HIV
not annotated - annotated - LINNAEUS only
20962079
Blood myeloid dendritic cells from HIV-1-infected individuals display a proapoptotic profile characterized by decreased Bcl-2 levels and by caspase-3+ frequencies that are associated with levels of plasma viremia and T cell activation in an exploratory study.
Reduced frequencies of myeloid and plasmacytoid dendritic cell (DC) subsets (mDCs and pDCs, respectively) have been observed in the peripheral blood of HIV-1-infected individuals throughout the course of disease. Accumulation of DCs in lymph nodes (LNs) may partly account for the decreased numbers observed in blood, but increased DC death may also be a contributing factor. We used multiparameter flow cytometry to evaluate pro- and antiapoptotic markers in blood mDCs and pDCs from untreated HIV-1-infected donors, from a subset of infected donors before and after receiving antiretroviral therapy (ART), and from uninfected control donors. Blood mDCs, but not pDCs, from untreated HIV-1-infected donors expressed lower levels of antiapoptotic Bcl-2 than DCs from uninfected donors. A subset of HIV-1-infected donors had elevated frequencies of proapoptotic caspase-3(+) blood mDCs, and positive correlations were observed between caspase-3(+) mDC frequencies and plasma viral load and CD8(+) T-cell activation levels. Caspase-3(+) mDC frequencies, but not mDC Bcl-2 expression, were reduced with viral suppression on ART. Apoptosis markers on DCs in blood and LN samples from a cohort of untreated, HIV-1-infected donors with chronic disease were also evaluated. LN mDCs displayed higher levels of Bcl-2 and lower caspase-3(+) frequencies than did matched blood mDCs. Conversely, LN pDCs expressed lower Bcl-2 levels than their blood counterparts. In summary, blood mDCs from untreated HIV-1-infected subjects displayed a proapoptotic profile that was partially reversed with viral suppression, suggesting that DC death may be a factor contributing to blood DC depletion in the setting of chronic, untreated HIV disease.
20962091
Macaque long-term nonprogressors resist superinfection with multiple CD8+ T cell escape variants of simian immunodeficiency virus.
Human immunodeficiency virus (HIV)-positive individuals can be superinfected with different virus strains. Individuals who control an initial HIV infection are therefore still at risk for subsequent infection with divergent viruses, but the barriers to such superinfection remain unclear. Here we tested long-term nonprogressors' (LTNPs') susceptibility to superinfection using Indian rhesus macaques that express the major histocompatibility complex class I (MHC-I) allele Mamu-B 17, which is associated with control of the pathogenic AIDS virus SIVmac239. The Mamu-B 17-restricted CD8(+) T cell repertoire is focused almost entirely on 5 epitopes. We engineered a series of SIVmac239 variants bearing mutations in 3, 4, or all 5 of these epitopes and used them to serially challenge 2 Mamu-B 17-positive LTNPs. None of the escape variants caused breakthrough replication in LTNPs, although they readily infected Mamu-B 17-negative naive macaques. In vitro competing coculture assays and examination of viral evolution in hosts lacking Mamu-B 17 suggested that the mutant viruses had negligible defects in replicative fitness. Both LTNPs maintained robust immune responses, including simian immunodeficiency virus (SIV)-specific CD8(+) and CD4(+) T cells and neutralizing antibodies. Our results suggest that escape mutations in epitopes bound by "protective" MHC-I molecules may not be sufficient to establish superinfection in LTNPs.
20962094
Yeast-elicited cross-reactive antibodies to HIV Env glycans efficiently neutralize virions expressing exclusively high-mannose N-linked glycans.
The HIV envelope (Env) protein uses a dense coat of glycans to mask conserved domains and evade host humoral immune responses. The broadly neutralizing antibody 2G12, which binds a specific cluster of high-mannose glycans on HIV Env, shows that the glycan shield can also serve as a target for neutralizing antibodies. We have described a triple mutant Saccharomyces cerevisiae strain that expresses high-mannose glycoproteins that bind to 2G12. When used to immunize rabbits, this yeast elicits antibodies that bind to gp120-associated glycans but fail to neutralize virus. Here we sought to determine the reason for these discordant results. Affinity purification of sera over columns conjugated with three 2G12-reactive yeast glycoproteins showed that these proteins could adsorb 80% of the antibodies that bind to gp120 glycans. Despite binding to monomeric gp120, these mannose-specific antibodies failed to bind cell surface-expressed trimeric Env. However, when Env was expressed in the presence of the mannosidase inhibitor kifunensine to force retention of high-mannose glycans at all sites, the purified antibodies gained the abilities to bind trimeric Env and to strongly and broadly neutralize viruses produced under these conditions. Combined, these data show that the triple mutant yeast strain elicits antibodies that bind to high-mannose glycans presented on the HIV envelope, but only when they are displayed in a manner not found on native Env trimers. This implies that the underlying structure of the protein scaffold used to present the high-mannose glycans may be critical to allow elicitation of antibodies that recognize trimeric Env and neutralize virus.
20962100
Dynamics of two separate but linked HIV-1 CRF01_AE outbreaks among injection drug users in Stockholm, Sweden, and Helsinki, Finland.
Detailed phylogenetic analyses were performed to characterize an HIV-1 outbreak among injection drug users (IDUs) in Stockholm, Sweden, in 2006. This study investigated the source and dynamics of HIV-1 spread during the outbreak as well as associated demographic and clinical factors. Seventy Swedish IDUs diagnosed during 2004 to 2007 were studied. Demographic, clinical, and laboratory data were collected, and the V3 region of the HIV-1 envelope gene was sequenced to allow detailed phylogenetic analyses. The results showed that the Stockholm outbreak was caused by a CRF01_AE variant imported from Helsinki, Finland, around 2003, which was quiescent until the outbreak started in 2006. Local Swedish subtype B variants continued to spread at a lower rate. The number of new CRF01_AE cases over a rooted phylogenetic tree accurately reflected the transmission dynamics and showed a temporary increase, by a factor of 12, in HIV incidence during the outbreak. Virus levels were similar in CRF01_AE and subtype B infections, arguing against differences in contagiousness. Similarly, there were no major differences in other baseline characteristics. Instead, the outbreak in Stockholm (and Helsinki) was best explained by an introduction of HIV into a standing network of previously uninfected IDUs. The combination of phylogenetics and epidemiological data creates a powerful tool for investigating outbreaks of HIV and other infectious diseases that could improve surveillance and prevention.
20980521
Characterization of cross-reactive CD8+ T-cell recognition of HLA-A2-restricted HIV-Gag (SLYNTVATL) and HCV-NS5b (ALYDVVSKL) epitopes in individuals infected with human immunodeficiency and hepatitis C viruses.
The immunologic mechanisms underlying the faster progression of hepatitis C virus (HCV) disease in the presence of human immunodeficiency virus (HIV) coinfection are not clearly understood. T-cell cross-reactivity between HCV and influenza virus-specific epitopes has been associated with rapid progression of HCV disease (S. Urbani, B. Amadei, P. Fisicaro, M. Pilli, G. Missale, A. Bertoletti, and C. Ferrari, J. Exp. Med. 201:675-680, 2005). We asked whether T-cell cross-reactivity between HCV and HIV could exist during HCV/HIV coinfection and affect pathogenesis. Our search for amino acid sequence homology between the HCV and HIV proteomes revealed two similar HLA-A2-restricted epitopes, HIV-Gag (SLYNTVATL [HIV-SL9]) and HCV-NS5b (ALYDVVSKL [HCV-AL9]). We found that 4 out of 20 HLA-A2-positive (HLA-A2(+)) HIV-infected individuals had CD8(+) T cells that recognized both the HIV-SL9 and HCV-AL9 epitopes. However, the AL9 epitope was generally shown to be a weak agonist. Although HCV-monoinfected individuals in our study did not show AL9-specific responses, we found that about half of HCV/HIV-coinfected individuals had dual responses to both epitopes. High dual T-cell recognition among coinfected subjects was usually due to separate T-cell populations targeting each epitope, as determined by pentamer staining. The one individual demonstrating cross-reactive T cells to both epitopes showed the most advanced degree of liver disease. In coinfected individuals, we observed a positive correlation between the magnitudes of T-cell responses to both the SL9 and the AL9 epitopes, which was also positively associated with the clinical parameter of liver damage. Thus, we find that HIV infection induces T cells that can cross-react to heterologous viruses or prime for T cells that are closely related in sequence. However, the induction of cross-reactive T cells may not be associated with control of disease caused by the heterologous virus. This demonstrates that degeneracy of HIV-specific T cells may play a role in the immunopathology of HCV/HIV coinfection.
20980524
Association of TRIM22 with the type 1 interferon response and viral control during primary HIV-1 infection.
Type 1 interferons (IFNs) induce the expression of the tripartite interaction motif (TRIM) family of E3 ligases, but the contribution of these antiviral factors to HIV pathogenesis is not completely understood. We hypothesized that the increased expression of select type 1 IFN and TRIM isoforms is associated with a significantly lower likelihood of HIV-1 acquisition and viral control during primary HIV-1 infection. We measured IFN-alpha, IFN-Beta, myxovirus resistance protein A (MxA), human TRIM5alpha (huTRIM5alpha), and TRIM22 mRNA levels in peripheral blood mononuclear cells (PBMCs) of high-risk, HIV-1-uninfected participants and HIV-1-positive study participants. Samples were available for 32 uninfected subjects and 28 infected persons, all within 1 year of infection. HIV-1-positive participants had higher levels of IFN-Beta (P = 0.0005), MxA (P = 0.007), and TRIM22 (P = 0.01) and lower levels of huTRIM5alpha (P < 0.001) than did HIV-1-negative participants. TRIM22 but not huTRIM5alpha correlated positively with type 1 IFN (IFN-alpha, IFN-Beta, and MxA) (all P < 0.0001). In a multivariate model, increased MxA expression showed a significant positive association with viral load (P = 0.0418). Furthermore, TRIM22 but not huTRIM5alpha, IFN-alpha, IFN-Beta, or MxA showed a negative correlation with plasma viral load (P = 0.0307) and a positive correlation with CD4(+) T-cell counts (P = 0.0281). In vitro studies revealed that HIV infection induced TRIM22 expression in PBMCs obtained from HIV-negative donors. Stable TRIM22 knockdown resulted in increased HIV-1 particle release and replication in Jurkat reporter cells. Collectively, these data suggest concordance between type 1 IFN and TRIM22 but not huTRIM5alpha expression in PBMCs and that TRIM22 likely acts as an antiviral effector in vivo.
21034776
A versatile vector for the production of pseudotyped viruses expressing gp120 antigens from different clades of primary HIV-1 isolates.
A novel HIV-1 Env expression vector (SF162-Z) was developed by introducing two new cloning sites on the backbone of an existing vector that produces a full length Env from HIV-1 SF162 isolate. These sites facilitate the swapping of the gp120 portion of the SF162 Env with matching gp120 antigens from HIV-1 isolates of different genetic clades. Final production of functional pseudotyped viruses will express chimeric Env antigens, including gp41 of the parental SF162 and gp120 from other primary isolates. This system is useful for testing the neutralizing sensitivity of partial env gene products frequently identified in viral quasi species in patients infected with HIV or when only partial gp120 gene products are available.
21272794
Emerging opportunistic yeast infections.
A growing population of immunosuppressed patients has resulted in increasingly frequent diagnoses of invasive fungal infections, including those caused by unusual yeasts. The incidence of non-albicans species of Candida is increasing compared with that of Candida albicans, and several species, such as Candida glabrata and Candida krusei, may be resistant to azole antifungal therapy. Trichosporon species are the second most common cause of fungaemia in patients with haematological malignant disease and are characterised by resistance to amphotericin and echinocandins and poor prognosis. Rhodotorula species belong to the family Cryptococcaceae, and are a cause of catheter-related fungaemia, sepsis, and invasive disease in severely immunosuppressed patients. An increasing number of sporadic cases of invasive fungal infections by non-neoformans cryptococci have been reported in immunocompromised hosts, especially for patients with advanced HIV infection or cancer who are undergoing transplant. Other uncommon yeasts that can cause invasive disease in severely immunosuppressed patients include Geotrichum, Hansenula, Malassezia, and Saccharomyces. Host immune status is a crucial determinant of the type of invasive fungal infection a patient is at risk for. Diagnosis can be challenging and relies heavily on traditional cultures of blood and other sterile sites, although serum (1,3)-Beta-D-glucan testing might have an adjunctive role. Although rare yeasts are emerging as opportunistic human pathogens, diagnosis remains challenging and treatment suboptimal.
21371656
Seasonal influenza epidemiology in sub-Saharan Africa: a systematic review.
Acute respiratory infection (ARI) is a leading cause of mortality worldwide, of which influenza is an important cause that can be prevented with vaccination. We did a systematic review of research published from 1980 to 2009 on seasonal influenza epidemiology in sub-Saharan Africa to identify data strengths and weaknesses that might affect policy decisions, to assess the state of knowledge on influenza disease burden, and to ascertain unique features of influenza epidemiology in the region. We assessed 1203 papers, reviewed 104, and included 49 articles. 1-25% of outpatient ARI visits were caused by influenza (11 studies; mean 9*5%; median 10%), whereas 0*6-15*6% of children admitted to hospital for ARI had influenza identified (15 studies; mean 6*6%; median 6*3%). Influenza was highly seasonal in southern Africa. Other data were often absent, particularly direct measurement of influenza incidence rates for all ages, within different patient settings (outpatient, inpatient, community), and for all countries. Data from sub-Saharan Africa are insufficient to allow most countries to prioritise strategies for influenza prevention and control. Key data gaps include incidence and case-fatality ratios for all ages, the contribution of influenza towards admission of adults to hospital for ARI, representative seasonality data, economic burden, and the interaction of influenza with prevalent disorders in Africa, such as malaria, HIV, and malnutrition.
21429803
European guidelines on the clinical management of HIV-1 tropism testing.
Viral tropism is the ability of viruses to enter and infect specific host cells and is based on the ability of viruses to bind to receptors on those cells. Testing for HIV tropism is recommended before prescribing a chemokine receptor blocker. In most European countries, HIV tropism is identified with tropism phenotype testing. New data support genotype analysis of the HIV third hypervariable loop (V3) for the identification of tropism. The European Consensus Group on clinical management of tropism testing was established to make recommendations to clinicians and clinical virologists. The panel recommends HIV-tropism testing for the following groups: drug-naive patients in whom toxic effects are anticipated or for whom few treatment options are available; patients who have poor tolerability to or toxic effects from current treatment or who have CNS pathology; and patients for whom therapy has failed and a change in treatment is considered. In general, an enhanced sensitivity Trofile assay and V3 population genotyping are the recommended methods. Genotypic methods are anticipated to be used more frequently in the clinical setting because of their greater accessibility, lower cost, and faster turnaround time than other methods. For the interpretation of V3 loop genotyping, clinically validated systems should be used when possible. Laboratories doing HIV tropism tests should have adequate quality assurance measures. Similarly, close collaboration between HIV clinicians and virologists is needed to ensure adequate diagnostic and treatment decisions.
20980508
Norovirus GII.4 strain antigenic variation.
Noroviruses are the principal cause of epidemic gastroenteritis worldwide. Multiple reports have concluded that the major capsid proteins of GII.4 strains, which cause 80% of norovirus infections worldwide, are evolving rapidly, resulting in new epidemic strains. Surrogate neutralization assays using sera from outbreaks and from immunized mice suggest that, as with influenza virus, antigenic variation maintains GII.4 persistence in the face of human population herd immunity. To test this hypothesis, mice were hyperimmunized with virus-like particles (VLPs) representing an early (GII.4-1987) and a contemporary (GII.4-2006) GII.4 strain. Anti-GII.4-1987 IgG monoclonal antibodies (MAbs) strongly reacted with GII.4 VLPs derived between only 1987 and 2002. Ligand binding blockade was more efficient with GII.4-1987 and GII.4-1997 VLPs than with GII.4-2002. Anti-GII.4-2006 IgG MAbs recognized either a broad panel of GII.4 VLPs (1987 to 2006) or a subset of contemporary (2004 to 2006) VLPs. Most 2006 antibodies did not recognize or only poorly recognized GII.4 VLPs of 2007 or 2008, documenting rapid antigenic evolution of GII.4 capsids. Generally, 2006 MAbs blocked homotypic VLP-ligand binding but were unable to block VLPs representing strains primarily circulating during or earlier than 2002. These analyses demonstrate that both subtle and significant evolutionary change has occurred within antibody epitopes between epidemic strains, providing direct evidence that the GII.4 noroviruses are undergoing antigenic variation, likely in response to herd immunity. As with influenza virus, HIV, and hepatitis C virus, norovirus antigenic variation will significantly influence the design of efficacious vaccines and immunotherapeutics against these important human pathogens.
21126914
Tracking a century of global expansion and evolution of HIV to drive understanding and to combat disease.
Since the isolation of HIV, multiple transmissions are thought to have occurred between man and other old-world primates. Assessment of samples from apes and human beings with African equatorial forest ancestry has traced the origin of HIV-1 to chimpanzees, and dated its most recent common ancestor to 1908. The evolution of HIV-1 has been rapid, which has resulted in a complex classification, worldwide spread, and intermixing of strains; at least 48 circulating recombinant forms are currently identified. In addition to posing a nearly insurmountable challenge for diagnosis, treatment, vaccine development, and prevention, this extreme and divergent evolution has led to differences in virulence between HIV-1 groups, subtypes, or both. Coincidental changes in human migration in the Congo river basin also affected spread of disease. Research over the past 25 years and advances in genomic sequencing methods, such as deep DNA sequencing, have greatly improved understanding and analysis of the thousands to millions of full infectious HIV-1 genomes.
21227500
Continuing challenge of infectious diseases in India.
In India, the range and burden of infectious diseases are enormous. The administrative responsibilities of the health system are shared between the central (federal) and state governments. Control of diseases and outbreaks is the responsibility of the central Ministry of Health, which lacks a formal public health department for this purpose. Tuberculosis, malaria, filariasis, visceral leishmaniasis, leprosy, HIV infection, and childhood cluster of vaccine-preventable diseases are given priority for control through centrally managed vertical programmes. Control of HIV infection and leprosy, but not of tuberculosis, seems to be on track. Early success of malaria control was not sustained, and visceral leishmaniasis prevalence has increased. Inadequate containment of the vector has resulted in recurrent outbreaks of dengue fever and re-emergence of Chikungunya virus disease and typhus fever. Other infectious diseases caused by faecally transmitted pathogens (enteric fevers, cholera, hepatitis Ahepatitis A and E viruses) and zoonoses (rabies, leptospirosis, anthrax) are not in the process of being systematically controlled. Big gaps in the surveillance and response system for infectious diseases need to be addressed. Replication of the model of vertical single-disease control for all infectious diseases will not be efficient or viable. India needs to rethink and revise its health policy to broaden the agenda of disease control. A comprehensive review and redesign of the health system is needed urgently to ensure equity and quality in health care. We recommend the creation of a functional public health infrastructure that is shared between central and state governments, with professional leadership and a formally trained public health cadre of personnel who manage an integrated control mechanism of diseases in districts that includes infectious and non-infectious diseases, and injuries.
21420161
Tuberculosis.
Tuberculosis results in an estimated 1*7 million deaths each year and the worldwide number of new cases (more than 9 million) is higher than at any other time in history. 22 low-income and middle-income countries account for more than 80% of the active cases in the world. Due to the devastating effect of HIV on susceptibility to tuberculosis, sub-Saharan Africa has been disproportionately affected and accounts for four of every five cases of HIV-associated tuberculosis. In many regions highly endemic for tuberculosis, diagnosis continues to rely on century-old sputum microscopy; there is no vaccine with adequate effectiveness and tuberculosis treatment regimens are protracted and have a risk of toxic effects. Increasing rates of drug-resistant tuberculosis in eastern Europe, Asia, and sub-Saharan Africa now threaten to undermine the gains made by worldwide tuberculosis control programmes. Moreover, our fundamental understanding of the pathogenesis of this disease is inadequate. However, increased investment has allowed basic science and translational and applied research to produce new data, leading to promising progress in the development of improved tuberculosis diagnostics, biomarkers of disease activity, drugs, and vaccines. The growing scientific momentum must be accompanied by much greater investment and political commitment to meet this huge persisting challenge to public health. Our Seminar presents current perspectives on the scale of the epidemic, the pathogen and the host response, present and emerging methods for disease control (including diagnostics, drugs, biomarkers, and vaccines), and the ongoing challenge of tuberculosis control in adults in the 21st century.
21459211
Increasing burden of liver disease in patients with HIV infection.
Introduction of effective combined antiretroviral therapy has made HIV infection a chronic illness. Substantial reductions in the number of AIDS-related deaths have been accompanied by an increase in liver-related morbidity and mortality due to co-infection with chronic hepatitis B and C viruses. Increases in non-alcoholic fatty liver disease and drug-induced hepatotoxicity, together with development of hepatocellular carcinoma, also potentiate the burden of liver disease in individuals with HIV infection. We provide an overview of the key causes, disease mechanisms of pathogenesis, and recommendations for treatment options including the evolving role of liver transplantation.
20980513
R5 HIV env and vesicular stomatitis virus G protein cooperate to mediate fusion to naive CD4+ T Cells.
Naive CD4(4) T cells are resistant to both HIV R5 env and vesicular stomatitis virus G protein (VSV-G)-mediated fusion. However, viral particles carrying both HIV R5 env and VSV-G infect naive cells by an unexplained mechanism. We show that VSV-G-pseudotyped virus cannot fuse to unstimulated cells because the viral particles cannot be endocytosed. However, virions carrying both HIV R5 env and VSV-G can fuse because CD4 binding allows viral uptake. Our findings reveal a unique mechanism by which R5 HIV env and VSV-G cooperate to allow entry to naive CD4(+) T cells, providing a tool to target naive CD4(+) T cells with R5 HIV to study HIV coreceptor signaling and latency.