CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

modes are successively organized as increasingly higher-order structures that culminate in a TRIM5 cage surrounding the capsid. Cage formation explains the mechanism of restriction and provides the structure/function context that links core recognition to ubiquitin-dependent processes that disable the retrovirus and signal the presence of an invader. Janet L. Smith , University of Michigan, Ann Arbor, MI, USA Human cells have a variety of schemes to distinguish self from non-self molecules. The zinc finger antiviral protein (ZAP) surveils the cytoplasm and directs the destruction of RNAs from a number of viruses. How this occurs was unknown until Bieniasz and co-workers discovered that ZAP recognizes CpG dinucleotides, which are naturally depleted in animal genomes and mRNAs [1]. The sensitivity of RNA viruses to ZAP is correlated with the CpG content of the viral genome. HIV-1 has both a low CpG content and a natural resistance to ZAP, but it became ZAP-sensitive when the CpG content was increased by synonymous mutation. Thus HIV-1 seems to have evolved to avoid ZAP inhibition. The ZAP protein has a 230-amino-acid N-terminal domain (NTD) for RNA recognition; this domain includes four ‘CCCH’ zinc finger structures, as exist in many RNA-binding proteins. The functions of the following WWE and poly(ADP-ribose) polymerase (PARP) domains of ZAP are unknown, but may include recruitment of enzymes for RNA destruction, for example the putative endonuclease, KHNYN, that is required for antiretroviral activity. We solved a crystal structure of the human ZAP NTD with an RNA oligomer from the CpG- enriched HIV-1 genome and discovered that only zinc finger 2 (ZnF2) recognizes the CpG dinucleotide [2]. Single amino acid substitutions in ZnF2 abolished selective binding of ZAP to CpG-enhanced regions of the HIV-1 genome and also eliminated the ability of ZAP to selectively inhibit CpG-enriched HIV-1. Analogous substitutions in ZnF1,3,4 had no impact on antiviral activity. Overall, ZAP seems to constrain the nucleotide sequence of the HIV-1 genome and may provide a defense against viruses whose genomes have higher CpG content. [1] Takata et al. & Bieniasz. Nature 550, 124-127 (2017). [2] Meagher, Takata et al., Bieniasz & Smith. PNAS 116, 24303-24309 (2019). The human integral membrane protein SERINC5 potently restricts HIV-1 infectivity by inhibiting viral entry and sensitises the virus to antibody- mediated neutralisation. To eliminate the effect of SERINC5, HIV 1 encodes the endocytic adaptor protein Nef, which redirects SERINC5 to endosomal compartments, thereby preventing its inclusion into budding viral particles. Understanding the molecular basis of retroviral restriction by SERINC5 and its down-regulation by HIV-1 Nef may aid in development of antiviral therapeutic approaches. We determined the three-dimensional structures of human SERINC5 and its ortholog from Drosophila melanogaster at subnanometer and near-atomic resolution, respectively, using cryo-electron microscopy. An extensive panel of SERINC5 mutants were tested for the ability to inhibit Nef- negative HIV-1 infectivity and localisation to the plasma membrane. The SERINC structures reveal a novel protein fold comprised of ten transmembrane helices organised into two subdomains and bisected by a long diagonal helix. Clusters of conserved residues and a lipid binding groove highlight potential functional sites. Extensive structure-based mutagenesis scan identified surface-exposed regions and the interface between the subdomains, as critical for SERINC5 restriction activity. The same regions are also important for viral sensitisation to neutralising antibodies, directly linking SERINC5 restriction activity with the remodelling of HIV-1 envelope glycoprotein. SERINC5 variants, which were not surface exposed, were unable to inhibit HIV-1 infectivity arguing that the protein must be located at the plasma membrane to exert its antiviral activity. Our structures and extensive functional data provide the first insights at the molecular level of SERINC proteins and their ability to restrict HIV-1 infection. 99 NEUROHIV IN THE GLOBAL CONTEXT: ADVANCING THE CONTINUUM OF CARE AND ACHIEVING EQUITY Kiran T. Thakur , Columbia University, New York, NY, USA Though significant advancements have been made in the field of neuroHIV, neurological and mental health conditions remain major contributors to morbidity and mortality worldwide, particularly in resource-limited settings. In this talk, we will discuss how HIV impacts brain health throughout the lifespan with a discussion on the current global epidemiology of neuroHIV (including 97 HIV-1 AVOIDS BEING ZAPPED 98 SERINC STRUCTURE AND RESTRICTION OF HIV-1 INFECTIVITY Valerie Pye , The Francis Crick Institute, London, UK

the global epidemiology of HIV neurocognitive disorder, CNS opportunistic infections, mental health disorders, etc). We will also identify epidemiological knowledge gaps, specifically highlighting gaps in resource-limited settings. We will discuss discoveries and achievements in neuroHIV since the beginning of the HIV epidemic and will highlight the importance of brain health in the HIV care continuummodel. We will then discuss important facets of neurological care across the lifespan with a discussion on pediatric neuroHIV including HIV-associated neurocognitive effects in children and the impact of in-utero exposure to maternal HIV and antiretroviral medications. We will discuss neurological conditions amongst adolescents and adults, as well as gender- related issues in neurological and mental health. We will then focus on the chronic neurological care of people living with HIV, and discuss the impact of HIV on our growing global aging population. We will discuss the growth in dementia and stroke burden worldwide, and the "double burden" of traditional risk factors for cerebrovascular disease and cognitive decline and HIV infection. We will then discuss the current neurological care areas which specifically impact people living with HIV including access and availability of high quality neurological care and mental health resources, the availability of high quality drugs such as antiepileptic medications, access to diagnostic testing including laboratory infrastructure needs, and neurorehabilitation resources. We will focus on how to address disparities in care in vulnerable populations, and the associated stigma in people living with HIV with neurological conditions. We will identify mechanisms to reduce the burden of neurological conditions in people living with HIV worldwide, with an emphasis on improving access and quality of care over the coming decade. Finally, we will emphasize the importance of focusing on brain health as major priority in HIV care in the coming years. HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS AND AGING IN THE GLOBAL SETTING John Joska , 1University of Cape Town, Cape Town, South Africa HIV remains highly prevalent in sub-Saharan Africa with nearly 1:5 adults aged 15-49 years infected in South Africa (SA). Although SA also has the largest antiretroviral (ART) program globally, with >2 million PLWH accessing care, a significant proportion of individuals remain ART naïve. The result is two sub-populations- one at high risk of the effects of immunocompromise, and the other living with chronic HIV and the emergent problems of aging. Despite early reports that clade C was less neuro-virulent, regional data suggest that HIV tat variants are not neuro-protective. The presence of neurocognitive impairment is likely impacted by education, early life adversity, neurologic and psychiatric co-morbidity and delays in entering care. ART neurotoxicity is not well understood at a population level, but the up-coming programmatic switch to first-line dolutegravir from efavirenz in SA may help. HAND is not routinely recognized or diagnosed in routine clinical care. Screening tools such as the IHDS and CAT-rapid have been validated in South Africa, with comparable sensitivity and specificity to the USA, but few providers are comfortable using them. Other tools, such as the Community Screening Instrument for Dementia have been used widely across multiple resource-limited settings, but in older persons. Other challenges to diagnosis include the risk of over-diagnosis, especially of mild HAND, the assessment of functional impairment, and the detection of co-morbidities. There are no effective adjuvant treatments for HAND. Effective viral control is key, with CSF escape likely very uncommon. Thoughtful psycho-education, treatment support, and possibly patient-tailored medication management and problem-solving strategies may help. HIV infection in persons >60 years is common and will become a growing problem. Neurodegenerative disorders, including Alzheimer’s and Vascular dementia, are prevalent in older South Africans. The contribution of HIV infection to morbidity is not well understood, even in well-resourced settings. A life-span, patient-centered approach may afford the best outcomes: improving early education, the effects of poverty, managing mid-life risk factors, early HIV diagnosis, and effective ART will probably reduce the disease burden substantially. If one is honest, current Alzheimer treatments are only modestly effective and unaffordable in low-resource settings. We will have to look for cheaper, disease-modifying treatments. 101 HIV AND MENTAL HEALTH: THE IMPACT OF THE COMORBIDITY IN RESOURCE-CONSTRAINED SETTINGS Bibilola D. Oladeji , University of Ibadan, Ibadan, Nigeria There is a complex bi-directional relationship between HIV infection and mental health. It is well recognized worldwide that the prevalence of mental 100

Oral Abstracts

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CROI 2020