The Quest for an AIDS Vaccine

More than fifty thousand cases of AIDS have been reported in the United States since the disease wasfirst described in 1981. Many times this number of people are infected with human immunodeficiency virus (HIV), which has been identified as the agent responsible for the illness. The seriousness of the disease, coupled with the relatively rapid spread of HIV, has fueled the effort for development of an effective vaccine. Much is now known about the life cycle of the virus, and about its structural components. This information, and information about methods of transmission of the virus, form the basis for a rational vaccine development program. A successful program depends both on technological advances and on the political will to create a climate in which interpretable vaccine trials can be undertaken. This review will focus on some of the impediments to rapid development and licensure of an AIDS vaccine

The Evolution of Mentorship Capacity Development in Low- and Middle-Income Countries: Case Studies from Peru, Kenya, India, and Mozambique.

Following the Fogarty International Center-supported "Mentoring the Mentors" workshops in South America, Africa, and Asia, approaches and guidelines for mentorship at institutions within these low- and middle-income country (LMIC) contexts, appropriate for the respective regional resources and culture, were implemented. Through the presentation of case studies from these three geographic regions, this article illustrates the institutional mentorship infrastructure before the workshop and the identified gaps used to implement strategies to build mentorship capacity at the Universidad Peruana Cayetano Heredia (Peru), Kenya Medical Research Institute (Kenya), Saint John's Research Institute (India), and Eduardo Mondlane University (Mozambique). These case studies illustrate three findings: first, that mentorship programs in LMICs have made uneven progress, and institutions with existing programs have exhibited greater advancement to their mentoring capacity than institutions without formal programs before the workshops. Second, mentoring needs assessments help garner the support of institutional leadership and create local ownership. Third, developing a culture of mentorship that includes group mentoring activities at LMIC institutions can help overcome the shortage of trained mentors. Regardless of the stage of mentoring programs, LMIC institutions can work toward developing sustainable, culturally effective mentorship models that further the partnership of early career scientists and global health

Predictors of Acute Liver Failure in Patients With Acute Hepatitis A: An Analysis of the 2016-2018 San Diego County Hepatitis A Outbreak.

Background:Between 2016 and 2018, San Diego County experienced a hepatitis A outbreak with a historically high mortality rate (3.4%) that highlighted the need for early recognition of those at risk of developing acute liver failure (ALF). Methods:A retrospective case series of adult hospitalized patients with acute hepatitis A. Results:One hundred six patients with hepatitis A were studied, of whom 11 (10.4%) developed ALF, of whom 7 (6.6%) died. A history of alcohol abuse, hyperbilirubinemia, hypoalbuminemia, hyponatremia, and anemia were associated with increased odds of developing ALF. Initial Maddrey's and Model of End-Stage Liver Disease Sodium (MELD-Na) scores were also associated with the development of ALF. Multivariable analysis showed that a higher initial MELD-Na score (odds ratio [OR], 1.205; 95% confidence interval [CI], 1.018-1.427) and a lower initial serum albumin concentration (OR, 9.35; 95% CI, 1.15-76.9) were associated with increased odds of developing ALF. Combining serum albumin and MELD-Na (SAM; C-statistic, 0.8878; 95% CI, 0.756-0.988) yielded a model that was not better than either serum albumin (C-statistic, 0.852; 95% CI, 0.675-0.976) or MELD-Na (C-statistic, 0.891; 95% CI, 0.784-0.968; P = .841). Finally, positive blood cultures were more common among patients with ALF compared with those without ALF (63.6% vs 4.3%; P < .00001). Conclusions:Hypoalbuminemia was associated with an increased risk of ALF in patients with acute hepatitis A. Positive blood cultures and septic shock as a cause of death were common among patients with ALF. Providers caring for patients with acute hepatitis A should monitor for early signs of sepsis and consider empiric antibiotics, especially in patients presenting with hypoalbuminemia

Molecular Detection of Leptospira spp. in Rodents Trapped in the Mozambique Island City, Nampula Province, Mozambique

Introduction: Leptospirosis is a neglected zoonotic disease caused by a bacteria of the genus Leptospira. In Africa, it is frequently mistaken for frequently occurring conditions such as malaria. The aim of this study was to identify rodent species involved in the transmission of the disease, the prevalence of pathogenic Leptospira spp. in selected rodent species and risk factors for human leptospirosis. Material and Methods: We conducted a descriptive and exploratory epidemiological and molecular study in Mozambique Island city in 2015. Six neighborhoods, comprising 30 households each were randomly selected. People from the selected 180 households were interviewed regarding their awareness of the disease, the presence of rodents in their houses, chemicals used to eliminate them, sewage disposal, water supply system, and other key issues related to the disease. In each neighborhood, we trapped 10 rodents for a morphometric study to identify their species and for molecular isolation of Leptospira DNA. We extracted kidneys from 57/60 of rodents trapped and performed nested polymerase chain reaction targeting rrs 16S ribosomal RNA and lipL32 genes for identification of Leptospira genus and pathogenic Leptospira spp. respectively. Results: Of the 180 participants 92 (51%) reported having heard of leptospirosis;107 (59%) have had the disease; 151 (83%) reported the existence of rats in their house; 100 (56%) had latrines; 118 (66%) used chemicals to kill the rats; 102 (57%) used well water and 114 (63%) used trash containers. The most prevalent rodent species captured was Rattus norvegicus 36/60 (60%), followed by Rattus rattus 19/60 (31.67%) and Mus musculus 3/60 (5%). Sequences of rrs 16S rRNA gene were identified rrs 16S ribosomal DNA RNA was identified in 20/57 (35.%) rodents. Out these two were positive for lipL32 gene, giving an overall pathogenic Leptospira infection of 3.5% (2/57). The rodent species identified as carriers of pathogenic Leptospira were Rattus norvegicus (1) and R. rattus (1). Conclusion: This is the first study in Mozambique to identify the presence of pathogenic species of Leptospira using molecular tools. Leptospirosis risk factors in Mozambique Island city are rodent’s infestation, limited disease awareness, lack of access to clean water, insufficient resources for waste collection, greater clustering of households, poor sanitation environment and degradation of living conditions. Pathogenic Leptospira spp. are present in the area studied and at least two species of rodents, the R. rattus and R. norvegicus are potentially involved in the transmission of the causal agents of the disease.publishersversionpublishe

The new paradigm of hepatitis C therapy: integration of oral therapies into best practices.

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels

The Virome of Cerebrospinal Fluid: Viruses Where We Once Thought There Were None.

Traditionally, medicine has held that some human body sites are sterile and that the introduction of microbes to these sites results in infections. This paradigm shifted significantly with the discovery of the human microbiome and acceptance of these commensal microbes living across the body. However, the central nervous system (CNS) is still believed by many to be sterile in healthy people. Using culture-independent methods, we examined the virome of cerebrospinal fluid (CSF) from a cohort of mostly healthy human subjects. We identified a community of DNA viruses, most of which were identified as bacteriophages. Compared to other human specimen types, CSF viromes were not ecologically distinct. There was a high alpha diversity cluster that included feces, saliva, and urine, and a low alpha diversity cluster that included CSF, body fluids, plasma, and breast milk. The high diversity cluster included specimens known to have many bacteria, while other specimens traditionally assumed to be sterile formed the low diversity cluster. There was an abundance of viruses shared among CSF, breast milk, plasma, and body fluids, while each generally shared less with urine, feces, and saliva. These shared viruses ranged across different virus families, indicating that similarities between these viromes represent more than just a single shared virus family. By identifying a virome in the CSF of mostly healthy individuals, it is now less likely that any human body site is devoid of microbes, which further highlights the need to decipher the role that viral communities may play in human health

Disease management at the wildlife-livestock interface: using whole-genome sequencing to study the role of elk in Mycobacterium bovis transmission in Michigan, USA

The role of wildlife in the persistence and spread of livestock diseases is difficult to quantify and control. These difficulties are exacerbated when several wildlife species are potentially involved. Bovine tuberculosis (bTB), caused by Mycobacterium bovis, has experienced an ecological shift in Michigan, with spillover from cattle leading to an endemically infected white‐tailed deer (deer) population. It has potentially substantial implications for the health and well‐being of both wildlife and livestock and incurs a significant economic cost to industry and government. Deer are known to act as a reservoir of infection, with evidence of M. bovis transmission to sympatric elk and cattle populations. However, the role of elk in the circulation of M. bovis is uncertain; they are few in number, but range further than deer, so may enable long distance spread. Combining Whole Genome Sequences (WGS) for M. bovis isolates from exceptionally well‐observed populations of elk, deer and cattle with spatiotemporal locations, we use spatial and Bayesian phylogenetic analyses to show strong spatiotemporal admixture of M. bovis isolates. Clustering of bTB in elk and cattle suggests either intraspecies transmission within the two populations, or exposure to a common source. However, there is no support for significant pathogen transfer amongst elk and cattle, and our data are in accordance with existing evidence that interspecies transmission in Michigan is likely only maintained by deer. This study demonstrates the value of whole genome population studies of M. bovis transmission at the wildlife‐livestock interface, providing insights into bTB management in an endemic system

Factors Associated With Viral Rebound in HIV-1-Infected Individuals Enrolled in a Therapeutic HIV-1 \u3ci\u3egag\u3c/i\u3e Vaccine Trial

Background. Human immunodeficiency virus type 1 (HIV-1) vaccines directed to the cell-mediated immune system could have a role in lowering the plasma HIV-1 RNA set point, which may reduce infectivity and delay disease progression. Methods. Randomized, placebo-controlled trial involving HIV-1-infected participants who received a recombinant adenovirus serotype 5 (rAd5) HIV-1 gag vaccine or placebo. Sequence-based HLA typing was performed for all 110 participants who initiated analytic treatment interruption (ATI) to assess the role of HLA types previously associated with HIV prognosis. Plasma HIV-1 gag and pol RNA sequences were obtained during the ATI. Virologic endpoints and HLA groups were compared between treatment arms using the 2-sample rank sum test. A linear regression model was fitted to derive independent correlates of ATI week 16 plasma viral load (w16 PVL). Results. Vaccinated participants with neutral HLA alleles had lower median w16 PVLs than did vaccinated participants with protective HLA alleles (P 5 .01) or placebo participants with neutral HLA alleles (P 5 .02). Factors independently associated with lower w16 PVL included lower pre-antiretroviral therapy PVL, greater Gag sequence divergence from the vaccine sequence, decreased proportion of HLA-associated polymorphisms in Gag, and randomization to the vaccine arm. Conclusions. Therapeutic vaccination with a rAd5-HIV gag vaccine was associated with lower ATI week 16 PVL even after controlling for viral and host genetic factors

Factors Associated With Viral Rebound in HIV-1-Infected Individuals Enrolled in a Therapeutic HIV-1 \u3ci\u3egag\u3c/i\u3e Vaccine Trial

Background. Human immunodeficiency virus type 1 (HIV-1) vaccines directed to the cell-mediated immune system could have a role in lowering the plasma HIV-1 RNA set point, which may reduce infectivity and delay disease progression. Methods. Randomized, placebo-controlled trial involving HIV-1-infected participants who received a recombinant adenovirus serotype 5 (rAd5) HIV-1 gag vaccine or placebo. Sequence-based HLA typing was performed for all 110 participants who initiated analytic treatment interruption (ATI) to assess the role of HLA types previously associated with HIV prognosis. Plasma HIV-1 gag and pol RNA sequences were obtained during the ATI. Virologic endpoints and HLA groups were compared between treatment arms using the 2-sample rank sum test. A linear regression model was fitted to derive independent correlates of ATI week 16 plasma viral load (w16 PVL). Results. Vaccinated participants with neutral HLA alleles had lower median w16 PVLs than did vaccinated participants with protective HLA alleles (P 5 .01) or placebo participants with neutral HLA alleles (P 5 .02). Factors independently associated with lower w16 PVL included lower pre-antiretroviral therapy PVL, greater Gag sequence divergence from the vaccine sequence, decreased proportion of HLA-associated polymorphisms in Gag, and randomization to the vaccine arm. Conclusions. Therapeutic vaccination with a rAd5-HIV gag vaccine was associated with lower ATI week 16 PVL even after controlling for viral and host genetic factors