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The pathogenesis and immunopathological damage of severe forms of COVID-19 resemble acute autoimmune disease sparked by SARS-CoV-2, including an early systemic overproduction of proinflammatory cytokines. Such immunopathological features provide a rationale for the use of passive immunotherapy with convalescent plasma as a source of neutralizing anti-viral antibodies and of anti-inflammatory plasma components. While convalescent plasma therapy is now being evaluated in prospective clinical trials, we further consider the therapeutic potential of human hyper immune globulins, and of heterologous, engineered and monoclonal neutralizing antibodies as anti-viral agents to treat COVID-19. Good medical practice procedures are still needed and is why we also discuss the potential use of polyclonal polyspecific immunoglobulins (IVIG), a therapeutic plasma derivative, with potent anti-inflammatory activity, in severe forms of Covid-19.

International audience; No abstract available

In September, 2015, the member states of the UN endorsed Sustainable Development Goals (SDGs) for 2030, which aspire to human-rights-centred approaches to ensuring the health and wellbeing of all people. The SDGs embody both the UN Charter values of rights and justice for all and the responsibility of states to rely on the best scientific evidence as they seek to better humankind. In April, 2016, these same states will consider control of illicit drugs, an area of social policy that has been fraught with controversy and thought of as inconsistent with human rights norms, and in which scientific evidence and public health approaches have arguably had too limited a role.The previous UN General Assembly Special Session (UNGASS) on drugs in 1998—convened under the theme, “A drug-free world—we can do it!”—endorsed drug-control policies with the goal of prohibiting all use, possession, production, and trafficking of illicit drugs. This goal is enshrined in national laws in many countries. In pronouncing drugs a “grave threat to the health and wellbeing of all mankind”, the 1998 UNGASS echoed the foundational 1961 convention of the international drug-control regime, which justified eliminating the “evil” of drugs in the name of “the health and welfare of mankind”. But neither of these international agreements refers to the ways in which pursuing drug prohibition might affect public health. The war on drugs and zero-tolerance policies that grew out of the prohibitionist consensus are now being challenged on multiple fronts, including their health, human rights, and development impact.The Johns Hopkins–Lancet Commission on Drug Policy and Health has sought to examine the emerging scientific evidence on public health issues arising from drug-control policy and to inform and encourage a central focus on public health evidence and outcomes in drug-policy debates, such as the important deliberations of the 2016 UNGASS on drugs. The Commission is concerned that drug policies are often coloured by ideas about drug use and dependence that are not scientifically grounded. The 1998 UNGASS declaration, for example, like the UN drug conventions and many national drug laws, does not distinguish between drug use and drug misuse. A 2015 report by the UN High Commissioner for Human Rights, by contrast, emphasised that drug use “is neither a medical condition, nor does it necessarily lead to drug dependence”. The idea that all drug use is dangerous and evil has led to enforcement-heavy policies and has made it difficult to see potentially dangerous drugs in the same light as potentially dangerous foods, tobacco, and alcohol, for which the goal of social policy is to reduce potential harms.

Summary The women, men, and transgender people who sell sex globally have disproportionate risks and burdens of HIV in countries of low, middle, and high income, and in concentrated and generalised epidemic contexts. The greatest HIV burdens continue to be in African female sex workers. Worldwide, sex workers still face reduced access to needed HIV prevention, treatment, and care services. Legal environments, policies, police practices, absence of funding for research and HIV programmes, human rights violations, and stigma and discrimination continue to challenge sex workers' abilities to protect themselves, their families, and their sexual partners from HIV. These realities must change to realise the benefits of advances in HIV prevention and treatment and to achieve global control of the HIV pandemic. Effective combination prevention and treatment approaches are feasible, can be tailored for cultural competence, can be cost-saving, and can help to address the unmet needs of sex workers and their communities in ways that uphold their human rights. To address HIV in sex workers will need sustained community engagement and empowerment, continued research, political will, structural and policy reform, and innovative programmes. But such actions can and must be achieved for sex worker communities everywhere.

Background Although there is evidence of the effectiveness of needle and syringe programme (NSP), opioid substitution therapy (OST) and antiretroviral therapy (ART) in reducing HIV prevalence, most Central and Eastern European sub-regions still have low or no coverage of most or all of these interventions. Methods We conducted a modelling analysis to consider the potential impact on HIV incidence and prevalence of OST, NSP and ART in three illustrative epidemic scenarios: Russia (St. Petersburg); Estonia (Tallinn) and Tajikistan (Dushanbe). For each intervention, we consider the coverage needed of each intervention separately or in combination to: (1) achieve a 30% or 50% relative reduction in HIV incidence or prevalence over 10 years; and (2) reduce HIV incidence to below 1% or HIV prevalence below 10% after 20 years. A sensitivity analysis for St. Petersburg considered the implications of greater on no risk heterogeneity, none or more sexual HIV transmission, like-with-like mixing, different injecting cessation rates and assuming a lower HIV acute phase cofactor. Results For St. Petersburg, when OST, NSP and ART are combined, only 14% coverage of each intervention is required to achieve a 30% reduction in HIV incidence over 10 years. Similar findings are obtained for Tallinn and Dushanbe. In order to achieve the same reductions in HIV prevalence over 10 years, over double the coverage level is required relative to what was needed to achieve the same reduction in HIV incidence in that setting. To either reduce HIV incidence to less than 1% or HIV prevalence to less than 10% over 20 years, with all interventions combined, projections suggest that very high coverage levels of 74–85% are generally required for the higher prevalence settings of Tallinn and St. Petersburg, whereas lower coverage levels (23–34%) are needed in Dushanbe. Coverage requirements are robust to increased sexual HIV transmission, risk heterogeneity and like-with-like mixing, as well as to assuming a lower HIV acute phase cofactor or different injecting cessation rate. Conclusion The projections suggest that high but achievable coverage levels of NSP can result in large decreases (30%) in HIV incidence in settings with high HIV prevalence among PWID. Required coverage levels are much lower when interventions are combined or in lower prevalence settings. However, even when all three interventions are combined, the targets of reducing HIV incidence to less than 1% or prevalence to less than 10% in 20 years may be hard to achieve except in lower prevalence settings.

Objective In 2010 the international HIV/AIDS community called on countries to take action to prevent HIV transmission among people who inject drugs (PWID). To set a baseline we proposed an "accountability matrix", focusing upon six countries accounting for half of the global population of PWID: China, Malaysia, Russia, Ukraine, Vietnam and the USA. Two years on, we review progress. Design We searched peer-reviewed literature, conducted online searches, and contacted experts for ‘grey' literature. We limited searches to documents published since December 2009 and used decision rules endorsed in earlier reviews. Results Policy shifts are increasing coverage of key interventions for PWID in China, Malaysia, Vietnam and Ukraine. Increases in PWID receiving antiretroviral treatment (ART) and opioid substitution treatment (OST) in both Vietnam and China, and a shift in Malaysia from a punitive law enforcement approach to evidence-based treatment are promising developments. The USA and Russia have had no advances on PWID access to needle and syringe programmes (NSP), OST or ART. There have also been policy setbacks in these countries, with Russia reaffirming its stance against OST and closing down access to information on methadone, and the USA reinstituting its Congressional ban on Federal funding for NSPs. Conclusions Prevention of HIV infection and access to HIV treatment for PWID is possible. Whether countries with concentrated epidemics among PWID will meet goals of achieving universal access and eliminating new HIV infections remains unknown. As long as law enforcement responses counter public health responses, health-seeking behaviour and health service delivery will be limited.

The malaria parasite Plasmodium falciparum induces a number of novel adhesion properties in the erythrocytes that it infects. One of these properties, the ability of infected erythrocytes to bind uninfected erythrocytes to form rosettes, is associated with severe malaria and may play a direct role in the pathogenesis of disease. Previous work has shown that erythrocytes deficient in complement receptor (CR) 1 (CR1, CD35; C3b/C4b receptor) have greatly reduced rosetting capacity, indicating an essential role for CR1 in rosette formation. Using deletion mutants and mAbs, we have localized the region of CR1 required for the formation of P. falciparum rosettes to the area of long homologous repeat regions B and C that also acts as the binding site for the activated complement component C3b. This result raises the possibility that C3b could be an intermediary in rosetting, bridging between the infected erythrocyte and CR1. We were able to exclude this hypothesis, however, as parasites grown in C3-deficient human serum formed rosettes normally. We have also shown in this report that rosettes can be reversed by mAb J3B11 that recognizes the C3b binding site of CR1. This rosette-reversing activity was demonstrated in a range of laboratory-adapted parasite strains and field isolates from Kenya and Malawi. Thus, we have mapped the region of CR1 required for rosetting and demonstrated that the CR1-dependent rosetting mechanism occurs commonly in P. falciparum isolates, and could therefore be a potential target for future therapeutic interventions to treat severe malaria.

Where surveillance has been done, it has shown that men (MSM) who have sex with men bear a disproportionate burden of HIV. Yet they continue to be excluded, sometimes systematically, from HIV services because of stigma, discrimination, and criminalisation. This situation must change if global control of the HIV epidemic is to be achieved. On both public health and human rights grounds, expansion of HIV prevention, treatment, and care to MSM is an urgent imperative. Effective combination prevention and treatment approaches are feasible, and culturally competent care can be developed, even in rights-challenged environments. Condom and lubricant access for MSM globally is highly cost effective. Antiretroviral-based prevention, and antiretroviral access for MSM globally, would also be cost effective, but would probably require substantial reductions in drug costs in high-income countries to be feasible. To address HIV in MSM will take continued research, political will, structural reform, community engagement, and strategic planning and programming, but it can and must be done.

Resume Bien que les immunoglobulines intraveineuses (IgIV) soient utilisees depuis une vingtaine d’annees dans les maladies auto-immunes et inflammatoires, les mecanismes moleculaires a la base de leur effet benefique ne sont pas completement elucides. Ces mecanismes dependent des fragments constants (Fc) et/ou variables (Fab’)2. Les IgIV interagissent avec de nombreux composants du systeme immunitaire comme les recepteurs Fc, le complement, les cytokines, les lymphocytes T et B, les cellules dendritiques, les granulocytes et les cellules NK. Nous presenterons dans cette revue les donnees recentes sur les mecanismes d’action anti-inflammatoire des IgIV, en mettant l’accent sur l’importance du fragment Fc sialyle. Ces avancees permettront peut-etre de concevoir de meilleures strategies therapeutiques contre les maladies auto-immunes et inflammatoires.

The present study demonstrates that human breast milk and normal human polyclonal immunoglobulins purified from plasma [intravenous immunoglobulins (IVIg)] contain functional natural immunoglobulin A (IgA) and IgG antibodies directed against the carbohydrate recognition domain (CRD) domain of the dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) molecule, which is involved in the binding of human immunodeficiency virus (HIV)-1 to dendritic cells (DCs). Antibodies to DC-SIGN CRD were affinity-purified on a matrix to which a synthetic peptide corresponding to the N-terminal CRD domain (amino-acid 342-amino-acid 371) had been coupled. The affinity-purified antibodies bound to the DC-SIGN peptide and to the native DC-SIGN molecule expressed by HeLa DC-SIGN+ cells and immature monocyte-derived dendritic cells (iMDDCs), in a specific and dose-dependent manner. At an optimal dose of 200 microg/ml, natural antibodies to DC-SIGN CRD peptide purified from breast milk and IVIg stained 25 and 20% of HeLa DC-SIGN+ cells and 32 and 12% of iMDDCs, respectively. Anti-DC-SIGN CRD peptide antibodies inhibited the attachment of virus to HeLa DC-SIGN by up to 78% and the attachment to iMDDCs by only 20%. Both breast milk- and IVIg-derived natural antibodies to the CRD peptide inhibited 60% of the transmission in trans of HIV-1(JRCSF), an R5-tropic strain, from iMDDCs to CD4+ T lymphocytes. Taken together, these observations suggest that the attachment of HIV to DCs and transmission in trans to autologous CD4+ T lymphocytes occur through two independent mechanisms. Our data support a role of natural antibodies to DC-SIGN in the modulation of postnatal HIV transmission through breast-feeding and in the natural host defence against HIV-1 in infected individuals.

The clinical use of intravenous immunoglobulin (IVIg) based on its immunomodulatory and anti-inflammatory potential remains an ongoing challenge. Fcγ receptor-mediated effects of IVIg, although well elucidated in certain pathologies, cannot entirely account for its proven benefit in several autoimmune disorders mediated by autoreactive T cells. In this study, we show that prophylactic infusion of IVIg prevents the development of experimental autoimmune encephalomyelitis (EAE), an accepted animal model for multiple sclerosis (MS). The protection was associated with peripheral increase in CD4+CD25+Foxp3+ regulatory T cell (Treg) numbers and function. The protection was Treg-mediated because IVIg failed to protect against EAE in mice that were depleted of the Treg population. Rather than inducing de novo generation from conventional T cells, IVIg had a direct effect on proliferation of natural Treg. In conclusion, our results highlight a novel mechanism of action of IVIg and provide a rationale to test the use of IVIg as an immunomodulatory tool to enhance Treg in early onset MS and other autoimmune and inflammatory conditions.

International audience; BACKGROUND: Macroeconomic policy requirements may limit the capacity of national and international policy-makers to allocate sufficient resources for scaling-up access to HIV care and treatment in developing countries. METHOD: An endogenous growth model, which takes into account the evolution of society's human capital, was used to assess the macroeconomic impact of policies aimed at scaling-up access to HIV/AIDS treatment in six African countries (Angola, Benin, Cameroon, Central African Republic, Ivory Coast and Zimbabwe). RESULTS: The model results showed that scaling-up access to treatment in the affected population would limit gross domestic product losses due to AIDS although differently from country to country. In our simulated scenarios of access to antiretroviral therapy, only 10.3% of the AIDS shock is counterbalanced in Zimbabwe, against 85.2% in Angola and even 100.0% in Benin (a total recovery). For four out of the six countries (Angola, Benin, Cameroon, Ivory Coast), the macro-economic gains of scaling-up would become potentially superior to its associated costs in 2010. CONCLUSION: Despite the variability of HIV prevalence rates between countries, macro-economic estimates strongly suggest that a massive investment in scaling-up access to HIV treatment may efficiently counteract the detrimental long-term impact of the HIV pandemic on economic growth, to the extent that the AIDS shock has not already driven the economy beyond an irreversible 'no-development epidemiological trap'.

Initially used for the treatment of immunodeficiencies, intravenous immunoglobulins (IVIg) have increasingly been used as immunomodulatory agents in autoimmune and inflammatory disorders. The mode of action of IVIg is enigmatic, probably involving Fc-dependent and/or F(ab')2-dependent nonexclusive mechanisms of action. IVIg broadly interacts with the different components of the immune system: cytokines, complement, Fc receptors, and several cell surface immunocompetent molecules. IVIg has also an impact on effector functions of immune cells. These mechanisms of action of IVIg reflect the importance of natural antibodies in the maintenance of immune homeostasis. We discuss here the recent advances in the understanding of immunoregulatory effects of IVIg, and we pointed out the need for new strategies to overcome the predicted increasing worldwide shortage of IVIg.

Advances in our understanding of the pathogenesis of rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus have led to the emergence of immunoglobulin-based therapy as a major therapeutic force. Numerous monoclonal antibodies that target proinflammatory cytokines or their receptors (e.g. infliximab, adalimumab, tocilizumab, belimumab, HuMax-IL-15), and cell-surface or co-stimulatory molecules (e.g. rituximab) are either in clinical development or have been approved for clinical use. These antibodies are safe and effective in the long-term therapy of many rheumatic diseases. In addition, polyclonal immunoglobulins (intravenous immunoglobulin) obtained from pooled plasma from healthy blood donors are an effective therapeutic approach in certain rheumatic diseases. The mechanisms of action of monoclonal antibodies and intravenous immunoglobulin include cytolysis of target cells through complement or antibody-dependent cell-mediated cytotoxicity, induction of apoptosis of target cells, blockade of co-stimulatory molecules, and neutralization of pathogenic antibodies and soluble factors such as cytokines and their receptors, which ultimately lead to amelioration of the inflammatory process. The success of currently available therapeutic immunoglobulins has led to considerable interest in the identification of novel molecular therapeutic targets in rheumatic diseases.

Initially used for the treatment of immunodeficiencies, intravenous immunoglobulins (IVIg) have increasingly been used as immunomodulatory agent in autoimmune and inflammatory disorders. The mode of action of IVIg is enigmatic, probably involving Fc-dependent and/or F(ab')2-dependent non-exclusive mechanisms of action. IVIg broadly interacts with the different components of the immune system: cytokines, complement, Fc receptors and several cell surface immunocompetent molecules. IVIg also has an impact on effector functions of immune cells. These mechanisms of action of IVIg reflect the importance of natural antibodies in the maintenance of immune homeostasis. We discuss here the recent advances in the understanding of immunoregulatory effects of IVIg, and we pointed out the need of new strategies to overcome the predicted increasing worldwide shortage of IVIg.

In the present study, we demonstrated that opsonization of primary HIV-1 with human complement enhances infection of immature monocyte-derived dendritic cells (iDC) and transmission in trans of HIV to autologous CD4+ T lymphocytes. Infection of iDC by opsonized primary R5- and X4-tropic HIV was increased 3- to 5-fold as compared with infection by the corresponding unopsonized HIV. Enhancement of infection was dependent on CR3 as demonstrated by inhibition induced by blocking Abs. The interaction of HIV with CCR5 and CXCR4 on iDC was affected by opsonization. Indeed, stromal-derived factor-1 was more efficient in inhibiting infection of iDC with opsonized R5-tropic HIV-1BaL (45%) than with heat-inactivated complement opsonized virus and similarly RANTES inhibited more efficiently infection of iDC with opsonized X4-tropic HIV-1NDK (42%) than with heat-inactivated complement opsonized virus. We also showed that attachment of complement-opsonized virus to DC-specific ICAM-grabbing nonintegrin (DC-SIGN) molecule on iDC and HeLa DC-SIGN+ CR3− cells was 46% and 50% higher compared with heat-inactivated complement opsonized virus, respectively. Hence, Abs to DC-SIGN suppressed up to 80% and 60% the binding of opsonized virus to HeLa cells and iDC, respectively. Furthermore, Abs to DC-SIGN inhibited up to 70% of the infection of iDC and up to 65% of infection in trans of autologous lymphocytes with opsonized virus. These results further demonstrated the role of DC-SIGN in complement opsonized virus uptake and infection. Thus, the virus uses complement to its advantage to facilitate early steps leading to infection following mucosal transmission of HIV.

BACKGROUND Sequence variations in HR-1 gp41 env gene region encoding the target for T-20 have previously been reported among patients naive to inhibitory fusion. OBJECTIVE To evaluate whether a previous therapeutic history of patients could have an impact on a differential evolution of the gp41 polymorphism. METHODS We assessed the genetic polymorphism within the critical HR-1 gp41 env gene region in HIV-1 variants from 108 T-20-naive patients (Groups I-III) and 12 patients receiving T-20 as part of a salvage regimen (Group IV). T-20-naive patients included 50 patients exhibiting variants harboring resistance mutations to NRTIs, NNRTIs, and PIs (Group I), 24 patients with variants harboring resistance mutations for NRTIs and/or NNRTIs (Group II), and 34 antiretroviral drug-naive patients (Group III). RESULTS In T-20-naive patients whose HIV harbored resistance mutations to NRTIs, NNRTIs, and/or PIs, the mean number of synonymous mutations (ds) per patient was decreased and the mean number of nonsynonymous (da) mutations per patient was increased, resulting in a significant decrease in the mean Sigmads/Sigmada ratio as compared with antiretroviral drug-naive patients (Group III; 4.1 vs. 11.6; P < 0.0001). The mean number of polymorphic mutations in HR-1 gp41 per patient was two-fold higher in patients exhibiting antiretroviral drug resistance mutations (Groups I and II) than in antiretroviral drug-naive patients (Group III; 0.41 vs. 0.20; P < 0.05). CONCLUSION Our observations indicate that the HR-1 gp41 T-20 target is subjected to high genetic variability, including intrinsic polymorphism and selection of T-20 resistance mutations under T-20 intake, that is increased by the presence of resistance mutations to NRTIs, NNRTIs, and/or PIs. Our data provide a basis for a potential impact of previous antiretroviral drug history on the therapeutic efficacy of T-20.

1132 www.thelancet.com Vol 386 September 19, 2015 How is it possible to achieve gender equality (Goal 5) when women pay the heaviest toll for small drug off ences all over the world? How do we promote decent work for all (Goal 8) while drug users are not given the means to stabilise their use and to engage in a regular professional life? How will we make cities and human settlements inclusive and safe (Goal 11) when drug users are congregated in defined spaces and suffer daily humiliation? How do we promote peaceful and inclusive societies (Goal 16) when a whole part of it is rejected even without doing any harm to others? How are we to strengthen global partnerships (Goal 17) when they focus primarily on supply reduction measures in the drugs fi eld, leading to incarceration, and the use of death penalty in many cases? The commitment taken by the UN to ensure that all future policies should operate within the sustainable development framework is crucial. Leaving no one behind also means leaving no drug user behind.

Viscum album (VA) preparations consist of aqueous extracts of different types of lectins of mistletoe. VA exert cytotoxic and immunomodulatory properties that may be relevant for the inhibition of tumor growth. We addressed the effects of VA preparation VA Qu FrF on growth of B16F1 melanoma implanted in mice and on proliferation and cytokine synthesis of splenocytes. In C57BL6 mice, inhibition of tumor growth by VA was associated with an enhancement of splenocyte proliferation and with an up-regulation of IL-12 secretion. In IL-12-deficient strain of mice the inhibition of melanoma growth by VA and the splenocyte proliferation were abrogated. Results from the present study strongly suggest a crucial role of IL-12 in the anti-tumor properties of VA extracts.

Intravenous immunoglobulin (IVIG) is increasingly used in the treatment of diverse immune-mediated disorders. Since several preparations of IVIG are available for therapy, it is possible that different manufacturing processes might influence clinical efficacy of IVIG. An insight into the mechanisms of action of such different IVIG preparations is therefore necessary that will provide further guidelines for the utility of IVIG preparations in autoimmune and inflammatory diseases. Since endothelial cells (EC) influence the inflammatory process via production of cytokines, chemokines and expression of adhesive molecules, we analyzed the anti-inflammatory effect on EC of two IVIG preparations: caprylated IVIG (IVIG-C) versus solvent/detergent-treated IVIG (IVIG-SD) preparation. We found that both IVIG preparations inhibit in an equivalent manner, the expression of different pro-inflammatory factors such as IL-6, IL-8, GM-CSF, IL-1beta and TNF-alpha and the adhesion molecules ICAM-1 and VCAM-1. Our results thus suggest that the caprylate while inactivating the virus and enhancing the yield of IgG during IVIG formulation, does not modulate the immunomodulatory properties of IVIG at EC level and that the two preparations show similar anti-inflammatory effects.

Intravenous immunoglobulin (IGIV) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases in addition to supportive therapy of immunodeficient patients. IGIV is beneficial in several diseases, including acute and chronic/relapsing diseases, autoimmune diseases and inflammatory disorders. Therapeutic efficacy of IGIV has also been established in a number of dermatologic diseases. Although a considerable progress has been made in understanding the mechanisms by which IGIV exerts immunomodulatory functions in autoimmune diseases, they remain not fully elucidated. The mode of action of IGIV is complex, involving modulation of expression and function of Fc receptors, interference with activation of complement and the cytokine network, modulation of idiotype network, regulation of cell growth, alteration of cellular adhesion process, and effects on the activation differentiation and effector functions of T and B cells and of antigen-presenting cells. The therapeutic effects of IGIV most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy people. The ability of IGIV to interact through V regions with complementary V regions of antibodies and antigen receptors as well as with relevant soluble and surface molecules provides the basis for inducing the selection of immune repertoires. Since IGIV is frequently used to treat autoimmune and inflammatory diseases for which evidence of its efficacy is insufficiently documented, controlled trials, particularly of some neurologic and dermatologic diseases, are imperative.

Objective: Viral rebounds inevitably follow interruption of antiretroviral treatment in HIV-1-infected individuals. The randomized ANRS 093 aimed at investigating whether a therapeutic immunization was effective in containing the long-term viral replication following discontinuation of antiretroviral drugs in patients. Methods: Seventy HIV-1-infected patients effectively treated with antiretroviral drugs were randomized to continue treatment alone or in combination with four boosts of ALVAC 1433 and HIV-LIPO-6T vaccines followed by three cycles of subcutaneous interleukin-2. The impact of vaccination on viral replication was assessed by interrupting antiretroviral drugs first at week 40 and thereafter during follow-up until week 100. Antiretroviral drugs were re-initiated according to predefined criteria. Results: The median cumulative time (days) off treatment was greater in the vaccine group (177) than in the control group (89) (P = 0.01). The proportion of time (mean, SE) without antivirals per-patient was 42.8% (5.1) and 26.5% (4.2) in the vaccine and control groups, respectively (P = 0.005). Viremia (median log10 copies/ml), 4 weeks following the first, second and third treatment interruption was higher in control patients (4.81, 4.44, 4.53) in comparison with vaccinated patients (4.48, 4.00, 3.66) (P = 0.42, 0.015 and 0.024, respectively). HIV-specific CD4 and CD8 T-cell responses elicited by the therapeutic immunization strongly correlated with the reduction of the time of antiviral therapy (P = 0.0027 and 0.016, respectively). Conclusion: Our findings provide evidence that therapeutic immunization significantly impacts on HIV-1 replication. This translated into a decrease of up to 40% in the duration of exposure to antiretroviral drugs over 15 months of patients' follow-up.

Immunoglobulins have initially been illustrated as proteins produced by the immune system for binding and neutralizing foreign molecules potentially harmful to the organism. The number of V(H), D(H), J(H), V(L) and J(L) genes that encode the variable regions of immunoglobulins and the junctional diversity that occurs at the time of somatic rearrangement determine the extent of the repertoire of antibodies that may be potentially produced by an organism. This potential repertoire includes antibodies the antigen binding site of which may recognize external as well as autologous antigens, or may structurally resemble the active site of enzymes and be endowed with enzymatic activity. Under physiological conditions, B cell clones that produce antibodies naturally endowed with catalytic activity are negatively regulated and subjected to apoptosis. Catalytic antibodies are expressed only following active immunization, or if the physiological regulatory mechanisms that control the expression of catalytic antibody-producing B cell clones are perturbed, e.g. in the context of pregnancy or in the course of autoimmune diseases.

Liver mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTI) in human immunodeficiency virus (HIV) patients has been associated with a wide range of liver involvement ranging from low-grade hepatotoxicity, asymptomatic lactacidemia to severe liver insufficiency, with massive steatosis and life-threatening lactic acidosis. Considerable efforts have been made in the last few years to establish clinical guidelines to avoid life-threatening NRTI-associated lactic acidosis. However, the important issue of low-grade NRTI-associated hepatotoxicity still needs to be unravelled since its natural history is largely unknown. We have recently reported a series of 13 monoinfected HIV patients with low-grade NRTI-associated toxicity. Our results outlined the heterogeneity of NRTI-induced hepatotoxicity and raised the question of its diagnosis. The present study evaluates the expression of cytochrome oxidase (COX) subunits I and IV, encoded by mitochondrial and nuclear DNA, respectively, in NRTI hepatotoxicity. The aim of our study was to compare the detection rate of mitochondrial abnormalities of immunohistochemistry for COX subunit I with electron microscopy. COX subunit I and IV labeling was performed together with light microscopy and ultrastructural analysis in a series of 55 liver biopsies from HIV monoinfected and HIV-hepatitis C virus coinfected patients. Clinical data were also recorded. Our major findings were: (i) decreased COX subunit I labeling is associated with severe ultrastructural mitochondrial alterations and may represent overt NRTI-induced mitochondrial cytopathy; (ii) mild ultrastructural damage associated with normal COX subunit I labeling is of unknown clinical significance. The results of the study suggest that COX subunit I labeling may be a valuable tool for the diagnosis of mitochondrial liver disease in HIV patients.

HIV-infected men who have sex with men remain at high risk of developing anal cancer despite the widespread use of highly active antiretroviral therapy (HAART). In HIV-infected women, however, there is some evidence that HAART may be associated with regression of human papillomavirus (HPV)-related cervical disease. So far, epidemiologic data provided by cancer registries have shown no reduction in the incidence of cervical and anal cancer in patients with HIV infection since the initiation of HAART in 1996. Recent data suggest that HPV infection occurs in the anal canal of immunocompromised patients, as an opportunistic infection, in the absence of receptive anal intercourse. Taken together, these lines of evidence support the need for developing anal and cervical cancer screening programs for patients with HIV, whether untreated or on HAART.

Infection with human immunodeficiency virus (HIV) is characterized by a progressive depletion of CD4(+) T cells that parallels a dysfunction of the B cell compartment and a disturbed recognition of self-antigens. The relationship between T lymphocyte homeostasis and abnormalities in the selection of self-reactive B cells is not clear as yet. We have therefore compared repertoires of natural antibodies of healthy donors and of patients at various stages of HIV infection. The reactivity of IgM and IgG antibodies in plasma of healthy blood donors and of HIV-positive patients with high and low CD4(+) T cell counts was assessed by semi-quantitative immunoblotting using self-antigens extracted from normal human tissues. Repertoires of reactivites were compared between groups of individuals by means of multiparametric statistical analysis. We observed that repertoires of self-reactive IgM and IgG from HIV-seropositive patients exhibited significantly altered patterns of reactivity, as compared to those of healthy controls. Further, self-reactive repertoires of IgM and IgG of patients with high CD4(+) T cell counts differed significantly from those of patients with low CD4(+) T cell counts. A longitudinal analysis of self-reactive antibody repertoires of progressor and non-progressor patients suggested an influence of CD4(+) T cell counts on immunoglobulin reactivity toward self-antigens. These observations support the hypothesis that altered T cell/B cell interactions due to altered CD4(+) T cell help severely impact on the selection of self-reactive antibody repertoires and may contribute to the onset of pathological autoimmunity in HIV disease.

Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over 25 years. It is a safe preparation with no long-term side effects. IVIg was first demonstrated to be effective in autoimmune disorders, two decades ago, in the treatment of acute immune thrombocytopenia. Since then, the therapeutic efficacy of IVIg has been established in Guillain Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), dermatomyositis (DM), Kawasaki syndrome and the prevention of graft-versus-host disease in recipients of allogeneic bone marrow transplants and reported in a large number of other autoimmune and systemic inflammatory conditions.

Sepsis is the leading cause of death in intensive care units and results from a deleterious systemic host response to infection. Although initially perceived as potentially deleterious, catalytic antibodies have been proposed to participate in removal of metabolic wastes and protection against infection. Here we show that the presence in plasma of IgG endowed with serine protease-like hydrolytic activity strongly correlates with survival from sepsis. Variances of catalytic rates of IgG were greater in the case of patients with severe sepsis than healthy donors (P< 0.001), indicating that sepsis is associated with alterations in plasma levels of hydrolytic IgG. The catalytic rates of IgG from patients who survived were significantly greater than those of IgG from deceased patients (P< 0.05). The cumulative rate of survival was higher among patients exhibiting high rates of IgG-mediated hydrolysis as compared with patients with low hydrolytic rates (P< 0.05). An inverse correlation was also observed between the markers of severity of disseminated intravascular coagulation and rates of hydrolysis of patients' IgG. Furthermore, IgG from three surviving patients hydrolyzed factor VIII, one of which also hydrolyzed factor IX, suggesting that, in some patients, catalytic IgG may participate in the control of disseminated microvascular thrombosis. Our observations provide the first evidence that hydrolytic antibodies might play a role in recovery from a disease.

Intravenous immunoglobulin (IVIg) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases, and in supportive therapy of immunodeficient patients. Available clinical and experimental evidence suggests, however, that a wide spectrum of immune-mediated conditions could benefit from IVIg, including acute and chronic/relapsing diseases and autoimmune diseases mediated by pathogenic autoantibodies or by autoaggressive T-cells. Dendritic cells (DCs) are professional antigen-presenting cells and because of their capacity to stimulate naïve T-cells, they play a central role in the initiation of primary immune responses. Several immunomodulatory agents have been shown to inhibit DC activation. Recently, we examined the effects of IVIg on differentiation, maturation, and functions of DCs. We demonstrate that DCs are one of the targets for the immunomodulatory effects of IVIg.

Resume Utilisation therapeutique Les immunoglobulines intraveineuses (IgIV) sont des preparations therapeutiques d’IgG humaines normales obtenues a partir d’un pool de plasmas provenant de plus de 1 000 individus sains. Elles sont utilisees dans le traitement d’un grand nombre de maladies auto-immunes, qu’elles soient associees a la mise en evidence d’auto-anticorps ou de lymphocytes T autoreactifs, ainsi que dans le traitement de maladies inflammatoires systemiques. Des mecanismes d’action multiples et intriques Depuis 20 ans, de nombreux mecanismes d’action des IgIV au cours de ces maladies ont ete identifies. Ils comprennent : la modulation de l’expression des recepteurs Fc a la surface des leucocytes et des cellules endotheliales ; la modulation du systeme du complement ; la modulation de la synthese et de la liberation des cytokines et des chemokines ; la modulation de la proliferation cellulaire et de l’apoptose ; la remyelinisation ; la neutralisation des auto-anticorps circulants ; la selection des repertoires des lymphocytes B et des lymphocytes T ; l’interaction avec d’autres molecules a la surface des lymphocytes et des monocytes ; l’epargne cortisonique. Ces mecanismes d’action sont multiples et souvent intriques. Ils ne sont cependant pas encore completement elucides et le champ des investigations a effectuer reste large dans ce domaine.

Summary Background Generic fixed-dose combinations have been prequalified by WHO to treat HIV-infected patients in resource-limited countries. Despite their widespread use they are, however, not yet recommended by some of the major donor agencies owing to scarcity of clinical data on effectiveness, safety, and quality. We aimed to assess these issues for one of the most frequently prescribed treatments in Africa, a generic fixed-dose combination of nevirapine, stavudine, and lamivudine. Methods 60 patients were followed in an open-label, 24-week multicentre trial in Cameroon. All patients received one tablet of the fixed-dose combination drug twice daily. The primary outcome measure was the proportion of patients with viral load less than 400 copies per mL at the end of the study period, in an intention-to-treat analysis. Findings At baseline, 92% of patients (n=55) had AIDS; median CD4 count was 118 cells per μL (IQR 78–167) and median plasma HIV-1 RNA was 104 736 copies per mL (40 804–243 787). The proportion of patients with undetectable viral load ( 10 copies per mL (–2·5 to –3·6) and in CD4 count 83 cells per μL (40–178). The probability of remaining alive or free of new AIDS-defining events was 0·85 (95% CI 0·73–0·92). Frequency of disease progression was 32·0 (95% CI 16·6–61·5), severe adverse effects 17·8 (7·4–42·7), and genotypic resistance mutations 7·1 (1·8–28·4) per 100 person-years. Mean reported adherence rate was 99%. Median drug concentrations in tablets were 96% of expected values for nevirapine, 89% for stavudine, and 99% for lamivudine. Interpretation Our findings lend support to use and funding of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine as first-line antiretroviral treatment in developing countries.

The objective was to describe contraceptive use in women with HIV infection in France over the past decade. The study included 575 sexually active women of reproductive age who knew the serologic status of their steady partners. It is part of a prospective observational study initiated in 1993 that was designed to investigate the gynecologic status of HIV-infected women. Women answered a standardized questionnaire about contraceptive use and sexual activity at each semiannual visit. Multivariate models were used to investigate parameters associated with the use of contraceptive methods. Contraceptive use was reported in 91% of the visits of women with an HIV-seronegative partner and 69% of women with an HIVseropositive partner (P = 0.0001). Consistent condom use was higher in serodiscordant couples than in seroconcordant couples (odds ratio [OR] = 6.1 95% CI = 0.1–0.2 P < 0.001). The use of oral contraception and intrauterine devices was higher in seroconcordant than in serodiscordant couples (OR = 2.1 95% CI =1.5–2.9 P < 0.001). Among women with an HIV-seronegative partner the use of oral contraception and intrauterine devices decreased after the introduction of highly active antiretroviral therapy in 1998 (P = 0.02) and was higher in couples with inconsistent condom use (OR = 2.0 95% CI = 1.3– 3.3). These data emphasize that contraception counseling should include a discussion on reproductive issues as well as transmission of HIV and other sexually transmitted infections taking into account the partner’s serostatus. (authors)

The characteristics and functions of CD4+CD25+ regulatory cells have been well defined in murine and human systems. However, the interaction between CD4+CD25+ T cells and dendritic cells (DC) remains unclear. In this study, we examined the effect of human CD4+CD25+ T cells on maturation and function of monocyte-derived DC. We show that regulatory T cells render the DC inefficient as APCs despite prestimulation with CD40 ligand. This effect was marginally reverted by neutralizing Abs to TGF-β. There was an increased IL-10 secretion and reduced expression of costimulatory molecules in DC. Thus, in addition to direct suppressor effect on CD4+ T cells, regulatory T cells may modulate the immune response through DC.

Natural polyreactive IgM autoantibodies, encoded by unmutated germline Ig V genes, represent a major fraction of the normal circulating IgM repertoire. We have previously shown that therapeutic preparation of pooled IgM exerts immunomodulatory effects as assessed by in vitro and in vivo studies. Here, we show that the IgM preparation induces cell death in lymphoblastoid cell lines and in human peripheral blood mononuclear cells. The IgM-induced cell death involved classical features of apoptosis such as nuclear fragmentation and activation of caspases. Treatment of leukemic cells with IgM resulted in the cleavage of poly-(A)DP ribose polymerase, a substrate of caspase, and in a reduction in mitochondrial transmembrane potential during the early period of apoptosis induction. Natural IgM-induced apoptosis was inhibited by soluble Fas molecules and affinity-purified Fas antibodies from pooled IgM preparation induced apoptosis in lymphoblastoid cells, suggesting the involvement of the Fas receptor. Our results suggest a role for normal IgM in controlling cell death and proliferation, and imply a possible therapeutic role for IgM in autoimmune and lymphoproliferative disorders.

Background: The impact of highly active antiretroviral therapy (HAART) on the natural history of HPV infection and anal squamous intraepithelial lesions (SIL) in HIV-infected men who have sex with men (MSM) is poorly documented. Goal: The goal of this study was to evaluate the prevalence of anal HPV infection and SIL inpatients under HAART. Study Design: Forty-five HIV-infected protease inhibitor-experienced MSM were enrolled in a cross-sectional study. Each patient provided anal samples for anal cytology, histology, and human papillomavirus (HPV) DNA testing. Results: The patients had previously received HAART for a median of 32 months. Anal cytology was abnormal in 32 of 45 (71%) patients, including high-grade SIL in 10 patients (22%), low-grade SIL in 19 patients (42%), and atypical squamous cells of undetermined significance in 3 patients (7%). HPV DNA was detected 36/45 men (80%). The prevalence of anal SIL and HPV infection were similar in patients exhibiting a significant increase in CD4+ cell count after HAART initiation compared with those who did not. Conclusion: Our results demonstrate a high prevalence of anal SIL, including high-grade SIL, and anal HPV infection in HIV-infected MSM despite immune restoration under HAART.

Human papillomavirus (HPV) infections play an important role in the pathogenesis of anogenital cancer and its precursors. HIV-infected individuals exhibit a high prevalence of HPV DNA. Several studies have further shown that HIV-infected individuals have an increased prevalence of squamous intraepithelial lesions (SIL) of the cervix, vulva and anus. The incidence of invasive cervical cancer is also elevated in HIV-positive women as well as that of anal cancer in HIV-positive women and men. Given the relationship between HIV-induced immunosuppression and HPV-associated disease, treatment with highly active antiretroviral therapy (HAART) has the potential, through immune reconstitution of the host, to alter the natural history of HPV infection and SIL. However, data on the impact of HAART on HPV disease are sparse and mixed results have been reported.

Objective Alterations in the function of dendritic cells (DCs) may explain the systemic autoimmune responses that characterize systemic lupus erythematosus (SLE). Even though several reports have documented the beneficial effect of intravenous immunoglobulin (IVIG) in SLE, the underlying mechanisms of action remain poorly understood. Considering the effect of serum factors, including interferon-α (IFNα), on the activity of DCs, we investigated the effects of IVIG on the differentiation of DCs mediated by serum from SLE patients. Methods DCs were differentiated from peripheral blood monocytes obtained from SLE patients and from healthy blood donors, in the presence of SLE serum. IVIG was used at a concentration of 0.15 mM. A functional assay was performed to assess the inhibitory effect of IVIG on the uptake of nucleosomes by DCs. Results IVIG interfered with the differentiation of DCs from SLE patients and healthy donors cultured in the presence of SLE serum. Treatment of DCs with IVIG inhibited the ingestion of nucleosomes by immature DCs, by up to 36%. Conclusion The present findings indicate that IVIG, by down-regulating the IFNα-mediated differentiation of DCs and by inhibiting uptake of nucleosomes, may exert an essential immunoregulatory effect in SLE patients at the onset of the immune response, at the DC level. Given the critical role of HLA molecules and the costimulatory signals delivered by CD80 and CD86 in optimal antigen presentation and T cell activation, inhibition of expression of HLA and CD80/CD86 on DCs by IVIG offers a plausible explanation for the efficacy of IVIG in SLE and other immune-mediated inflammatory conditions.

Intravenous immunoglobulins (IVIg) exert a broad range of immunoregularoty functions that provide a basis for the beneficial effects of IVIg in autoimmune and systemic inflammatory disorders. This review focuses on the effects f IVIg on humoral and cellular inmmunity that may be of relevance for the treatment of inflammatory neurological diseases.

Objective: To evaluate the feasibility and the relevance of the implementation of an alternative technique to flow cytometry (FC) for enumerating CD4 T cells (Dynabeads; Dynal Biotech Oslo Norway) based on quantifying CD4 T cells by epifluorescent microscopy following their isolation using anti-CD4 monoclonal antibody-coated magnetic beads. Design: International multi-center study. Five consecutive runs of dual CD4 T-lymphocyte enumeration by both techniques in six sites in five countries of West Africa. Methods: A total of 657 pairs of values of CD4 cell counts were generated by 43 technicians by both FC (TruCount; Becton Dickinson Immunocytometry Systems San Jose California USA) and Dynabeads from blood samples obtained from 301 HIVinfected patients seen in one (n = 112) two (n = 61) three (n = 75) four (n = 40) or five (n = 13) occasions. Results: The correlation coefficient between the results of the two techniques was 0.89. The overall systematic difference between Dynabeads and FC was -16 x 10(6) cells/l (P < 10(-4)). The median difference was insignificant (+7.5 cells) for CD4 cell counts below 200 x 10(6) cells/l and increased with CD4 levels. Patients were consistently classified at the threshold of 200 x 10(6) cells/l by both methods in 88.7% of cases. Among the 74 discrepant pairs of values only 31 (4.7%) exhibited a difference of more than 100 x 10(6) cells/l. Conclusions: Results from Dynabeads and FC were highly correlated. The ability of the alternative method to consistently classify results in agreement with FC at thresholds of CD4 cell counts relevant for clinical care was high. The implementation of this low-cost method was easy and successful in the West African context. (authors)

In patients with clinical symptoms of coronary atherosclerosis, T cells are activated and directed to autologous proteins contained in the active plaques, suggesting that autoimmune responses may play a role in atherosclerosis progression. Organ-specific autoimmune diseases are sometimes accompanied by broad alterations of serum autoreactive antibody repertoires. We thus investigated antibody repertoires at a global level, using a technique of immunoblotting that allows for the quantitative screening of antibody reactivities in complex antibody mixtures toward a large panel of antigens derived from homologous tissue extracts, followed by multiparametric statistical analysis of the data. We analyzed the autoreactive IgG repertoire in 20 patients with documented coronary atherosclerosis and in 20 matched healthy controls. Total proteins from atherosclerotic carotid specimens and normal arterial tissues (target organs) and from kidney, liver, and stomach (non-target control organs) were used as panels of antigens. Patients had a significantly perturbed antibody repertoire and an enhanced autoreactivity of IgG to target and non-target organs, as compared with controls. Reactivity of purified IgG to plaque and normal artery proteins was greater in patients, but reactivity of IgG in the whole serum toward normal arterial tissue was lower than in controls; this suggests that, in patients, autoreactivity toward normal arteries is regulated by serum factors. Our data indicate that atherosclerotic patients develop a perturbed humoral immune response directed toward arterial proteins, which impacts on the overall autoreactive repertoire. These findings further substantiate that autoimmune processes take place in atherosclerosis and most likely influence disease progression.