Background The latent HIV-1 reservoir in treated patients primarily consists of resting memory CD4 + T cells. Stimulating the T-cell receptor (TCR), which facilitates transition of resting into effector T cells, is the most effective strategy to purge these latently infected cells. Here we supply evidence that TCR-stimulated effector T cells still frequently harbor latent HIV-1. Methods Primary HIV-1 infected cells were used in a latency assay with or without dendritic cells (DCs) and reversion of HIV-1 latency was determined, in the presence or absence of specific pathway inhibitors. Findings Renewed TCR-stimulation or subsequent activation with latency reversing agents (LRAs) did not overcome latency. However, interaction of infected effector cells with DCs triggered further activation of latent HIV-1. When compared to TCR-stimulation only, CD4 + T cells from aviremic patients receiving TCR + DC-stimulation reversed latency more frequently. Such a “one-two punch” strategy seems ideal for purging the reservoir. We determined that DC contact activates the PI3K-Akt-mTOR pathway in CD4 + T cells. Interpretation This insight could facilitate the development of a novel class of potent LRAs that purge latent HIV beyond levels reached by T-cell activation.

Introduction: Recurrent urinary tract infections (rUTI) largely contribute to antibiotic use in older adults. Understanding the genetic characteristics of Escherichia coli (E.coli) is needed to identify patients at risk for recurrence. The aim of this study was to obtain a greater understanding of the genetics of E. coli rUTI in nursing home residents. Methods: This is a secondary analysis of a multicenter Dutch nursing home study (PROGRESS). E. coli strains from residents with a suspected UTI and positive urine culture were analyzed using antimicrobial susceptibility testing and whole-genome sequencing (WGS). Same-strain recurrences were identified by single-nucleotide polymorphism (SNP) analysis. Result: In total, 121 E. coli strains were analyzed using WGS, of which 54 belonged to a rUTI episode. One third of E. coli rUTI episodes were caused by the same strain (n = 18, 33.3%). Same-strain recurrence occurred anywhere between 30 and 434 days after the index UTI, caused by sequence types (ST): ST12, ST23, ST73, ST131, ST453, ST538 and ST2522, in seven nursing home residents. In both single UTI and rUTI, antimicrobial resistance rates were low. Conclusion: Recurrent UTI in nursing home residents are caused by same-strain E. coli as well as due to different E. coli strains or other uropathogens. Same-strain recurrence can occur over 400 days after the index UTI, suggesting that some strains have the ability to colonize the bladder or gut for longer periods.

No abstract