Recombinant HIV-2 Tat Protein (BEN)

Human immunodeficiency virus (HIV) attacks human immune system and causes life-threatening acquired immune deficiency syndrome (AIDS). Treatment with combination antiretroviral therapy (cART) could inhibit virus growth and slow progression of the disease, however, at the same time posing various adverse effects. Host ubiquitin-proteasome pathway (UPP) plays important roles in host immunity against pathogens including viruses by inducing degradation of viral proteins. Previously a series of methods for retargeting substrates for ubiquitin-proteasome degradation have been successfully established. In this study, we attempted to design and construct artificial chimeric ubiquitin ligases (E3s) based on known human E3s in order to manually target HIV-1 integrase for ubiquitin proteasome pathway-mediated degradation. Herein, a series of prototypical chimeric E3s have been designed and constructed, and original substrate-binding domains of these E3s were replaced with host protein domains which interacted with viral proteins. After functional assessment screening, 146LI was identified as a functional chimeric E3 for HIV-1 NL4-3 integrase. 146LI was then further optimized to generate 146LIS (146LI short) which has been shown to induce Lys48-specific polyubiquitination and reduce protein level of HIV-1 NL4-3 integrase more effectively in cells. Lymphocyte cells with 146LIS knock-in generated by CRISPR/Cas-mediated homology-directed repair (HDR) showed remarkably decreased integration of HIV-1 NL4-3 viral DNAs and reduced viral replication without obvious cell cytotoxicity. Our study successfully obtained an artificial chimeric E3 which can induce Lys48-specific polyubiquitination and proteasome-mediated degradation of HIV-1 NL4-3 integrase, thus effectively inhibiting viral DNA integration and viral replication upon virus infection.

Background: Test and Treat has been widely adopted throughout sub-Saharan Africa, whereby all HIV-positive individuals initiate antiretroviral therapy (ART) immediately upon diagnosis and continue for life. However, clients who feel healthy may delay ART initiation, despite being eligible under new treatment guidelines. Objective: We examined health care worker (HCW) perceptions and experiences on how feeling healthy positively or negatively influences treatment initiation among HIV-positive clients in Malawi. Methods: We conducted 12 focus group discussions with 101 HCWs across six health facilities in Central Malawi. Data were analyzed through constant comparison methods using Atlas.ti7.5. Results: Feeling healthy influences perceptions of ART initiation among HIV-positive clients. HCWs described that healthy clients feel that there are few tangible benefits to immediate ART initiation, but numerous risks. Fear of stigma and unwanted disclosure, disruption of daily activities, fear of side effects, and limited knowledge about the benefits of early initiation were perceived by HCWs to deter healthy clients from initiating ART. Conclusion: Feeling healthy may exacerbate barriers to ART initiation. Strategies to reach healthy clients are needed, such as chronic care models, differentiated models of care that minimize disruptions to daily activities, and community sensitization on the benefits of early initiation.