CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

Background: HIV set point viral load (spVL; log 10 RNA copies/ml) strongly correlates with progression and transmission. Genome-wide association studies have shown that ~25% of the variability in spVL is due to host genetics, with the HLA and CCR5 regions being the primary drivers. However, previous studies have focused on individuals of European ancestry, thus assessing only a fraction of human genetic variation. We sought to address this gap by performing a genetic study of spVL in a large sample of individuals of African ancestry. Methods: A discovery set of 2,517 African American individuals with genome- wide genotyping and spVL data was obtained from four independent studies through the International Collaboration for the Genomics of HIV. As a replication sample, we accessed genome-wide data for 533 individuals from 3 studies in eastern and southern Africa and performed direct genotyping in 117 individuals of African descent living in Switzerland (Ncombined=3,167). Association was tested between spVL and genetic variants by linear regression. Discovery and replication results were combined by meta-analysis. Bioinformatic analysis included variant annotation for modification of protein function and gene expression. Results: In the discovery sample, we observed a novel association between spVL and rs77029719 (p=5.7x10-8; β=-0.30) which was confirmed in the replication set (Pcombined=7x10-10 ; βcombined=-0.31). The effect of rs77029719 was remarkably consistent across populations, with the G allele associating with lower spVL in all groups (range = -0.2 to -0.5 log 10 (copies/ ml)). This variant being located on chromosome 1, this association cannot be explained by the known effects of HLA (chr6) or CCR5 (chr3). rs77029719 falls within a lincRNA and shows strong linkage (r2 > 0.6) with several variants across four genes (CHD1L, FMO5, PDIA3P, PRKAB2). Bioinformatic analysis suggests that rs77029719 plays a role in regulating splicing and expression of CHD1L, which encodes a DNA helicase protein that interacts with PARP1, an enzyme implicated in HIV integration. Interestingly, rs77029719 is only present in populations of African descent, suggesting a population-specific mechanism of HIV control. Conclusion: We identified an African specific genetic locus that controls HIV replication in vivo with a potential role in modulating HIV integration. These findings suggest a potential new target for anti-HIV drug development and demonstrate the critical need to perform genetic studies in multiple populations. 15 HOST FACTORS ASSOCIATED WITH BNAB DEVELOPMENT IN HIV-1 CONTROLLERS 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 University of California San Diego, La Jolla, CA, USA, 3 MIT Institute for Medical Engineering & Science, Cambridge, MA, USA, 4 Brigham and Women’s Hospital, Boston, MA, USA Background: Induction of broadly neutralizing antibodies (bNAbs) is highly desired for a preventive vaccine against HIV-1. Typically, bNAbs develop under high levels of viremia and immune activation; nevertheless, Abs with high neutralizing breadth are also produced in some untreated HIV-1 controllers with low viral loads. However, specific host factors promoting these Ab responses have not been identified yet. Here, we analyzed transcriptional and functional features of primary conventional dendritic cells (cDCs), monocytes (Mo) and B cells from HIV-1 controller groups with different levels of neutralizing Ab breadth against HIV-1. Methods: RNAseq was performed from sorted circulating cDC, B cells and Mo from HIV-1 controllers with (Neut, n=46) or without (Non Neut, n=15) any detectable neutralizing Ab breadth against 11 tested HIV-1 strains. In addition, the ability of primary cDC to prime allogeneic naïve CD4+ T cells into CXCR5+ PD-1+ Bcl-6+ T follicular helper cells (Tfh) was analyzed in functional in vitro assays. Results: Transcriptional signatures in cDC from controllers with neutralization breadth exhibited two distinct patterns: one group (Neut1; n=25) overlapping with Non Neuts and a separate subgroup of controllers (Neut2; n=21) characterized by up-regulation of inflammatory genes and activation of pathways supporting Tfh polarization. Consistently, cDC from Neut2 patients displayed superior abilities to prime Tfh-like cells in vitro compared to cDC from Neut1 (p=0.04) or Non Neut (p=0.01). Importantly, transcriptional signatures of cDCs from Neut2 appeared to be predicted by IL-12 as an upstream regulator, while Tfh-priming function of these cells was dependent on signaling through IL-12R (p=0.02) and could be enhanced in vitro by the addition of IL-12 to Enrique Martin-Gayo 1 , Hsiao Rong Chen 1 , Ce Gao 1 , Zhengyu Ouyang 2 , Dhohyung Kim 1 , Kellie E. Kolb 3 , Alex K. Shalek 3 , Bruce D. Walker 1 , Mathias Lichterfeld 4 , Xu G. Yu 1

researchers and health care workers has seen Kenyan scientists contribute to major innovations for the HIV prevention and care agenda. Capacity has included bi – directional north -south exchange programs. Infrastructure expansion and renovation of buildings and with leveraged support from philanthropic donor support has supported new clinical research sites and comprehensive care centers in the regions most affected by HIV. Community: By mid-2015, the Family AIDS Care Services (FACES) had initiated over 150,000 individuals on HIV treatment and Care, working in 150 clinics. Services provided included HTC, PMTCT, VMMC and cervical cancer screening and treatment. Collaboration: Both HIV prevention research and HIV care are qualities of the FACES program that impact the community, to reduce stigma and improve health and livelihood outcomes for individuals and their families. Success stories include participation in studies that led to the licensure and roll out of pre-exposure prophylaxis (PrEP); the proof of a 'test and treat strategy which surpassed the UNAIDS 90:90:90 targets'; enhancement of differentiated care models for HIV; a family care model for HIV care, options for integration of family planning and HIV care services, and the ongoing response to the concerns of hormonal contraception and HIV acquisition risk. The challenges of stigma, over reliance on external resources and adolescent friendly services for sexual and reproductive health and HIV care must be comprehensively addressed in order to meet the desired national and global goals. In 1981, AIDS was first recognized in gay men by astute clinicians in Los Angeles. Relatively simple epidemiologic studies pointed to an infectious etiology and established transmission routes before the identification of HIV. Subsequent studies showed the virus posed a risk to healthcare workers through occupational exposure, but was not transmitted by casual contact or mosquito bites, and provided the evidence base for health communication messages. Gay advocacy groups played an important role in expediting the approval of new antiretroviral drugs. Funding from sources such as PEPFAR and the Global Fund provided lifesaving treatment to infected persons in low-income countries. Lessons learned from the early AIDS epidemic will be tested by emerging infectious disease threats. Overall, the world is better prepared to respond to these threats now than it was in 1981. The International Health Regulations and the Global Health Security Agenda provide a framework for global health preparedness. The application of new data analytic tools to electronic health records and social media data can facilitate disease detection, and new genetic techniques help us better understand the spread of infectious diseases. Yet, effective health communication to address public fears of contagion remains a challenge, and human behavior remains difficult to change. Ending the AIDS epidemic as a public health threat will be hard, but is the goal we must pursue. Tuberculosis (TB) remains a major killer worldwide, with more than 10 million new cases each year, and 1.5 million deaths. TB is also the leading cause of death in HIV+ people throughout the world. Although effective drug treatment exists, the regimen is long (at least 6 months) and the drugs have side effects; there is also a large increase in drug resistant strains of Mycobacterium tuberculosis , complicating treatment. In addition, diagnosis of TB is not always timely, leading to transmission and delay of treatment. Although most countries vaccinate newborns with an attenuated mycobacterial strain, BCG, this vaccine has variable efficacy against infection and disease. New vaccines are urgently needed against TB, yet the types of immune responses that will provide durable protection are not clear. Novel technologies and improved animal models have led to new insights into M. tuberculosis infection, and provide clues for improved vaccines and interventions. This talk will review new approaches to our understanding of tuberculosis in humans and animal models.

Oral Abstracts

12 THE EARLY DAYS OF AIDS: LOOKING BACK AND THINKING AHEAD Harold W. Jaffe , CDC, Atlanta, GA, USA

13 PATHOGENESIS OF TUBERCULOSIS AND VACCINE PREVENTION JoAnne L. Flynn , University of Pittsburgh, Pittsburgh, PA, USA

14 IDENTIFICATION OF A NOVEL LOCUS OF HIV REGULATION IN POPULATIONS OF AFRICAN DESCENT Paul J. McLaren 1 , Deepti Gurdassani 2 , Manj Sandhu 2 , Jacques Fellay 3

1 Public Health Agency of Canada, Winnipeg, MB, Canada, 2 Wellcome Trust Sanger Institute, Hinxton, UK, 3 École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

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CROI 2018