Matthew M. Hernandez
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Researcher at Icahn School of Medicine at Mount Sinai
Journal of Virology, 2019-12-04
HIV diversification facilitates immune escape and complicates antiretroviral therapy. In this study, we take advantage of a humanized mouse model to probe the contribution of APOBEC3 mutagenesis to viral evolution. Humanized mice were infected with isogenic HIV molecular clones (HIV-WT, HIV-45G, HIV-DSLQ) that differ only in their ability to counteract APOBEC3G (A3G). Infected mice remained naïve or were treated with the RT inhibitor lamivudine (3TC). Viremia, emergence of drug resistant variants and quasispecies diversification in the plasma compartment were determined throughout infection. While both HIV-WT and HIV-45G achieved robust infection, over time HIV-45G replication was significantly reduced compared to HIV-WT in the absence of 3TC treatment. In contrast, treatment response differed significantly between HIV-45G and HIV-WT infected mice. Antiretroviral treatment failed in 91% of HIV-45G infected mice while only 36% of HIV-WT infected mice displayed a similar negative outcome. Emergence of 3TC resistant variants and nucleotide diversity were determined by analyzing 155,462 single HIV reverse transcriptase (RT) and 6,985 vif sequences from 33 mice. Prior to treatment, variants with genotypic 3TC resistance (RT-M184I/V) were detected at low levels in over a third of all animals. Upon treatment, the composition of the plasma quasispecies rapidly changed leading to a majority of circulating viral variants encoding RT-184I. Interestingly, increased viral diversity prior to treatment initiation correlated with higher plasma viremia in HIV-45G but not in HIV-WT infected animals. Taken together, HIV variants with suboptimal anti-A3G activity were attenuated in the absence of selection but display a fitness advantage in the presence of antiretroviral treatment.
Background: Nosocomial respiratory virus outbreaks represent serious public health challenges. Rapid and precise identification of cases and tracing of transmission chains is critical to end outbreaks and to inform prevention measures. Methods: We combined conventional surveillance with Influenza A virus (IAV) genome sequencing to identify and contain a large IAV outbreak in a metropolitan healthcare system. A total of 381 individuals, including 91 inpatients and 290 health care workers (HCWs), were included in the investigation. Results: During a 12-day period in early 2019, infection preventionists identified 89 HCWs and 18 inpatients as cases of influenza-like illness (ILI), using an amended definition, without the requirement for fever. Sequencing of IAV genomes from available nasopharyngeal (NP) specimens identified 66 individuals infected with a nearly identical strain of influenza A H1N1 (43 HCWs, 17 inpatients, and 6 with unspecified affiliation). All HCWs infected with the outbreak strain had received the seasonal influenza virus vaccination. Characterization of five representative outbreak viral isolates did not show antigenic drift. In conjunction with IAV genome sequencing, mining of electronic records pinpointed the origin of the outbreak as a single patient and a few interactions in the emergency department that occurred one day prior to the index ILI cluster. Conclusions: We used precision surveillance to identify and control a large nosocomial IAV outbreak, mapping the source of the outbreak to a single patient rather than HCWs as initially assumed based on conventional epidemiology. These findings have important ramifications for more effective prevention strategies to curb nosocomial respiratory virus outbreaks.
New York City (NYC) has emerged as one of the epicenters of the current SARS-CoV2 pandemic. To identify the early events underlying the rapid spread of the virus in the NYC metropolitan area, we sequenced the virus causing COVID19 in patients seeking care at the Mount Sinai Health System. Phylogenetic analysis of 84 distinct SARS-CoV2 genomes indicates multiple, independent but isolated introductions mainly from Europe and other parts of the United States. Moreover, we find evidence for community transmission of SARS-CoV2 as suggested by clusters of related viruses found in patients living in different neighborhoods of the city.
New York City (NYC) emerged as a coronavirus disease 2019 (COVID-19) epicenter in March 2020, but there is limited information regarding potentially unrecognized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections before the first reported case. We utilized a sample pooling strategy to screen for SARS-CoV-2 RNA in de-identified, respiratory pathogen-negative nasopharyngeal specimens from 3,040 patients across our NYC health system who were evaluated for respiratory symptoms or influenza-like illness during the first 10 weeks of 2020. We obtained complete SARS-CoV-2 genome sequences from samples collected between late February and early March. Additionally, we detected SARS-CoV-2 RNA in pooled specimens collected in the week ending 25 January 2020, indicating that SARS-CoV-2 caused sporadic infections in NYC a full month before the first officially documented case.