Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms Graphical abstract Highlights d The magnitude of early CD4 + T cell responses correlates with severity of COVID-19 d Prior lung disease correlates with higher SARS-CoV-2specific CD8 + T cell responses d PASC is associated with a decline in N-specific interferon-gproducing CD8 + T cells d Neutralizing capacity correlates with SARS-CoV-2-specific CD4 + T cell responses

Interpretation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurveillance studies is limited by poorly defined performance of antibody assays over time in individuals with different clinical presentations. We measured antibody responses in plasma samples from 128 individuals over 160 days using 14 assays. We found a consistent and strong effect of disease severity on antibody magnitude, driven by fever, cough, hospitalization, and oxygen requirement. Responses to spike protein versus nucleocapsid had consistently higher correlation with neutralization. Assays varied substantially in sensitivity during early convalescence and time to seroreversion. Variability was dramatic for individuals with mild infection, who had consistently lower antibody titers, with sensitivities at 6 months ranging from 33 to 98% for commercial assays. Thus, the ability to detect previous infection by SARS-CoV-2 is highly dependent on infection severity, timing, and the assay used. These findings have important implications for the design and interpretation of SARS-CoV-2 serosurveillance studies.

Fully suppressive antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection requires the administration of drug combinations that target multiple sites on one or more proteins required for viral replication. Approved antiretrovirals (ARVs) include nucleoside/nucleotide and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively), protease inhibitors (PIs), entry inhibitors, and integrase strand-transfer inhibitors (INSTIs). With the exception of the NRTIs, which require intracellular phosphorylation, plasma drug concentrations are correlated with drug efficacy. At the same time, high drug concentrations are associated with excess toxicity.To durably suppress HIV replication in infected patients, ARV concentrations must reach and be maintained at levels that exceed the susceptibility of the virus to that drug. Treatment response is often hampered by the failure to achieve sufficient drug exposure (i.e., poor adherence and drug interactions), reduced drug susceptibility (i.e., viral drug resistance), or both. Drug concentrations within patients vary over time and, due to ease of sampling, are generally characterized by minimum (trough) concentrations (C trough ) immediately prior to administration of the next scheduled dose. Drug concentrations also vary considerably between individual patients as a result of differences in absorption, distribution, metabolism, and excretion. In addition, each drug characteristically binds to human plasma proteins to different extents. Furthermore, the susceptibility of HIV-1 variants, even in patients not previously exposed to drug therapy, varies over a range that is unique to each drug (23,24,46).In vivo clinical pharmacodynamic data are available for some, but not all, ARVs. Efficient collection of these data is difficult and ideally performed early in the drug development process. Alternative methods of incorporating ARV pharmacokinetics into therapeutic decision making are being explored. In vitro phenotypic drug susceptibility testing of individual patient viruses is now widely available and generates information that can be used to calculate an inhibitory quotient (IQ), defined as the ratio between the C trough and the drug concentration that inhibits in vitro replication by a defined percentage (e.g., 50% or 95% inhibitory concentration [IC 50 or IC 95 , respectively]) (27,35,43,56). Derivatives of the IQ, including the genotypic IQ (GIQ; C trough divided by the number of resistance-associated mutations for a given drug) have also been evaluated (36). Several studies have attempted to define the optimal IQ required to produce long-term viral suppression: in some cases, IQ has been retrospectively linked to clinical outcome (15,34,41,42,55), while in others, direct relationships between IQ and viral load response were not observed (5, 12).For most ARV drugs, few or no in vivo concentration-response data have been generated, or these data are inconsistent with clinical observations. Collectively, there is insufficient agr...

Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.

A series of inhibitors of mTOR kinase based on a quaternary-substituted dihydrofuropyrimidine was designed and synthesized. The most potent compounds in this series inhibited mTOR kinase with K(i) < 1.0 nM and were highly (>100×) selective for mTOR over the closely related PI3 kinases. Compounds in this series showed inhibition of the pathway and antiproliferative activity in cell-based assays. Furthermore, these compounds had excellent mouse PK, and showed a robust PK-PD relationship in a mouse model of cancer.