CROI 2017 Abstract e-Book

Abstract eBook

Oral Abstracts

secondary lymphoid tissues, establishment and expansion of T cell clones bearing clonally integrated proviruses, and other mechanisms, and provide the basis for experiments to evaluate the safety and in vivo activity of strategies to target residual viral reservoirs. Contributions of NHP studies to our understanding in these areas and recent developments will be reviewed, underscoring the key role that NHP models have played and will continue to play in our efforts to develop more definitive approaches for preventing, treating, and attempting to cure HIV infection. 11 N’GALY-MANN LECTURE: HIV/AIDS RESEARCH IN ZIMBABWE: PROVIDING THE EVIDENCE FOR QUALITY CARE James G. Hakim, University of Zimbabwe, Harare, Zimbabwe Following the report of the first case of AIDS in Zimbabwe in 1985 the epidemic escalated rapidly reaching an adult prevalence of 29% in the late 1990s. Given the heterosexual and generalized nature of the epidemic the social, health and economic consequences were devastating. This presentation will describe (a) some historical perspectives of AIDS and the current status of the epidemic in Zimbabwe (b) Zimbabwe’s contribution to cutting edge AIDS research (c) human and research capacity building as an essential aspect of the comprehensive response to the AIDS epidemic. As the health sector and the social fabric of the country reeled under the effects of the epidemic the government took a series of steps which proved visionary given the considerable resource constraints that beset the country. An aggressive behavior change campaign, the introduction of the AIDS levy (domestic financing scheme) and the local manufacture of ARVs defying patent restrictions stand out as significant home-grown solutions complementing the global support the country was receiving. Recent data show an adult prevalence of 14.6%, incidence of 0.48% (a drop of 50% over the past 1½ decades); 900,000 people on ART and a viral suppression rate of 60.4%. Challenges remain and achievement of global targets including ending AIDS are prime aspirations for the country. In the mid-90’s driven by a desire to understand the AIDS epidemic and to contribute to mitigating its effects a small band of researchers with collaborators in the US and UK embarked on high impact research in the face of meager resources and a challenging socioeconomic environment. Data emanating from these efforts have contributed significantly to local and international HIV/AIDS knowledge base and interventions. Personal relations between local and external researchers have been key ingredients in research capacity building and in escalating research in Zimbabwe. HIV prevention and therapeutics research encompassed pMTCT, microbicides, ART strategies and ART in naïve and experienced patients. Other research efforts included tuberculosis, cryptococcal disease, cervical cancer, Kaposi’s sarcoma, mental health and studies among commercial sex workers. In recent years opportunities provided by PEPFAR, NIH, Wellcome Trust and others have enabled the implementation of robust training programs to improve the quality of health delivery and create the next generation of competent researchers and health provider. HIV cure is a desirable goal for children and adults living with HIV who face stigma and life-long antiretroviral therapy (ART) that requires strict adherence. In addition, treatment cost poses a significant burden to national programs and global donors that could be alleviated were a cure available. The ultimate objective is to eliminate all cells capable of producing HIV – a near unattainable goal with current therapies. The field has re-calibrated the HIV cure target to a more achievable one of HIV remission, i.e., the ability to control viral replication after ART interruption to levels below detection. The major obstacle is, however, the seeding of the HIV reservoir that occurs early during acute HIV infection and sets the stage for the establishment of latent reservoirs, particularly in long-lived CD4+ T cells and lymphoid tissues. The unique aspects of the pediatric immune system in the composition of the CD4+ T cell compartment and defense against HIV may influence HIV persistence. Early ART is an important step in the path towards an HIV cure. The pediatric population offers a unique opportunity for immediate treatment because of the known timing of HIV exposure in most newborns. Similarly, acute HIV infection studies have demonstrated the ability to identify and treat very early infection in adults. Both children and adults treated in acute HIV infection achieve significantly smaller HIV reservoirs, preserved immune functions with little viral escape to immune pressure. These qualities could enhance the effects of immune-based interventions aimed at depleting HIV-infected cells. However, despite these favorable qualities, the majority of early treated individuals do not achieve HIV remission. Therefore, additional therapies will be needed that may include latency reversing agents and passive and active immune therapies. There are exciting new developments of broadly neutralizing antibodies and therapeutic HIV vaccines that could be beneficial to HIV cure. It is highly likely that combination therapies that can generate persistent and effective immune responses to control HIV will be required for a durable HIV remission and cure. In this early discovery phase of HIV cure research that is associated with risks and uncertainties, and further complicated by the difficult concepts of remission and cure, it is also important that ethical, behavioral and social research be conducted in parallel to basic and clinical research. 13 ADVANCES IN CELLULAR THERAPY IN CANCER AND HIV Carl H. June, Univ of Pennsylvania, Philadelphia, PA, USA Chimeric antigen receptor (CAR) T cells have proven that engineered immune cells can serve as a powerful new class of cancer therapeutics. Clinical experience has helped to define the major challenges that must be met to make engineered T cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors. Here I will discuss a road opened CAR T cells for cancer that leads to therapies for HIV. The emergence of synthetic biology approaches for cellular engineering is providing us with a broadly expanded set of tools for programming immune cells that can be used to contain or confer elite controller status on patients with HIV. The convergence of the field of HIV and Cancer is driven in part because both are chronic conditions of antigen overload, where chronic infections and tumors can lead to phenocopies of acquired tolerance and antigen escape. 14LB QUATERNARY CONFIGURATION OF THE FUNCTIONAL CD4-BINDING SITE IN THE HIV-1 ENV TRIMER Qingbo Liu 1 , Priyamvada Acharya 1 , Michael Dolan 1 , Peng Zhang 1 , Aliaksandr Druz 1 , William Rice 2 , Bridget Carragher 2 , Clinton Potter 2 , Peter D. Kwong 1 , Paolo Lusso 3 1 NIH, Bethesda, MD, USA, 2 New York Structural Bio Cntr, New York, NY, USA, 3 NIAID, Bethesda, MD, USA Background: Binding of the gp120 envelope glycoprotein to the CD4 receptor is the first step in the HIV-1 infectious cycle. Although the CD4-binding site has been extensively characterized by mutagenesis and co-crystallization with soluble CD4 (sCD4), most of these studies were performed with monomeric gp120 subunits, thus hindering the evaluation of the role of quaternary elements that may be involved in the initial CD4 interaction. Moreover, the initial receptor interaction has been difficult to study because of major CD4- induced structural rearrangements. Methods: The DS-SOSIP.664 trimer, 4-domain CD4, and PGT145 Fab were expressed in 293FS cells and purified for cryogenic electron microscopy (cryo-EM) analysis; data were acquired using the Leginon system installed on a Krios electron microscope operating at 300kV; for ELISA and SPR, wild-type (WT) and mutated SOSIP trimers and gp120 monomers were expressed in 293FS and extensively purified; WT and mutated full-length gp160 were expressed in 293T cells for flow cytometry and co-transfected with an HIV-1 backbone plasmid to produce infectious pseudoviruses; infectivity assays were performed in TZMbl cells. Results: Cryo-EM analysis of the stabilized DS-SOSIP.664 trimer, which remains in a pre-fusion closed conformation after interaction with CD4, permitted to visualize the initial contact with CD4 at 6.8-Å resolution. We found that the initial CD4-contact site in the HIV-1 Env trimer is constituted by a quaternary surface formed by coalescence of the previously defined CD4-binding region in the outer domain of one gp120 protomer with a second CD4-binding site (CD4-BS2) that encompasses discontinuous elements from the inner domain of a neighboring gp120 protomer. Disruption of CD4-BS2 destabilized CD4-trimer interaction and abrogated HIV-1 infectivity by preventing acquisition of coreceptor- binding competence. A corresponding reduction in HIV-1 infectivity occurred upon mutation of CD4 residues that interact with CD4-BS2. Quaternary interactions were also documented for selected neutralizing antibodies to the CD4 supersite, providing evidence that the CD4-BS2 region is immunogenic in vivo. Conclusion: These results document the critical role of quaternary interactions in the initial HIV-1 envelope-receptor contact, with implications for treatment and vaccine design. 12 THE EMERGING POTENTIAL FOR HIV CURE FOR INFANTS, CHILDREN, AND ADULTS Jintanat Ananworanich, US Military HIV Rsr Prog, USA and The Thai Red Cross AIDS Rsr Cntr, Thailand

Oral Abstracts

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CROI 2017