Qualitative characterizations of relationships among South African adolescent girls and young women and male partners: implications for engagement across HIV self-testing and pre-exposure prophylaxis prevention cascades.

INTRODUCTION: Adolescent girls and young women (AGYW) in sub-Saharan Africa have emerged as a priority population in need of HIV prevention interventions. Secondary distribution of home-based HIV self-test kits by AGYW to male partners (MP) is a novel prevention strategy that complements pre-exposure prophylaxis (PrEP), a female-controlled prevention intervention. The objective of this analysis was to qualitatively operationalize two HIV prevention cascades through the lens of relationship dynamics for secondary distribution of HIV self-tests to MP and PrEP for AGYW. METHODS: From April 2018 to December 2018, 2200 HIV-negative AGYW aged 16-24 years were enrolled into an HIV prevention intervention which involved secondary distribution of self-tests to MP and PrEP for AGYW; of these women, 91 participants or MP were sampled for in-depth interviews based on their degree of completion of the two HIV prevention cascades. A grounded theory approach was used to characterize participants' relationship profiles, which were mapped to participants' engagement with the interventions. RESULTS: In cases where AGYW had a MP with multiple partners, AGYW perceived both interventions as inviting distrust into the relationship and insinuating non-monogamy. Many chose not to accept either intervention, while others accepted and attempted to deliver the self-test kit but received a negative reaction from their MP. In the few cases where AGYW held multiple partnerships, both interventions were viewed as mechanisms for protecting one's health, and these AGYW exhibited confidence in accepting and delivering the self-test kits and initiating PrEP. Women who indicated intimate partner violence experiences chose not to accept either intervention because they feared it would elicit a violent reaction from their MP. For AGYW in relationships described as committed and emotionally open, self-test kit delivery was completed with ease, but PrEP was viewed as unnecessary. MP experience with the cascade corroborated AGYW perspectives and demonstrated how men can perceive female-initiated HIV prevention options as beneficial for AGYW and a threat to MP masculinity. CONCLUSIONS: Screening to identify AGYW relationship dynamics can support tailoring prevention services to relationship-driven barriers and facilitators. HIV prevention counseling for AGYW should address relationship goals or partner's influence, and engage with MP around female-controlled prevention interventions.

Glucose depletion inhibits translation initiation via eIF4A loss and subsequent 48S preinitiation complex accumulation, while the pentose phosphate pathway is coordinately up-regulated.

Cellular stress can globally inhibit translation initiation, and glucose removal from yeast causes one of the most dramatic effects in terms of rapidity and scale. Here we show that the same rapid inhibition occurs during yeast growth as glucose levels diminish. We characterize this novel regulation showing that it involves alterations within the 48S preinitiation complex. In particular, the interaction between eIF4A and eIF4G is destabilized, leading to a temporary stabilization of the eIF3-eIF4G interaction on the 48S complex. Under such conditions, specific mRNAs that are important for the adaptation to the new conditions must continue to be translated. We have determined which mRNAs remain translated early after glucose starvation. These experiments enable us to provide a physiological context for this translational regulation by ascribing defined functions that are translationally maintained or up-regulated. Overrepresented in this class of mRNA are those involved in carbohydrate metabolism, including several mRNAs from the pentose phosphate pathway. Our data support a hypothesis that a concerted preemptive activation of the pentose phosphate pathway, which targets both mRNA transcription and translation, is important for the transition from fermentative to respiratory growth in yeast.

Stress-dependent relocalization of translationally primed mRNPs to cytoplasmic granules that are kinetically and spatially distinct from P-bodies.

Cytoplasmic RNA granules serve key functions in the control of messenger RNA (mRNA) fate in eukaryotic cells. For instance, in yeast, severe stress induces mRNA relocalization to sites of degradation or storage called processing bodies (P-bodies). In this study, we show that the translation repression associated with glucose starvation causes the key translational mediators of mRNA recognition, eIF4E, eIF4G, and Pab1p, to resediment away from ribosomal fractions. These mediators then accumulate in P-bodies and in previously unrecognized cytoplasmic bodies, which we define as EGP-bodies. Our kinetic studies highlight the fundamental difference between EGP- and P-bodies and reflect the complex dynamics surrounding reconfiguration of the mRNA pool under stress conditions. An absence of key mRNA decay factors from EGP-bodies points toward an mRNA storage function for these bodies. Overall, this study highlights new potential control points in both the regulation of mRNA fate and the global control of translation initiation.

Regulation of translation initiation by the yeast eIF4E binding proteins is required for the pseudohyphal response.

The eukaryotic translation initiation factor eIF4E is responsible for the recognition of the mRNA cap structure and, as such, plays a key role in the selection of mRNAs for translation. The interaction of eIF4E with the 'multi-adaptor' eIF4G (and thus recruitment of ribosomes to mRNA) can be regulated via competitive binding of 4E-binding proteins (4E-BPs). 4E-BPs have broad functions in cell growth, proliferation and development. We have found that disruption of the genes for either of the yeast 4E-BPs (Eap1p or Caf20p) leads to an inhibition of pseudohyphal growth in the resulting diploid yeast strain following nitrogen limitation. Specific 4E-binding domain mutations destroy the capacity of each 4E-BP gene to complement the non-pseudohyphal phenotype, suggesting that a translational function for the 4E-BPs is important for pseudohyphal growth. In addition, neither of the 4E-BP deletion strains is deficient in global or stress-regulated protein synthesis. However, our evidence reveals that the two 4E-BPs are functionally distinct with regard to pseudohyphal growth. Therefore, this work supports a model where the yeast 4E-BPs are acting on specific mRNAs to facilitate a defined proliferative response to environmental stress in yeast.