RESUMO
PURPOSE OF REVIEW: In 2019, the US government launched an initiative to decrease new HIV infections by 90% over the next decade. Studies have demonstrated the efficacy of HIV preexposure prophylaxis (PrEP) for high-risk populations, and the United States Preventative Services Task Force has issued a grade A recommendation for PrEP, indicating substantial net benefit. However, questions have been raised about the effectiveness of PrEP in clinical settings and whether PrEP use might promote antiretroviral drug resistance and increased sexual risk behaviors, which could increase transmission of bacterial sexually transmitted infections. In this narrative review, we summarize recent evidence of the effectiveness of PrEP when provided in clinical and community settings, the emergence of antiretroviral drug resistance during PrEP use, and associations between PrEP use and increased sexual risk behaviors. We also review novel PrEP modalities that are being developed to optimize PrEP acceptability, adherence, and effectiveness. RECENT FINDINGS: Studies suggest that PrEP is effective when provided in clinical settings. However, PrEP uptake and impact have been limited in the USA thus far, and major disparities in access to PrEP exist. In addition, there is evidence that drug resistance can occur with PrEP use, particularly with inadvertent PrEP use during undiagnosed acute HIV infection. Risk compensation can also occur with PrEP use and has been associated with increased sexually transmitted infections. Promising new modalities for PrEP could expand options. PrEP has strong potential to decrease HIV incidence. However, disparities in access must be addressed to ensure equity and impact for PrEP. While drug resistance and risk compensation can occur with PrEP use, these are not valid reasons to withhold PrEP from patients given its substantial protective benefits.
RESUMO
Enteroaggregative Escherichia coli (EAEC) bacteria are exceptional colonizers that are associated with diarrhea. The genome of EAEC strain 042, a diarrheal pathogen validated in a human challenge study, encodes multiple colonization factors. Notable among them are aggregative adherence fimbriae (AAF/II) and a secreted antiaggregation protein (Aap). Deletion of aap is known to increase adherence, autoaggregation, and biofilm formation, so it was proposed that Aap counteracts AAF/II-mediated interactions. We hypothesized that Aap sterically masks heat-resistant agglutinin 1 (Hra1), an integral outer membrane protein recently identified as an accessory colonization factor. We propose that this masking accounts for reduced in vivo colonization upon hra1 deletion and yet no colonization-associated phenotypes when hra1 is deleted in vitro. Using single and double mutants of hra1, aap, and the AAF/II structural protein gene aafA, we demonstrated that increased adherence in aap mutants occurs even when AAF/II proteins are genetically or chemically removed. Deletion of hra1 together with aap abolishes the hyperadherence phenotype, demonstrating that Aap indeed masks Hra1. The presence of all three colonization factors, however, is necessary for optimal colonization and for rapidly building stacked-brick patterns on slides and cultured monolayers, the signature EAEC phenotype. Altogether, our data demonstrate that Aap serves to mask nonstructural adhesins such as Hra1 and that optimal colonization by EAEC is mediated through interactions among multiple surface factors. IMPORTANCE Enteroaggregative Escherichia coli (EAEC) bacteria are exceptional colonizers of the human intestine and can cause diarrhea. Compared to other E. coli pathogens, little is known about the genes and pathogenic mechanisms that differentiate EAEC from harmless commensal E. coli. EAEC bacteria attach via multiple proteins and structures, including long appendages produced by assembling molecules of AafA and a short surface protein called Hra1. EAEC also secretes an antiadherence protein (Aap; also known as dispersin) which remains loosely attached to the cell surface. This report shows that dispersin covers Hra1 such that the adhesive properties of EAEC seen in the laboratory are largely produced by AafA structures. When the bacteria colonize worms, dispersin is sloughed off, or otherwise removed, such that Hra1-mediated adherence occurs. All three factors are required for optimal colonization, as well as to produce the signature EAEC stacked-brick adherence pattern. Interplay among multiple colonization factors may be an essential feature of exceptional colonizers.