Download full-text


Available from: Huldrych F Günthard, Jan 26, 2015
1 Follower
11 Reads
  • Source
    • "Longitudinal samples were collected from seven HIV/HCV-coinfected individuals enrolled in the Swiss HIV Cohort Study ([SHCS], [29] who underwent IFN-α/RBV treatment (Table S1). All subjects had PBMC samples available before, during and after IFN-α/RBV treatment (a post-treatment sample was not available for Subject A), were ART-naïve, and had detectable HIV-1 RNA at baseline. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Interferon-α (IFN-α) treatment suppresses HIV-1 viremia and reduces the size of the HIV-1 latent reservoir. Therefore, investigation of the molecular and immunologic effects of IFN-α may provide insights that contribute to the development of novel prophylactic, therapeutic and curative strategies for HIV-1 infection. In this study, we hypothesized that microRNAs (miRNAs) contribute to the IFN-α-mediated suppression of HIV-1. To inform the development of novel miRNA-based antiretroviral strategies, we investigated the effects of exogenous IFN-α treatment on global miRNA expression profile, HIV-1 viremia, and potential regulatory networks between miRNAs and cell-intrinsic anti-HIV-1 host factors in vivo. Methods Global miRNA expression was examined in longitudinal PBMC samples obtained from seven HIV/HCV-coinfected, antiretroviral therapy-naïve individuals before, during, and after pegylated interferon-α/ribavirin therapy (IFN-α/RBV). We implemented novel hybrid computational-empirical approaches to characterize regulatory networks between miRNAs and anti-HIV-1 host restriction factors. Results miR-422a was the only miRNA significantly modulated by IFN-α/RBV in vivo (p<0.0001, paired t test; FDR<0.037). Our interactome mapping revealed extensive regulatory involvement of miR-422a in p53-dependent apoptotic and pyroptotic pathways. Based on sequence homology and inverse expression relationships, 29 unique miRNAs may regulate anti-HIV-1 restriction factor expression in vivo. Conclusions The specific reduction of miR-422a is associated with exogenous IFN-α treatment, and likely contributes to the IFN-α suppression of HIV-1 through the enhancement of anti-HIV-1 restriction factor expression and regulation of genes involved in programmed cell death. Moreover, our regulatory network analysis presents additional candidate miRNAs that may be targeted to enhance anti-HIV-1 restriction factor expression in vivo.
    PLoS ONE 10/2014; 9(10):e109220. DOI:10.1371/journal.pone.0109220 · 3.23 Impact Factor
  • Source
    • "All clinical specimens were derived from adult participants enrolled in the Zurich center of the Swiss HIV Cohort Study [98] or the ZPHI study [99]. All studies were approved by the ethics committee of the University Hospital Zurich and written informed consent was obtained from all individuals. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Variable loops 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 perform two key functions: ensuring envelope trimer entry competence and shielding against neutralizing antibodies. While preserving entry functionality would suggest a high need for V1V2 sequence optimization and conservation, shielding efficacy is known to depend on a high flexibility of V1V2 giving rise to its substantial sequence variability. How entry competence of the trimer is maintained despite the continuous emergence of antibody escape mutations within V1V2 has not been resolved. Since HIV cell-cell transmission is considered a highly effective means of virus dissemination, we investigated whether cell-cell transmission may serve to enhance infectivity of V1V2 variants with debilitated free virus entry.ResultsIn a detailed comparison of wt and V1V2 mutant envelopes, V1V2 proved to be a key factor in ascertaining free virus infectivity, with V1V2 mutants displaying significantly reduced trimer integrity. Despite these defects, cell-cell transmission was able to partially rescue infectivity of V1V2 mutant viruses. We identified two regions, encompassing amino acids 156 to 160 (targeted by broadly neutralizing antibodies) and 175 to 180 (encompassing the ¿4ß7 binding site) which were particularly prone to free virus infectivity loss upon mutation but maintained infectivity in cell-cell transmission. Of note, V1V2 antibody shielding proved important during both free virus infection and cell-cell transmission.Conclusions Based on our data we propose a model for V1V2 evolution that centers on cell-cell transmission as a salvage pathway for virus replication. Escape from antibody neutralization may frequently result in V1V2 mutations that reduce free virus infectivity. Cell-cell transmission could provide these escape viruses with sufficiently high replication levels that enable selection of compensatory mutations, thereby restoring free virus infectivity while ensuring antibody escape. Thus, our study highlights the need to factor in cell-cell transmission when considering neutralization escape pathways of HIV-1.
    Retrovirology 09/2014; 11(1):75. DOI:10.1186/PREACCEPT-1148975491133162 · 4.19 Impact Factor
  • Source
    • "Additional data on the prevalence of IDU among HIV-infected patients stem from the Swiss HIV Cohort Study (SHCS), which originated in 1988 [25]. Since then, the study has continuously followed patients with HIV who undergo treatment at any of the five university hospitals in Switzerland, or in SHCS-associated regional hospitals or private doctors’ offices [26]. By March 2009, the SHCS covered a total of 15,624 patients, which is estimated to represent 45% of the cumulative number of HIV infections known to SFOPH and 69% of individuals with AIDS who reside in Switzerland. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background We have sought to identify ethnic- and gender-specific differences in HIV prevalence among heroin users receiving opioid maintenance treatment in the canton of Zurich, Switzerland. Methods We used a generalized linear model (GEE) to analyze data from the anonymized case register for all opioid maintenance treatments in the canton of Zurich. Patients who received either methadone or buprenorphine between 1991 and 2012 (n = 11,422) were evaluated for gender (male vs. female), ethnic background (Swiss vs. non-Swiss), and lifetime method of drug use (ever injector vs. non-injector). We addressed missing data by multiple imputation. Results The overall prevalence of HIV among patients declined substantially from 33.7% in 1991 to 10.6% in 2012 in the complete dataset. In the imputed datasets, the respective prevalence dropped from 32.8% in 1991 to 9.7% in 2012. Non-injectors had a four to five times lower risk ratio (RR) compared to the reference group, ‘Swiss males who ever injected’. In addition, we found a significantly higher risk ratio of HIV prevalence among females who had ever injected; this was true both for the complete dataset and the imputed dataset (Swiss RR 1.18 CI 95% 1.04–1.34, non-Swiss RR 1.58 CI 95% 1.18–2.12). Conclusion In this population, gender, ethnic background, and lifetime method of drug use influenced the risk of being HIV positive. Different access to treatment and different characteristics of risk exposure among certain subgroups might explain these findings. In particular, the higher risk for women who inject drugs—especially for those with an immigrant background—warrants additional research. Further exploration should identify what factors deter women from using available HIV-prevention measures and whether and how these measures can be better adapted to high-risk groups.
    Harm Reduction Journal 08/2014; 11(1):23. DOI:10.1186/1477-7517-11-23 · 1.26 Impact Factor
Show more