A quantitative approach for measuring the reservoir of latent HIV-1 proviruses.

A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection

Characterization and longitudinal analysis of reservoir dynamics in non-human primate models of HIV-1 infection

Approximately 37 million individuals are infected with HIV-1, with 2 million new cases and 1.4-1.7 million deaths each year (2021, unaids.org). Although antiretroviral therapy (ART) blocks new infection of susceptible cells and inhibits viral replication, HIV-1 infection remains incurable due to a stably integrated, but transcriptionally silent form of the virus which persists in resting memory CD4+ T cells. This small pool of latently infected cells decays very slowly with a half-life measured in years (~3.7 years) and is the major barrier to cure. SIV-infected macaques are a critical model for HIV-1 infection. Previous studies suggest the SIV latent reservoir stabilizes around 36 weeks on ART, at a frequency of intact proviruses 1-2 logs higher than in people living with HIV-1 (PLWH). However, studies assessing the dynamics of the SIV latent reservoir have been hampered by their short duration and lack of a method to quantify defective proviruses, making it unclear how the size and composition of the SIV latent reservoir compares to PLWH on long-term ART. Using a panel of ddPCR-based assays, we describe the first longitudinal analysis of the size, composition, and decay rate of the SIVmac251 latent reservoir in 10 rhesus macaques on ART for >2 years. We found that the SIV latent reservoir changes both in composition and size beyond the first year on ART – challenging assumptions that this pool of cells stabilizes around 6 months – and that intact and defective proviruses decay with different kinetics. These results indicate that further studies are required to understand the mechanisms driving persistence of infected cells and provide key insights for researchers to evaluate the efficacy of interventions aimed at reducing the size of the SIV latent reservoir

A quantitative approach for measuring the reservoir of latent HIV-1 proviruses.

A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection

Search for the dimuon decay of the Higgs boson in pppp collisions at s\sqrt{s} = 13 TeV with the ATLAS detector

International audienceA search for the dimuon decay of the Higgs boson was performed using data corresponding to an integrated luminosity of 36.1  fb-1 collected with the ATLAS detector in pp collisions at s=13  TeV at the Large Hadron Collider. No significant excess is observed above the expected background. The observed (expected) upper limit on the cross section times branching ratio is 3.0 (3.1) times the Standard Model prediction at the 95% confidence level for a Higgs boson mass of 125 GeV. When combined with the pp collision data at s=7  TeV and s=8  TeV, the observed (expected) upper limit is 2.8 (2.9) times the Standard Model prediction