CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

proteins of epidemic HIV1 group O viruses target a region adjacent to the deletion in human tetherin to increase virion release from infected CD4+ T cells. Thus, potent tetherin counteraction may be a prerequisite for the efficient spread of lentiviruses in the human population. The coevolution of tetherin with primate lentiviruses, the molecular mechanisms underlying its antagonism and implications for spread and pathogenesis of human immunodeficiency viruses will be presented. 123-A Innate Sensing of HIV-1 in Macrophages Martin R. Jakobsen Aarhus University, Aarhus C, Denmark Given the important role of cytosolic DNA in stimulating innate immune responses, there is an intense interest in defining the sensors of HIV DNA and the cellular mechanisms underlying subsequent induction of Interferon (IFN). The innate immune response is orchestrated in a complex manner where various pathogen recognition receptors scavenge for pathogen associated molecular patterns. Within the last years our understanding of how HIV is sensed by immune cells has increased significantly. The major break-through was the identification of cyclic GMP-AMP (cGAMP) synthetase (cGAS) as the innate sensor of foreign DNA. Activation of cGAS initiates the production of cGAMP, which in turn acts as the second messenger binding to the ER-bound protein STING and triggering IFN production. The role of cGAS as the pivotal DNA sensor is very compelling and supported by in vitro data, crystal structures, and a strong phenotype of cGAS-deficient mice. Accumulating evidence suggests, however, that another DNA sensor, Interferon gamma inducible factor 16 (IFI16), also play a key role in the recognition of HIV DNA. IFI16 was originally described as a nuclear protein involved in the regulation of transcription, and chromatic remodeling. In 2010 it was shown, however, that cytosolic IFI16 is responsible for recognizing HSV-1 DNA (Unterholzner, Nature Immunology, 2010). At the same time as cGAS was described as a HIV sensor (Gao et al. Science 2013), we demonstrated that IFI16 was critical for triggering innate immune responses against HIV in macrophages and that IFI16 depletion significantly increased HIV replication (Jakobsen et al, PNAS 2013). More recent data now suggest that IFI16 may also play an essential role in the depletion of CD4+ T cells by recogniting reverse transcriptase intermediates from abortive infections, which lead to caspase-1 activation and IL-1ß release (Doitsh et al. Nature 2014). In conclusion, IFI16 and cGAS clearly play key roles in sensing HIV, but perhaps even more importantly, we now know that recognition of HIV triggers robust antiviral and inflammatory responses, as well as cell death mechanisms that impact HIV immunopathogenesis. In this talk, I will discuss the interplay between HIV-1 infection and cytosolic PRRs recognition. Furthermore, I will touch upon new interesting functions of IFI16 in the cGAS-STING pathway and in directly suppressing HIV transcription. 124 Innate Sensing and Signaling to HIV-1 in Dendritic Cells Teunis Geijtenbeek Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands Dendritic cells (DCs) are central players in the induction of innate and adaptive immunity to HIV-1. Innate sensing of pathogens by pattern recognition receptors (PRRs) triggers signaling pathways that lead to the induction of DC maturation, antiviral type I IFN responses and cytokine responses, and subsequent induction of specific T helper cell differentiation and adaptive immunity. It is becoming clear that early innate immune responses greatly affect susceptibility as well as chronic disease progression. Our recent data have uncovered an important role for type I IFN responses in the induction of follicular T helper cells, which can affect disease progression by inducing strong antibody responses. However, several viruses including HIV-1 have developed strategies to prevent innate sensing and/or innate signaling and identification of these mechanisms greatly facilitate development of novel strategies to combat infections. Here I will discuss the role of innate signaling by different pattern recognition receptors, including DC-SIGN and TLR8, in infection of DCs and modulation of innate and adaptive immune responses. Recent data strongly sugges that although DCs are equipped with innate sensors for HIV-1, the virus has developed various strategies to either escape or counteract sensing and induction of antiviral immunity. 125 How HIV-1 Evades DNA Sensors Vineet KewalRamani National Cancer Institute, Frederick, MD, US Retroviruses must replicate their genomes in the presence of cytosolic DNA sensors capable of triggering an antiviral response. Here we demonstrate that HIV-1 reverse transcribed DNA products are shielded from cytosolic DNA sensors by the HIV-1 core. Treatment of HIV-1 infected cells with the capsid-binding drug PF-3450074 releases DNA products into the cytosol where they can stimulate the cGAS-STING pathway and produce a type I IFN response. HIV-1 coordinates reverse transcription and uncoating to minimize exposure of DNA products, and perturbation of either process can influence the ability of HIV-1 to induce a type I IFN response. Both wild-type and capsid-mutant HIV-1 isolates stimulate an antiviral response in macrophages that is dependent on viral DNA synthesis and impedes subsequent rounds of virus infection. Collectively, these results illustrate the interdependence of reverse transcription and uncoating, and the importance of coordinating these two viral activities to avoid immune stimulation. Session S-5 Symposium Room 6D 4:00 pm– 6:00 pm Advancing HIV Prevention: Lessons from Biology, Medicine, and Public Health Law 126 The Biology of HIV Transmission: What We ThinkWe Know and HowWe Know It Julie M. Overbaugh Fred Hutchinson Cancer Research Center, Seattle, WA, US Biomedical prevention of HIV depends on blocking early events in the transmission process. Thus, designing and testing prevention strategies using appropriate model systems that mimic the biology of HIV transmission may help optimize the chances for success. There is, in fact, little direct information about the biology of HIV transmission in humans because this window is difficult to capture. However, plausible theories about this process can be inferred from studies of the properties of transmitted viruses and from early events in model systems. This lecture will discuss how these findings have helped inform our understanding of HIV transmission biology as well as the limitations of this knowledge. 127 HIV Phylogenetics: Lessons for HIV Prevention Christophe Fraser Imperial College London, London, United Kingdom HIV phylogenetics, the study of viral genetic sequences, is used to track the spread of different viral lineages, and to identify likely transmission events, chains and clusters. Phylogenetics enhances HIV prevention science by quantifying the risk factors for onwards transmission, resolving epidemics into sub-epidemics, and identifying common routes of transmission. In discordant pair studies, such as HPTN 052, phylogenetics is used to determine whether transmission events could or could not have occurred within the studied couple. This increases the power and accuracy of such studies.

Oral Abstracts

161

CROI 2015