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McCann et al. describe the development and characterization of a new mouse model for studying HIV-specific T cell responses and testing various immunotherapeutic strategies, which they validate by demonstrating enhanced therapeutic effects of autologous HIV-specific T cells augmented with cytokine-loaded nanogels., HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This “participant-derived xenograft” model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.

OBJECTIVES/GOALS: HIV-specific CD8+ T-cells play a critical role in partially controlling viral replication in infected-individuals, but ultimately fail to eliminate infection. Enhancing these T-cell responses through lymphocyte engineering approaches has the potential as a novel therapy capable of achieving durable control or eradication of infection. METHODS/STUDY POPULATION: IL-15 Superagonist (IL-15SA) potently supports the in vivo persistence and antiviral activity of adoptively transferred CD8+ T-cells. The Deep-PrimingTM technology platform, developed by Torque, allows for loading of immunomodulators onto the surface of T-cells via electrostatic ‘nanogels’, which slowly release to deliver sustained autocrine immune stimulation without the harmful effects of systemic exposure. Here, we investigate the impact of IL-15SA Deep-Priming on HIV-specific CD8+ T-cells in a humanized mouse model of HIV infection. Humanized mice were generated by engrafting NOD-scid-IL2Rgnull mice with memory CD4+ T-cells isolated from an ARV-suppressed HIV+ donor. An autologous HIV-specific Cytotoxic T-Lymphocyte (CTL) clone was isolated, and killing potential confirmed. Four weeks post humanization, mice were infected with HIV and received an infusion of unmodified HIV-Specific CTLs, or IL-15SA Deep-Primed HIV-specific CTLs (CTL-DP). T-cell numbers and plasma viral loads were quantified weekly by flow cytometry and qRT-PCR. RESULTS/ANTICIPATED RESULTS: Mice receiving unmodified CTLs trended toward reduced viral loads compared to the No Treatment condition, while mice receiving CTL-DP saw significant, 2-Log10 reductions in VL (p < 0.01). At 41 days post-infection 100% (5/5) of the No Treatment, 66.7% (4/6) of the CTL treatment, and 16.7% (1/6) of CTL-DP treatment mice had detectable viremia. IL-15SA Deep-Priming increased CTL expansion and persistence in peripheral blood which correlated with improved CD4+T-cell preservation. DISCUSSION/SIGNIFICANCE OF IMPACT: Here we demonstrate the first in vivo analysis of IL-15SA Deep-Priming of HIV-Specific CTLs. These data suggest that Deep-Priming of patient T-cells can enhance in vivo function and persistence, leading to improved viral suppression; a significant advancement in the field of HIV cure research. CONFLICT OF INTEREST DESCRIPTION: Austin Boesch, Thomas Andresen, and Douglas Jones are employees of Torque. Darrell Irvine is a co-founder of Torque and Chairman of Torque’s Scientific Advisory Board.

The DC Cohort is an ongoing longitudinal observational study of persons living with HIV. To better understand HIV-1 drug resistance and potential transmission clusters among these participants, we performed targeted, paired-end next-generation sequencing (NGS) of protease, reverse transcriptase and integrase amplicons. We elected to use free, publicly-available software (HyDRA Web, Stanford HIVdb and HIV-TRACE) for data analyses so that laboratory personnel without extensive bioinformatics expertise could use it; making the approach accessible and affordable for labs worldwide. With more laboratories transitioning away from Sanger-based chemistries to NGS platforms, lower frequency drug resistance mutations (DRMs) can be detected, yet their clinical relevance is uncertain. We looked at the impact choice in cutoff percentage had on number of DRMs detected and found an inverse correlation between the two. Longitudinal studies will be needed to determine whether low frequency DRMs are an early indicator of emerging resistance. We successfully validated this pipeline against a commercial pipeline, and another free, publicly-available pipeline. RT DRM results from HyDRA Web were compared to both SmartGene and PASeq Web; using the Mantel test, R2 values were 0.9332 (p

To compare different intervention models for promoting male circumcision (MC) to prevent HIV transmission in Western China. A total of 1690 male participants from multiple study sites were cluster randomly allocated to three-stage (Model A), two-stage (Model B), and one-stage (Model C) educational interventions. In all three interventions models, knowledge about MC significantly increased and the reported willingness to accept MC increased to 52.6% (255/485), 67.0% (353/527), and 45.5% (219/481) after intervention, respectively (P

The primary objective of this study was to obtain insights into the outcomes of people living with HIV who accessed services through HIV/AIDS sentinel hospital-based and ART service delivery in China. Post-hoc analyses of an open cohort from an observational database of 22 qualified HIV/AIDS sentinel hospital-based and two CDC-based drug delivery facilities (DDFs) in Guangdong Province was completed. Linkage to care, mortality and survival rates were calculated according to WHO criteria. 12,966 individuals received ART from HIV/AIDS sentinel hospitals and 1,919 from DDFs, with linkage to care rates of 80.7% and 79.9%, respectively (P > 0.05). Retention rates were 94.1% and 84.0% in sentinel hospitals and DDFs, respectively (P

Extranasal sites are common reservoirs of Staphylococcus aureus colonization and may be relevant for methicillin-resistant S. aureus (MRSA) screening and infection control strategies. The objective here was to determine whether inguinal specimens could also be screened using Xpert SA Nasal Complete assay for MRSA. Results were compared to broth enrichment culture. Among 162 consented adults seeking care in the emergency department for cutaneous abscesses, inguinal specimens were found positive for MRSA more often than nares specimens, 24% and 26% by PCR or culture, respectively, compared to 19% each by PCR or culture. Overall, 6% of adults colonized with MRSA would have been missed by nares screening alone. Compared to culture, Xpert SA Nasal Complete assay demonstrated sensitivity and specificity of 89% and 97%, respectively, for detecting nares and/or inguinal MRSA colonization. In conclusion, inguinal specimens were a more common reservoir for MRSA than nares specimens in this population of patients.

Background Enormous efforts have been made to decentralise HIV service delivery in China, gradually developing a network of thousands of Centres For Disease Control And Prevention (CDCs) with or without local hospitals providing antiretroviral therapy (ART) to every village or equivalent. However, in the Guangdong Province, China, most infected patients from CDCs delivering HIV services have been switched to sentinel hospitals, providing an opportunity to examine this shift on linkage to care, retention, and mortality among people living with HIV. We examined long-term outcomes of people living with HIV who accessed services through sentinel hospitals and CDCs in the Guangdong Province. Methods This is a post-hoc analyses of an open cohort from an observational database of 22 qualified HIV/AIDS sentinel hospitals and two CDC-based drug delivery health facilities in Guangdong. We recruited all outpatients of health facilities receiving ART from Jan 1, 2005, to June 1, 2014. Patients were excluded if they did not start triple drug therapy based ART, had missing treatment regimen information, or used ART outside of national guidelines. We followed up the patients for 10 years. We defined and calculated linkage to initial ART, mortality, overall survival, and retention rate according to the WHO Guideline 2006 for ART in HIV infection in adult. The institutional review board of the Guangzhou Eighth People's Hospital approved this analysis. Written informed consent was obtained from all patients. Findings Of the 18 921 people living with HIV, 14 885 (79%) were initiated ART with follow-up, and thus were available for analysis. Among these participants, 12 966 (87%) individuals received ART from hospitals and 1919 (13%) received ART from a CDC, the linkage to care was 80·7% in hospitals and 79·9% in CDC facilities (p=0·352). Excess mortality was 1·4 deaths per 100 person-years (95% CI 1·1–1·8) in CDC facilities compared with 0·4 deaths per 100 person-years (0·3–0·5) in hospitals (p=0·001). A Cox-regression analysis showed that mortality was much higher in patients receiving ART from the CDC-based health facilities than in those receiving ART from the sentinel hospitals, with an adjusted hazard ratio (HR) of 3·3 (95% CI 2·3–4·6). Kaplan–Meier analysis showed a mean overall survival time of 105·3 months (95% CI 104·6–106·1) in the hospital group compared with 78·7 months (76·2–81·2) in the CDC group (p Interpretation Sentinel hospital HIV service delivery had better retention, and substantially lower mortality than did CDC-based service delivery. This study has implications for the expansion HIV service delivery, and should be made to adopt a sentinel hospital-based system of integrated HIV care and treatment. Funding This study was supported by Twelve Fifth Key Research grant from the Ministry of Science and Technology, People's Republic of China ( 2012ZX10001003–003 ), Science and Technology Program of Guangzhou ( 201300000092 ), and the US National Institutes of Health Fogarty International Center Global Infectious Diseases Training Grant ( 1D43TW009532–01 ). These fundings had no role in study design and data analyses.