Development of a clinical scoring system for assessment of immunosuppression in patients with tuberculosis and HIV infection without access to CD4 cell testing--results from a cross-sectional study in Ethiopia.

Background: Currently, antiretroviral therapy (ART) is recommended for all HIV-positive patients with tuberculosis (TB). The timing of ART during the course of anti-TB treatment is based on CD4 cell counts. Access to CD4 cell testing is not universally available; this constitutes an obstacle for the provision of ART in low-income countries.

Chronic hepatitis C in Swedish subjects receiving opiate substitution therapy--factors associated with advanced fibrosis.

Background: Opiate substitution therapy (OST) reduces the risk of death from directly drug-related causes in heroin users, allowing other chronic health problems to emerge. People who inject drugs (PWID) are exposed to hepatitis C virus (HCV), with an associated risk of chronic liver disease. We investigated HCV prevalence and liver-related morbidity in a cohort of OST recipients, and analyzed factors associated with significant hepatic fibrosis.

Structural insights on the role of antibodies in HIV-1 vaccine and therapy.

Despite 30 years of effort, there is no effective vaccine for HIV-1. However, antibodies can prevent HIV-1 infection in humanized mice and macaques when passively transferred. New single-cell-based methods have uncovered many broad and potent donor-derived antibodies, and structural studies have revealed the molecular bases for their activities.

Electron tomography of HIV-1 infection in gut-associated lymphoid tissue.

Critical aspects of HIV-1 infection occur in mucosal tissues, particularly in the gut, which contains large numbers of HIV-1 target cells that are depleted early in infection. We used electron tomography (ET) to image HIV-1 in gut-associated lymphoid tissue (GALT) of HIV-1-infected humanized mice, the first three-dimensional ultrastructural examination of HIV-1 infection in vivo. Human immune cells were successfully engrafted in the mice, and following infection with HIV-1, human T cells were reduced in GALT.

Intensified tuberculosis case-finding in HIV-positive adults managed at Ethiopian health centers: diagnostic yield of Xpert MTB/RIF compared with smear microscopy and liquid culture.

Background: Detection of active tuberculosis (TB) before antiretroviral therapy (ART) initiation is important, but optimal diagnostic methods for use in resource-limited settings are lacking. We assessed the prevalence of TB, evaluated the diagnostic yield of Xpert MTB/RIF in comparison with smear microscopy and culture, and the impact of Xpert results on clinical management in HIV-positive adults eligible for ART at health centers in a region of Ethiopia.

Methods: Participants were prospectively recruited and followed up at 5 health centers.

Development of macrolide resistance in Mycoplasma pneumoniae-infected Swedish patients treated with macrolides.

Background: The proportion of Mycoplasma pneumoniae isolates carrying point mutations in the 23S region of the genome associated with macrolide resistance has increased. We evaluated the probability of developing M. pneumoniae macrolide resistance mutations during macrolide treatment.

CD4 cell levels during treatment for tuberculosis (TB) in Ethiopian adults and clinical markers associated with CD4 lymphocytopenia.

Background: The clinical correlations and significance of subnormal CD4 levels in HIV-negative patients with TB are unclear. We have determined CD4 cell levels longitudinally during anti-tuberculosis treatment (ATT) in patients, with and without HIV co-infection, and their associations with clinical variables.

Method: Adults diagnosed with TB (maximum duration of ATT for 2 weeks, and with no history of antiretroviral therapy (ART) in HIV-positive subjects) were included consecutively in eight out-patient clinics in Ethiopia.

Structural basis for enhanced HIV-1 neutralization by a dimeric immunoglobulin G form of the glycan-recognizing antibody 2G12.

The human immunoglobulin G (IgG) 2G12 recognizes high-mannose carbohydrates on the HIV type 1 (HIV-1) envelope glycoprotein gp120. Its two antigen-binding fragments (Fabs) are intramolecularly domain exchanged, resulting in a rigid (Fab)2 unit including a third antigen-binding interface not found in antibodies with flexible Fab arms. We determined crystal structures of dimeric 2G12 IgG created by intermolecular domain exchange, which exhibits increased breadth and >50-fold increased neutralization potency compared with monomeric 2G12.

Decentralised paediatric HIV care in Ethiopia: a comparison between outcomes of patients managed in health centres and in a hospital clinic.

Background: In order to increase access to antiretroviral therapy (ART) in HIV-infected children, paediatric HIV care has been introduced in health centres in Ethiopia, where patients are managed by health professionals with limited training.

Objective: To compare outcomes of paediatric HIV care in hospital and health centre clinics and to determine risk factors for death and loss to follow-up (LTFU).

Design: Retrospective comparison of patient characteristics and outcomes among children managed in a public hospital and all five public health centres in the uptake area.

HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice.

Effective control of HIV-1 infection in humans is achieved using combinations of antiretroviral therapy (ART) drugs. In humanized mice (hu-mice), control of viremia can be achieved using either ART or by immunotherapy using combinations of broadly neutralizing antibodies (bNAbs). Here we show that treatment of HIV-1-infected hu-mice with a combination of three highly potent bNAbs not only resulted in complete viremic control but also led to a reduction in cell-associated HIV-1 DNA.

Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues.

Advances in single-cell antibody cloning methods have led to the identification of a variety of broadly neutralizing anti-HIV-1 antibodies. We developed a computational tool (Antibody Database) to help identify critical residues on the HIV-1 envelope protein whose natural variation affects antibody activity. Our simplifying assumption was that, for a given antibody, a significant portion of the dispersion of neutralization activity across a panel of HIV-1 strains is due to the amino acid identity or glycosylation state at a small number of specific sites, each acting independently.

Restricting HIV-1 pathways for escape using rationally designed anti-HIV-1 antibodies.

Recently identified broadly neutralizing antibodies (bNAbs) that potently neutralize most HIV-1 strains are key to potential antibody-based therapeutic approaches to combat HIV/AIDS in the absence of an effective vaccine. Increasing bNAb potencies and resistance to common routes of HIV-1 escape through mutation would facilitate their use as therapeutics. We previously used structure-based design to create the bNAb NIH45-46(G54W), which exhibits superior potency and/or breadth compared with other bNAbs.

Phenotypic properties of transmitted founder HIV-1.

Defining the virus-host interactions responsible for HIV-1 transmission, including the phenotypic requirements of viruses capable of establishing de novo infections, could be important for AIDS vaccine development. Previous analyses have failed to identify phenotypic properties other than chemokine receptor 5 (CCR5) and CD4+ T-cell tropism that are preferentially associated with viral transmission. However, most of these studies were limited to examining envelope (Env) function in the context of pseudoviruses.

Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization.

Broadly neutralizing antibodies (bNAbs) to HIV-1 can prevent infection and are therefore of great importance for HIV-1 vaccine design. Notably, bNAbs are highly somatically mutated and generated by a fraction of HIV-1-infected individuals several years after infection. Antibodies typically accumulate mutations in the complementarity determining region (CDR) loops, which usually contact the antigen.

Structural basis for HIV-1 gp120 recognition by a germ-line version of a broadly neutralizing antibody.

Efforts to design an effective antibody-based vaccine against HIV-1 would benefit from understanding how germ-line B-cell receptors (BCRs) recognize the HIV-1 gp120/gp41 envelope spike. Potent VRC01-like (PVL) HIV-1 antibodies derived from the VH1-2*02 germ-line allele target the conserved CD4 binding site on gp120. A bottleneck for design of immunogens capable of eliciting PVL antibodies is that VH1-2*02 germ-line BCR interactions with gp120 are uncharacterized.

Dynamic tailoring of treatment durations improves efficiency of hepatitis C treatment with pegylated interferon and ribavirin.

The treatment durations for hepatitis C are guided by the analysis of hepatitis C virus (HCV) RNA in blood at certain time points. This multicentre, randomized open label trial evaluated the utility and performance of individualized treatment durations guided by viral decline rates in 103 patients with HCV genotype 1 infection. Pegylated interferon 2a and ribavirin were given as standard of care (SOC) for 24, 48 or 72 weeks or as dynamic treatment (DT) for 24-72 weeks.

Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies.

Broadly neutralizing HIV antibodies (bNAbs) can recognize carbohydrate-dependent epitopes on gp120. In contrast to previously characterized glycan-dependent bNAbs that recognize high-mannose N-glycans, PGT121 binds complex-type N-glycans in glycan microarrays. We isolated the B-cell clone encoding PGT121, which segregates into PGT121-like and 10-1074-like groups distinguished by sequence, binding affinity, carbohydrate recognition, and neutralizing activity.

HIV therapy by a combination of broadly neutralizing antibodies in humanized mice.

Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design.

A mouse model for HIV-1 entry.

Passive transfer of neutralizing antibodies against HIV-1 can prevent infection in macaques and seems to delay HIV-1 rebound in humans. Anti-HIV antibodies are therefore of great interest for vaccine design. However, the basis for their in vivo activity has been difficult to evaluate systematically because of a paucity of small animal models for HIV infection.

Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120.

A large number of anti-HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined.

Electron tomography of late stages of FcRn-mediated antibody transcytosis in neonatal rat small intestine.

The neonatal Fc receptor (FcRn) transports maternal immunoglobulin (IgG) across epithelia to confer passive immunity to mammalian young. In newborn rodents, FcRn transcytoses IgG from ingested milk across the intestinal epithelium for release into the bloodstream. We used electron tomography to examine FcRn transport of Nanogold-labeled Fc (Au-Fc) in neonatal rat jejunum, focusing on later aspects of transport by chasing Au-Fc before fixation.

Low prevalence of transmitted drug resistance in patients newly diagnosed with HIV-1 infection in Sweden 2003-2010.

Transmitted drug resistance (TDR) is a clinical and epidemiological problem because it may contribute to failure of antiretroviral treatment. The prevalence of TDR varies geographically, and its prevalence in Sweden during the last decade has not been reported. Plasma samples from 1,463 patients newly diagnosed with HIV-1 infection between 2003 and 2010, representing 44% of all patients diagnosed in Sweden during this period, were analyzed using the WHO 2009 list of mutations for surveillance of TDR.

The risk of cancer among persons with a history of injecting drug use in Sweden - a cohort study based on participants in a needle exchange program.

Background: Injecting drug use (IDU) may lead to exposure to a range of carcinogenic agents. We investigated the risk and distribution of cancers among individuals with a history of IDU in Sweden.

Material And Methods: The cancer incidence in a cohort of longitudinally followed participants in a needle exchange program (NEP), recruited between 1987 and 2007, was compared to that in the Swedish general population, matching for age group and gender.

Frequent detection of respiratory agents by multiplex PCR on oropharyngeal samples in Swedish school-attending adolescents.

Background: Respiratory agents may be detected in the oropharynx of healthy individuals. The extent of this condition and the reasons behind it are largely unknown. The objective of this study was to determine the factors associated with the presence of respiratory agents in the oropharynx of adolescents healthy enough to attend school activities.

Intracellular neutralization of viral infection in polarized epithelial cells by neonatal Fc receptor (FcRn)-mediated IgG transport.

IgG was traditionally thought to neutralize virions by blocking their attachment to or penetration into mucosal epithelial cells, a common site of exposure to viruses. However, we describe an intracellular neutralizing action for an influenza hemagglutinin-specific monoclonal antibody, Y8-10C2 (Y8), which has neutralizing activity only at an acidic pH. When Y8 was applied to the basolateral surface of Madin-Darby canine kidney cells expressing the rat neonatal Fc receptor for IgG (FcRn), it significantly reduced viral replication following apical exposure of the cell monolayer to influenza virus.