase-dependent and caspase-independent signaling activities. The caspase-dependent signaling pathway induces apoptotic cell death in susceptible cells, whereas the caspase-independent signaling cascade leads to activation of nuclear factor κB and induces antiapoptotic signaling activities. Stimulation of nuclear factor κB via TNF-R1 is known to activate human immunodeficiency virus (HIV) replication in infected cells. Here we show that the broad range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (ZVAD) activates HIV replication in the chronically infected T-cell line ACH-2. Virus activation was caused by a sensitization of TNF-R1 toward endogenously produced tumor necrosis factor α (TNF-α). Neutralizing anti-TNF-α antibodies completely abolished the virus-inducing activity of ZVAD. Treatment of cells with TNF-α in the presence of ZVAD caused increased expression of TNF-α and induced enhanced virus replication. Activation of CD95, another member of the TNF receptor family, similarly triggered HIV replication, which was further enhanced in the presence of ZVAD. Our data show that caspase inhibitors sensitize both CD95 and TNF-R1 to mediate activation of HIV in latently infected cells. Activation of HIV replication in latent virus reservoirs is currently discussed as a therapeutic strategy to achieve eradication of HIV in patients treated with antiretroviral therapy. Our results point to a novel role for caspase inhibitors as activators of virus replication in vivo.

If synthetic biology is to thrive, the world needs to decide now how the field should be regulated and supported, says Volker ter Meulen.

The introduction and spread of plant pests and diseases has significant consequences for agriculture, horticulture, forestry, and natural habitats. Opportunities arising from scientific advances must be better used to inform regulation of trade and underpin chemical and alternative controls and breeding of plants resistant to biotic stress.

Measles still causes high mortality in children younger than 1 year of age. Administration of high titre measles vaccines before 7 months of age led to increased overall mortality, raising questions as to the immunological effects of measles vaccine in young infants. We investigated the immune response to standard titre vaccines given to children in Bangladesh in a single dose at age 9 months, or two doses at 6 and 9 months. Of the children vaccinated at age 9 months, 95% serocoverted, compared with 70% at age 6 months. Delayed-type-hypersensitivity reactions to candida antigen were significantly reduced in both vaccine groups at 6 weeks post-vaccination, but responses to other recall antigens studied were not significantly different from controls. In both vaccine groups, peripheral blood lymphocytes isolated at 6 and 24 weeks after vaccination showed significantly higher expression of activation markers upon in vitro stimulation, and a sustained increase in IL-2 production. These findings suggest prolonged immune activation after measles vaccination at the same time as some reduction in delayed hypersensitivity responses. Further study of the clinical effects of these changes is warranted.

After infection of CEM174.T2 cells [deficient for the transporter of antigen presentation (TAP)] with measles virus (MV) the nucleocapsid protein is recognized by Ld-restricted cytotoxic T cells in a TAP-independent, chloroquine-sensitive fashion. Presentation via the TAP-independent pathway requires virus replication. During MV infection of the cell the nucleocapsid as well as the matrix protein enter the endolysosomal compartment as indicated by colocalization with the lysosomal-associated membrane protein 1 (LAMP-1). Similarly, the nucleocapsid protein of canine distemper virus (CDV) is recognized in a TAP-independent fashion. In addition, a recombinant MV expressing bacterial β-galactosidase protein is able to introduce the recombinant antigen into the TAP-independent pathway whereas a vaccinia virus expressing β-galactosidase is not. These data and a report about TAP-independent recognition of parainfluenza virus type 1 suggest that members of the Paramyxoviridae family regularly introduce viral proteins into the TAP-independent antigen-processing pathway.

CD46 (or membrane cofactor protein) protects autologous cells from complement-mediated lysis and has been expressed as a transgene in pigs to overcome complement-mediated hyperacute rejection of porcine organs upon transplantation into primates. Since CD46 has been identified as a receptor for measles virus (MV), the susceptibility of CD46-transgenic (tg) pig peripheral blood mononuclear cells (PBMC) to infection with MV strains which do and do not use CD46 as receptor was investigated. Surprisingly, it was found that MV vaccine strains (e.g. Edmonston) bound to tg as well as non-tg pig PBMC. Phytohaemagglutinin-stimulated CD46-tg and non-tg pig PBMC were equally well infected with MV vaccine strains irrespective of CD46 expression. Upon infection, tg CD46 was downregulated from the cell surface. In contrast, the binding capacity for MV wild-type strains to pig and human PBMC was low, irrespective of CD46 expression. These MV strains did not infect tg or non-tg pig cells. Expression of endogenous pig CD46 was detected with polyclonal sera against human CD46. After infection of pig PBMC with MV strain Edmonston, endogenous pig CD46 was also downregulated. This suggests an interaction between MV Edmonston and pig CD46. However, polyclonal CD46 sera did not inhibit infection with MV Edmonston indicating that CD46 may not exclusively act as a receptor for MV on these cells. Interestingly, similar results were observed using human PBMC. Data suggest that CD46 downregulation after interaction with MV may also occur in porcine organs which express endogenous and/or human CD46 as a means of protection against complement-mediated damage.

In humans, maternal antibodies inhibit successful immunization against measles, because they interfere with vaccine-induced seroconversion. We have investigated this problem using the cotton rat model ( Sigmodon hispidus ). As in humans, passively transferred antibodies inhibit the induction of measles virus (MV)-neutralizing antibodies and protection after immunization with MV. In contrast, a recombinant vesicular stomatitis virus (VSV) expressing the MV hemagglutinin (VSV-H) induces high titers of neutralizing antibodies to MV in the presence of MV-specific antibodies. The induction of neutralizing antibodies increased with increasing virus dose, and all doses gave good protection from subsequent challenge with MV. Induction of antibodies by VSV-H was observed in the presence of passively transferred human or cotton rat antibodies, which were used as the models of maternal antibodies. Because MV hemagglutinin is not a functional part of the VSV-H envelope, MV-specific antibodies only slightly inhibit VSV-H replication in vitro. This dissociation of function and antigenicity is probably key to the induction of a neutralizing antibody in the presence of a maternal antibody.

Plasmids that expressed the nucleocapsid, haemagglutinin and fusion proteins of measles virus (MV) were used to immunize cotton rats (Sigmodon hispidus) against intranasal MV infection. After immunization with all three plasmids, T cell responses and MV-specific antibodies were induced. A reduction in virus titre was observed in lung tissue from animals immunized with plasmids expressing the viral glycoproteins. Histologically, however, a moderate peribronchitis was observed after immunization with the plasmid expressing the fusion protein whereas, after immunization with plasmids expressing haemagglutinin or both glycoproteins, only mild or focal peribronchitis was seen. Immunization with the nucleocapsid did not reduce virus titres, probably because of the failure to induce neutralizing antibodies. A disadvantage of plasmid immunization was its inefficacy in the presence of MV-specific ‘maternal’ antibodies. This indicates that genetic immunization has to be improved to be a useful alternative vaccine against measles.

To longitudinally determine T cell activation and turnover in early simian immunodeficiency virus (SIV) infection of macaques, immunological and virological parameters were monitored in 10 SIV-infected animals starting before infection until 40 weeks postinfection (wpi). Lymphocyte subsets in blood and lymph nodes (LNs) were characterized by three-color flow cytometry for expression of markers of activation, proliferation, and differentiation. As early as 1 wpi, CD69 expression was upregulated both on CD4+ and CD8+ T cells, indicative of an early activation of these cells. Whereas this activation led to increased proliferation, determined by expression of Ki-67, and absolute numbers of CD8+ T cells, CD4+ T cells showed a decreased expression of Ki-67 and reduced counts in blood at 2 wpi. Later, the percentage of Ki-67-expressing CD4+ T cells in blood and LNs increased again above preinfection levels in most animals but remained low in two monkeys progressing to AIDS. These findings suggest that T cells are activated after SIV infection, leading to increased T cell proliferation already in the early asymptomatic phase. In addition, we found a correlation between the capacity to regenerate CD4+ T cells by peripheral proliferation and the disease course. Moreover, our data indicate that the increased peripheral T cell proliferation during immunodeficiency virus infection is probably not caused by the effort of the immune system to maintain T cell homeostasis but may be a reflection of the ongoing immune response against the virus.