Looking at HIV-1 transmission in Quebec through a phylogenetic lens

Introduction: The year 2020 will mark 40 years since AIDS was first considered a global epidemic. An ambitious program by UNAIDS, called 90-90-90 initiative, was put in place in 2013. This initiative specifies that by 2020, there will be a significant decrease in HIV incidence. The objectives of the 90-90-90 program will not be realized in this time frame, and it is unlikely that progress can be made unless there can be an understanding of the transmission networks by which the virus continues to propagate.Objectives: A) Analyze the dynamics of spread of the HIV-1 MSM epidemic in Quebec using phylogenetic and clinical data. B) To determine the tropism of Transmission/Founder viruses from HIV infected patients. C) Determine the susceptibility of Cluster 185 (C185) viruses on integrase strand transfer inhibitors: Dolutegravir (DTG), Cabotegravir (CAB), and Bictegravir (BIC).Methods: Statistical analysis of datasets from the genotyping program was performed using SAS and Python. Tropism was determined by infecting U87 astroglioma cells expressing CD4 and CCR5 or CXCR4 co-receptors with HIV-1 primary isolates. Viral replication was monitored by measuring reverse transcriptase (RT) levels. MT-2 cells were treated with DTG, CAB or BIC were infected first with HIV lab strains NL4.3WT, NL4.3IN(R263K), NL4.3IN(G118R), or NL4.3IN(G140S/Q148H). Similarly, this procedure was conducted on C185 viruses C185.09WT, C185.15WT, and their respective R263K mutations. Drugs were removed from the media on the peak day of infection. Viral replication was monitored by measuring RT and integration was measured by qPCR.Results: Out of 6,600 patients, 41% were found to be part of a large cluster class (LC, 6 or more paired sequences), compared to 37% belonging to singletons (no pairing). Singletons were observed prominently during the 2002-2009 period; however, large cluster cases increased by 60% between 2010-2017. LC viruses were found to be significantly more recent infections (p<0.0001) than singletons, showing a percent median diversity of 0.4% (IQR 0.2-1.3). Age differences also were noted between the classes. The median age of LC members appeared to vary equally between 28 and 48 years old, whereas the median age for singleton patients was 48. Analysis of the median age per year as a function of year of visit showed a negative correlation (r2=-0.488) for LC patients compared to a positive correlation for singletons patients (r2=0.315). This was also observed on their clinical status, a strong negative correlation (r2=-0.840) was noted for patients who had been recently infected compared to a positive correlation (r2=0.646) for patients who had been infected longer than six months. It was also found that 50% of patients belonging to an LC class showed some form of drug-resistance related polymorphism. The tropism assay did not reveal any striking differences between LC viruses and singletons, showing mostly R5 tropism. It was noted that 68% of LC viruses had a better replication capacity than singletons. C185 isolates preserved the same dual-tropic properties and were selected for further experiments. The drug washout experiments reveal that DTG and BIC outperformed CAB in the highly resistant variant NL4.3IN(G140S/Q148H). The C185.15IN(R263K) virus could rebound under BIC treatment and showed 15-fold resistance. The presence of natural polymorphism M50I could explain these observations. Conclusions: The fast spread of LC viruses can be attributed to quick transmission events happening in a determined local structure that enhances the ability of infection. It is possible that the mixing of susceptible populations might be age-dependent, as noted in some of the yearly trends. LC viruses clearly show more selective advantage than singletons, including lower susceptibility to some INSTI, higher replicative capacity, and increased drug-resistance transmission

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.