Plug-and-Display: decoration of Virus-Like Particles via isopeptide bonds for modular immunization.

Virus-like particles (VLPs) are non-infectious self-assembling nanoparticles, useful in medicine and nanotechnology. Their repetitive molecularly-defined architecture is attractive for engineering multivalency, notably for vaccination. However, decorating VLPs with target-antigens by genetic fusion or chemical modification is time-consuming and often leads to capsid misassembly or antigen misfolding, hindering generation of protective immunity. Here we establish a platform for irreversibly decorating VLPs simply by mixing with protein antigen. SpyCatcher is a genetically-encoded protein designed to spontaneously form a covalent bond to its peptide-partner SpyTag. We expressed in E. coli VLPs from the bacteriophage AP205 genetically fused to SpyCatcher. We demonstrated quantitative covalent coupling to SpyCatcher-VLPs after mixing with SpyTag-linked to malaria antigens, including CIDR and Pfs25. In addition, we showed coupling to the VLPs for peptides relevant to cancer from epidermal growth factor receptor and telomerase. Injecting SpyCatcher-VLPs decorated with a malarial antigen efficiently induced antibody responses after only a single immunization. This simple, efficient and modular decoration of nanoparticles should accelerate vaccine development, as well as other applications of nanoparticle devices.

Viral Escape in the Central Nervous System with Multidrug-Resistant Human Immunodeficiency Virus-1

In this study, we report the case of a patient infected with human immunodeficiency virus (HIV)-1 who developed ataxia and neurocognitive impairment due to viral escape within the central nervous system (CNS) with a multidrug-resistant HIV-1 despite long-term viral suppression in plasma. Antiretroviral therapy optimization with drugs with high CNS penetration led to viral suppression in the CSF, regression of ataxia, and improvement of neurocognitive symptoms.

Ability to Work and Employment Rates in Human Immunodeficiency Virus (HIV)-1-Infected Individuals Receiving Combination Antiretroviral Therapy: The Swiss HIV Cohort Study

Background.  Limited data exist on human immunodeficiency virus (HIV)-infected individuals' ability to work after receiving combination antiretroviral therapy (cART). We aimed to investigate predictors of regaining full ability to work at 1 year after starting cART. Methods.  Antiretroviral-naive HIV-infected individuals <60 years who started cART from January 1998 through December 2012 within the framework of the Swiss HIV Cohort Study were analyzed. Inability to work was defined as a medical judgment of the patient's ability to work as 0%. Results.  Of 5800 subjects, 4382 (75.6%) were fully able to work, 471 (8.1%) able to work part time, and 947 (16.3%) were unable to work at baseline. Of the 947 patients unable to work, 439 (46.3%) were able to work either full time or part time at 1 year of treatment. Predictors of recovering full ability to work were non-white ethnicity (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), higher education (OR, 4.03; 95% CI, 2.47-7.48), and achieving HIV-ribonucleic acid <50 copies/mL (OR, 1.83; 95% CI, 1.20-2.80). Older age (OR, 0.55; 95% CI, .42-.72, per 10 years older) and psychiatric disorders (OR, 0.24; 95% CI, .13-.47) were associated with lower odds of ability to work. Recovering full ability to work at 1 year increased from 24.0% in 1998-2001 to 41.2% in 2009-2012, but the employment rates did not increase. Conclusions.  Regaining full ability to work depends primarily on achieving viral suppression, absence of psychiatric comorbidity, and favorable psychosocial factors. The discrepancy between patients' ability to work and employment rates indicates barriers to reintegration of persons infected with HIV.

Absence of Active Hepatitis C Virus Infection in Human Immunodeficiency Virus Clinics in Zambia and Mozambique.

Few studies have evaluated the prevalence of replicating hepatitis C virus (HCV) infection in sub-Saharan Africa. Among 1812 individuals infected with human immunodeficiency virus, no patient in rural Mozambique and 4 patients in urban Zambia were positive for anti-HCV antibodies. Of these, none had confirmed HCV replication.

Potential Impact of Sexual Transmission on Ebola Virus Epidemiology: Sierra Leone as a Case Study.

BACKGROUND Sexual transmission of Ebola virus disease (EVD) 6 months after onset of symptoms has been recently documented, and Ebola virus RNA has been detected in semen of survivors up to 9 months after onset of symptoms. As countries affected by the 2013-2015 epidemic in West Africa, by far the largest to date, are declared free of Ebola virus disease (EVD), it remains unclear what threat is posed by rare sexual transmission events that could arise from survivors. METHODOLOGY/PRINCIPAL FINDINGS We devised a compartmental mathematical model that includes sexual transmission from convalescent survivors: a SEICR (susceptible-exposed-infectious-convalescent-recovered) transmission model. We fitted the model to weekly incidence of EVD cases from the 2014-2015 epidemic in Sierra Leone. Sensitivity analyses and Monte Carlo simulations showed that a 0.1% per sex act transmission probability and a 3-month convalescent period (the two key unknown parameters of sexual transmission) create very few additional cases, but would extend the epidemic by 83 days [95% CI: 68-98 days] (p < 0.0001) on average. Strikingly, a 6-month convalescent period extended the average epidemic by 540 days (95% CI: 508-572 days), doubling the current length, despite an insignificant rise in the number of new cases generated. CONCLUSIONS/SIGNIFICANCE Our results show that reductions in the per sex act transmission probability via abstinence and condom use should reduce the number of sporadic sexual transmission events, but will not significantly reduce the epidemic size and may only minimally shorten the length of time the public health community must maintain response preparedness. While the number of infectious survivors is expected to greatly decline over the coming months, our results show that transmission events may still be expected for quite some time as each event results in a new potential cluster of non-sexual transmission. Precise measurement of the convalescent period is thus important for planning ongoing surveillance efforts.

Interferon-gamma and interleukin-4 mRNA expression by peripheral blood mononuclear cells from pregnant and non-pregnant cattle seropositive for bovine viral diarrhea virus

The acceptance of the fetal allograft by pregnant women and mice seems to be associated with a shift from a Th 1 dominated to a Th 2 dominated immune response to certain infectious agents. The goal of this study was to examine cytokine expression in peripheral blood mononuclear cells (PBMCs) from cattle immune to bovine viral diarrhea virus (BVDV) to determine whether pregnancy also has an influence on the type of immune response in this species. Forty-six heifers and cows between 14 months and 13 years of age were included in this study. Twenty-four were seropositive and 22 seronegative for BVDV. Eleven of the seropositive animals and 11 of the seronegative animals were in the eighth month of gestation, the remaining animals were virgin heifers. PBMC from these animals were analyzed for Interferon (IFN)-gamma and Interleukin (IL)-4 mRNA expression by real-time RT-PCR after stimulation with a non-cytopathic strain of BVDV. Additionally, an ELISA was performed to measure IFN-gamma in the supernatants of stimulated cell cultures. In BVDV seropositive animals, IFN-gamma mRNA levels were significantly higher than in BVDV seronegative animals and there was a significant positive correlation between the changes in IFN-gamma and IL-4 mRNA expression. There was, however, no significant difference in IFN-gamma and IL-4 mRNA levels between pregnant and non-pregnant animals. These results are inconsistent with BVDV inducing a Th1 or Th2 biased immune response. Furthermore, a shift in the cytokine pattern during bovine pregnancy was not evident.

Trends in incidences and risk factors for hepatocellular carcinoma and other liver events in HIV and hepatitis C virus co-infected individuals from 2001 to 2014: a multi-cohort study.

BACKGROUND  While liver-related deaths in HIV and hepatitis C virus (HCV) co-infected individuals have declined over the last decade, hepatocellular carcinoma (HCC) may have increased. We described the epidemiology of HCC and other liver events in a multi-cohort collaboration of HIV/HCV co-infected individuals. METHODS  We studied all HCV antibody-positive adults with HIV in the EuroSIDA Study, the Southern Alberta Clinic Cohort, the Canadian Co-infection Cohort, and the Swiss HIV Cohort Study from 2001 to 2014. We calculated the incidence of HCC and other liver events (defined as liver-related deaths or decompensations, excluding HCC) and used Poisson regression to estimate incidence rate ratios. RESULTS  Our study comprised 7,229 HIV/HCV co-infected individuals (68% male, 90% white). During follow-up, 72 cases of HCC and 375 other liver events occurred, yielding incidence rates of 1.6 (95% confidence interval (CI): 1.3, 2.0) and 8.6 (95% CI: 7.8, 9.5) cases per 1,000 person-years of follow-up, respectively. The rate of HCC increased 11% per calendar year (95% CI: 4%, 19%) and decreased 4% for other liver events (95% CI: 2%, 7%), but only the latter remained statistically significant after adjustment for potential confounders. High age, cirrhosis, and low current CD4 cell count were associated with a higher incidence of both HCC and other liver events. CONCLUSIONS  In HIV/HCV co-infected individuals, the crude incidence of HCC increased from 2001 to 2014, while other liver events declined. Individuals with cirrhosis or low current CD4 cell count are at highest risk of developing HCC or other liver events.

Contribution of Genetic Background and Clinical Risk Factors to Low-Trauma Fractures in Human Immunodeficiency Virus (HIV)-Positive Persons: The Swiss HIV Cohort Study.

Background.  The impact of human genetic background on low-trauma fracture (LTF) risk has not been evaluated in the context of human immunodeficiency virus (HIV) and clinical LTF risk factors. Methods.  In the general population, 6 common single-nucleotide polymorphisms (SNPs) associate with LTF through genome-wide association study. Using genome-wide SNP arrays and imputation, we genotyped these SNPs in HIV-positive, white Swiss HIV Cohort Study participants. We included 103 individuals with a first, physician-validated LTF and 206 controls matched on gender, whose duration of observation and whose antiretroviral therapy start dates were similar using incidence density sampling. Analyses of nongenetic LTF risk factors were based on 158 cases and 788 controls. Results.  A genetic risk score built from the 6 LTF-associated SNPs did not associate with LTF risk, in both models including and not including parental hip fracture history. The contribution of clinical LTF risk factors was limited in our dataset. Conclusions.  Genetic LTF markers with a modest effect size in the general population do not improve fracture prediction in persons with HIV, in whom clinical LTF risk factors are prevalent in both cases and controls.