CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

ORAL ABSTRACTS

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PROGRAM COMMITTEE WORKSHOP FOR NEW INVESTIGATORS AND TRAINEES Moderators: John W. Mellors 1 , Serena S. Spudich 2 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 Yale University, New Haven, CT, USA The Conference for Retroviruses and Opportunistic Infections (CROI) provides a forum for basic, clinical, and epidemiologic investigators to present and discuss discoveries relevant to HIV and other major human pathogens. In this 25th year of CROI, the annual Program Committee Workshop for New Investigators and Trainees again sets the stage for the new science to be presented at the conference, by providing background and perspective in the format of succinct overview talks that provide key updates across a range of basic and clinical topics. This year, the stage will be set by a narrated animation showing an overview of the HIV life cycle of HIV at a molecular scale, presented by Dr Janet Iwasa . Dr Frank Kirchhoff will then review recent new knowledge in the field of molecular virology, including an update on the function and relevance of HIV-1 accessory factors. Dr Alexandra Trkola will report on advances in developing broadly neutralizing antibodies for prevention, therapy and vaccines and provide new insights on HIV-1 interference with immune functions. Dr Richard Chaisson will discuss new developments in HIV-related tuberculosis (TB), including next-generation molecular diagnostic tests, progress in improving treatment for multidrug resistant and extensively drug resistant TB, and new findings on TB preventive therapy and its impact on survival. Dr Wafaa El-Sadr will review the status of the HIV epidemic with a focus on its evolution and the communities and populations that are bearing the brunt of new infections. She will highlight the evolution of HIV prevention efforts, challenges faced in achieving the desired impact of various interventions and highlight current and future prevention innovations. Finally, Dr Huldrych Günthard will give an overview on the current knowledge of the latent HIV reservoir and it’s implications for cure strategies. He will discuss different mechanisms of HIV-persistence, potential residual transcription and residual replication on antiretroviral therapy and current and new cure strategies. Speakers will identify areas of controversy or gaps in knowledge that require future investigation, and direct attendees to relevant work to be presented at CROI. Moderated discussion after each talk will provide opportunities for attendees to interact with the speakers and ask questions. Embedded notions of women have negatively impacted their representation in research as investigators, research participants and consumers of research products. Stereotypical perceptions about gender also limit the depth of research exploration of disease conditions that may affect men and women differently. There are significant gender differences in the way drugs are metabolized and tolerated, their side effects, and their benefits. Women have been grossly underrepresented in human clinical trials resulting in findings which may not apply to them. Even when both sexes are included, sex-specific analyses are generally not reported. Research ‘legislation’ on inclusion of women in research has not been effective. The limited number of female researchers and silencing of voices advocating for women’s health are barriers to good science. This session will highlight these issues with a focus on necessary and practical solutions. Discussants will highlight the importance of gender mainstreaming in the design and implementation of basic and clinical research, the crucial need to have women as investigators and leaders, and the complementary role of activism for women’s issues in research. Dr Dázon Dixon Diallo will discuss the role of women as activists in research. Dr Tonia Poteat will provide a perspective of women conducting research. Dr Monica Gandhi will discuss the importance of mentorship in developing the next generation of investigators. MARTIN DELANEY PRESENTATION ON WOMEN IN RESEARCH Moderator: Lisa Diane White , SisterLove, Inc, Atlanta, GA, USA

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VIRUS-LIKE NANOCARRIER FOR DELIVERY OF BIOMOLECULES BETWEEN CELLS Joerg Votteler , University of Utah, Salt Lake City, UT, USA Targeted delivery of biomolecules such as proteins, mRNAs, and DNA editing complexes is one of the biggest challenges in realizing the promise of treating many diseases. Emerging research is demonstrating the potential of engineering viral capsids directly as vehicles and/or as inspirations for designing new nanocarrier delivery systems. This approach is attractive because viral capsid proteins have evolved to assemble, package cargoes, exit cells to form extracellular virions, and enter new cells. I will review several natural carrier systems in which increasing structural and biochemical knowledge has provided the opportunity to re-design and improve upon their native properties. I will also review systems in which our increasing understanding of the sophisticated functions of capsid proteins has inspired the de-novo design of self-assembling protein nanocages. These approaches couple symmetric modelling with computational design of new protein–protein interfaces to generate new protein assemblies with atomic level accuracy. The computationally designed nanocages can then be further optimized using directed evolution approaches to optimize their biophysical properties and to incorporate desirable functions that are tailored to specific applications. Following these general principles, we have engineered protein nanocages that direct their own release from human cells inside small membrane enclosed vesicles in a manner that resembles viral assembly and release pathways. Robust enveloped protein nanocage (EPN) biogenesis requires three elements: membrane binding, self-assembly, and recruitment of the cellular ESCRT pathway (endosomal sorting complexes required for transport). When these elements are present, EPNs can be released from cells within small membrane enclosed vesicles that each contain multiple nanocages. We have identified various combinations of membrane binding, self-assembly, and ESCRT recruiting elements that can produce EPNs efficiently, indicating that the strategy is very general. EPNs pseudotyped with viral fusion proteins can enter target cells, thereby transferring their cargos from one cell to another. I will discuss how we are now extending these systems to create new synthetic delivery systems based on the principles of virus assembly and entry. 3D AND MULTI-SCALE IMAGING OF HIV-1 SPREAD IN TISSUES Pamela J. Bjorkman , California Institute of Technology, Pasadena, CA, USA Critical aspects of HIV-1 infection occur in mucosal tissues, which contain large numbers of HIV-1 target cells that are depleted early in infection. We used electron tomography (ET) to image HIV-1 in tissues of HIV-1–infected humanized mice. The resolution and preservation quality of reconstructed tissue volumes allowed identification of budding virions and free virions in both immature and mature states. Three-dimensional imaging of an active infection provided evidence of synchronous virus release and rapid maturation and revealed differences between cultured cell and tissue infection models. More recently, we combined tissue clearing and 3D-immunofluorescence with ET to longitudinally assess early HIV-1 spread in lymphoid tissues. Immunofluorescence revealed peak infection density in gut at 10-12 days post- infection when blood viral loads were low. Human CD4+ T-cells and HIV-1– infected cells localized predominantly to crypts and the lower third of intestinal villi. Free virions and infected cells were not readily detectable by ET at 5-days post-infection, whereas HIV-1–infected cells surrounded by pools of free virions were present in ~10% of intestinal crypts by 10-12 days. ET of spleen revealed thousands of virions released by individual cells and discreet cytoplasmic densities near sites of prolific virus production. These studies highlight the importance of multiscale imaging of HIV-1–infected tissues and are adaptable to other animal models and human patient samples.

Oral Abstracts

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CROI 2018