Project

33CS30_148522; Swiss HIV Cohort Study (SHCS); large nested project; viral variants; viral sequence traits; viral set-point; primary HIV infection; large nested project; 33CS30_148522; envelope; HIV-1; transmission; phylogeny; transmitter founder; Swiss HIV Cohort Study (SHCS)

Lead
Dieses Projekt will helfen, die Biologie von übertragenen HIV-1 Viren besser verstehen. Deshalb werden Viren von Individuen studiert, die diese an einen anderen Menschen weitergeben und zusätzlich wollen wir systematisch untersuchen, weshalb und wie häufig Superinfektion auftreten kann. Schliesslich werden wir die Uebertragung von resistenten HI-Viren studieren und v. a. auf nicht-B Subtypen fokussieren. Die Studie basiert auf zwei qualitativ hochstehenden longitudinalen Patientenstudien: der Schweizerischen HIV Kohortenstudie und der Zurich Primary HIV Infection Study.
Lay summary
Mit diesem Projekt wollen wir bestimmte Charakteristika der HIV-1 Infektion besser verstehen. Im 1. Teil wollen wir herausfinden, ob übertragene Viren spezielle genetische oder phänotypische Merkmale aufweisen. Oder in anderen Worten: Wir möchten studieren, ob Virus-Varianten, die übertragen werden bestimmte genetische oder biologische "Verhaltensmerkmale" aufweisen. Im 2. Teil wollen wir systematisch untersuchen, wie häufig HIV Superinfektionen (SI) auftreten  und welches die Risikofaktoren dafür sind. Bisher gibt es kaum systematische Studien zur Häufigkeit von Superinfektionen und deren Risikofaktoren in repräsentativen Populationen von HIV-1 infizierten Menschen. Bisher haben wir 150-312 potentielle SI Fälle identifizert. Diese werden wir mittels einer detaillierten virusgenetischen Analyse bestätigen und Rekombination und Risikofaktoren bestimmen. Wir werden auch Wirtsgenome analysieren, um zu schauen, ob allenfalls menschliche genetische Faktoren dafür mitverantwortlich sind. Zusätlich werden wir die virale Fitness und neutralisierende Antikörper bestimmen in den Patienten und die "viral setpoints" (virus equilibrium in Patienten vor Therapie) bestimmen in den SI Fällen und ausgewählten kontrollen, um zu testen, ob SI Individuen eine raschere Krankheitsprogression aufweisen. Im 3. Teil werden wir die Uebertragung von resistenten HIV-1 Viren untersuchen. Wir werden uns speziell auf Nicht-B Subtypen und auf neuere Medikamentenklassen konzentrieren. Zusätzlich wollen wir die Reversionsrate von pbertragenen resistenten Viren studieren, was uns Hinweise geben wird auf die "Fitnesskosten" welche diese Resistenzmutationen verursachen.

Direct link to Lay Summary

Last update: 25.03.2015

Number	Title	Start	Funding scheme

This translational research project is a continuation of SNF 130865. We aim to unravel traits of HIV transmission in three conceptually different situations of high clinical relevance: transmission leading to de novo infection (Aim 1), spread of HIV between infected individuals (conferred to as superinfection (SI); Aim 2) and transmission of drug resistant virus (Aim 3). The proposed studies are based on two renowned longitudinal studies with extensive biobanks: The Swiss HIV Cohort and the Zurich Primary HIV-1 infection study (ZPHI). AIM 1. Here we will determine whether specific genotypic and phenotypic viral traits of transmitted/founder viruses (T/F) exist. Characterization of T/F viruses, the earliest virus population that emerges in a newly infected individual, is of high interest as understanding their transmis-sion pathways may open avenues for prophylaxis and treatment. Current data on T/F virus features led to intriguing in-sights, but no definitive picture of genetic and phenotypic traits of T/F viruses has emerged. A limitation of previous studies was that features of T/F viruses had to be compared to unrelated viruses from chronically infected patients as transmitting individuals were in most cases not identified. Here using phylogenetically linked T/F viruses and their transmitters we will be able to study phylogenetically linked transmitter-recipient pairs. Thus far we identified 79 acutely HIV infected (recipients) and 107 chronically infected individuals with genetically related HIV strains which are their likely transmitters. Plasma samples close to estimated time of infection will be chosen for virus genomic analysis from transmitters and recipients to retrieve full length HIV-genomes employing Next Generation Sequencing (NGS) followed by haplotype reconstruction. T/F virus will be compared to variants present in the transmitter regarding, length, specific mutations, deletions/insertions, glycosylation sites, charge and frequency to define whether stochastic or non-stochastic transmission occurs. If genotypic traits are identified, gene transfer and mutagenesis experiments will be performed followed by phenotypic analysis to discern if indeed signifying characteristics of T/F viruses exist. To this end we will compare transmitter and T/F viruses for features implicated in shaping transmission including replication capacity, sensitivity to neutralizing antibodies and entry inhibitors, entry kinetics and interferon sensitivity. AIM 2: Here we will systematically explore frequency and risk factors for HIV-1 superinfection in the SHCS and ZPHI. A first phylogenetic screen based on pol sequences has revealed 150-312 potential SI cases. By retrieving longitudinal plasma samples before patients went on antiretroviral therapy we will seek to confirm SI by full length NGS and define approximate time points of SI events. In a detailed virus genomic analysis we aim to reconstruct haplotypes, study recombination events. A specific emphasis of our studies is on determining risk factors for acquiring SI using detailed patient, disease and host genomic data available. Viral fitness of initial circulating and superinfecting strains will be computed using machine learning techniques. To test whether SI is prevented by neutralizing antibody responses, those will be compared among superinfected and non-superinfected individuals. Finally, viral setpoint of cases and controls will be compared to determine the impact of SI on disease progression. AIM 3: Here we will investigate transmission of HIV-1 drug resistance mutations (TDR) within the SHCS, specifically focussing on the non-B compared to the subtype B epidemic, newer drugs, and reversion rates of TDR. We will study TDR prevalence over time for B and non- B subtypes in all drug naives and, specifically, in recently infected individuals. We will particularly focus on newer drugs. In patients with TDR we will determine reversion rates for specific TDR and fitness cost by taking into account the pol genotypic backbone indepen-dently of TDR. Furthermore, by performing phylogenetic analysis we will study whether there are differences in transmission dynamics between B- and non-B subtype TDR. This analysis will reveal whether TDR in the non-B subtypes is increasing as would be expected due to the recent, wide spread roll out of antiretroviral drugs in developing countries.