CROI 2025 Abstract eBook

Abstract eBook

Invited Session

NPC controls nucleocytoplasmic transport by establishing a ‘diffusion barrier’ at the centre of the pore. Often described as a ‘mesh’ or ‘filter’, the diffusion barrier is formed by intrinsically-disordered nucleoporin domains which project into the central pore. Critically, these domains are enriched for phenylalanine glycine (FG) dipeptide motifs that cause them to form a liquid-liquid phase separation which typically prevents the passive diffusion of molecules greater than ~25 kDa. Larger cargoes can be escorted across the nuclear pore by the action of karyopherins – chaperone proteins which can cross the diffusion barrier by virtue of their weak, multivalent, and specific interactions with the FG motifs. Recent studies have shown that the HIV capsid also possesses a conserved FG-binding pocket on it surface. Indeed, it is this same site that is targeted so successfully by the first-in-class anticapsid drug, lenacapavir. This ‘FG-pocket’ grants the capsid similar biophysical properties to the karyopherins, thereby licensing the capsid for nuclear entry without the need of chaperones. The karyopherin mimicry model explains how a structure as large as the HIV core can penetrate the nucleus despite being greater than 10,000 times the diffusion limit of the nuclear pore. Background: The HIV Preintegration Complex (PIC) mediates the integration of the viral reverse transcript into host cell chromosomes. The HIV core is composed of a shell of capsid protein that encases the viral RNA together with reverse transcriptase and integrase enzymes. Reverse transcription occurs within the viral core, and nicking of the viral DNA ends by integrase converts the reverse transcription complex into the integration-competent PIC. After circumventing the nuclear pore complex, the core traffics to interior regions of the nucleus for uncoating and integration. Integration into host chromosomes is non-random, and interactions between the capsid and integrase proteins with cognate host factors guides the core to transcriptionally active chromatin. The interaction of capsid with alternative polyadenylation host protein CPSF6 is required for cores to move beyond the nuclear rim, where they eventually congregate with nuclear speckles for integration into nearby speckle associated domains (SPADs) of chromatin. Interactions between integrase and transcriptional coactivator LEDGF/p75 direct integration into the mid-regions of active genes. Recent work has clarified that both CPSF6 and LEDGF/p75 possess liquid-liquid phase separation activity and that these activities can impact their roles as integration cofactors. Completion of reverse transcription can aid core dissolution or uncoating to reveal chromatin to the PIC for integrase-mediated integration of viral DNA. Transcriptional and Epigenetic Regulation of HIV-1 Gene Expression Melanie Ott Gladstone Institutes, San Francisco, CA, USA Background: Recent research underscored that HIV transcription remains a critical step in the viral life cycle. Especially the transition between active and latent infection is critically regulated by viral factors such as Tat and many host factors that either control the transcriptional activity of the virus directly or the epigenetic landscape around it. It has become apparent that during antiretroviral therapy 81% of the viral reservoir remains transcriptionally active while “true” latency mainly exists in viruses embedded in a very repressive chromatin environment especially near repetitive genomic elements. Reactivation of HIV transcription from latency involves a shift to a permissive chromatin state, driven by histone acetylation, recruitment of bromodomain containing proteins, and the viral protein Tat, which recruits the positive transcription elongation factor b to release RNA polymerase II from pausing. Therapeutically, modalities targeting epigenetic proteins such as histone deacetylases, bromodomains, or histone methyltransferases as well as Tat are being studied to either reactivate latent proviruses for eradication or reinforce latency to suppress reactivation. Successfully suppressing transcriptional activity in the reservoir during antiretroviral therapy is promising as it decreases the chances of viral reactivation and is critical to alleviate chronic immune activation, which otherwise fuels early appearance of chronic diseases of aging. We speculate that suppressing transcription will also change the epigenetic landscape of the integrated proviruses in a durable way to long-term tune down reactivation potential. We will discuss the mechanisms of HIV transcription in How HIV Integrates Into the Genome Alan Engelman Dana–Farber Cancer Institute, Boston, MA, USA

the context of chromatin and our ongoing efforts to inhibit the transcriptionally active reservoir. Landscape of Proviral Integration in HIV-1 Reservoir & Relationship to Latency & Reactivation Mary Kearney National Cancer Institute at Frederick, Frederick, MD, USA Background: HIV-1 persists in a mostly latent state within blood and tissues during suppressive ART. Proviral integration sites may play a critical role in the establishment and maintenance of this latent reservoir. Understanding the landscape of proviral integration is essential for deciphering the mechanisms behind HIV-1 latency and reactivation. Recent studies have shed light on the factors that regulate proviral latency, including host cell type, epigenetic modifications, and the influence of host immune responses. The interplay between viral and host factors in proviral integration and latency is complex, with integration site-specific transcriptional activity influencing the susceptibility to latency reversal agents. Continued exploration of this landscape offers promising avenues for therapeutic strategies aimed at eradicating HIV-1 through targeted interventions that either enhance immune responses or directly disrupt latent proviral genomes. Ultimately, a comprehensive understanding of proviral integration patterns is essential for designing therapies that could effectively eliminate the HIV-1 reservoir and achieve sustained viral remission without ongoing ART. Beyond Hot Flashes: Women's Lived Experience of Menopause Bridgette Picou The Well Project: Women's Research Initiative on HIV/AIDS, Brooklyn, NY, USA Background: This presentation will explore the lived experience of women living with HIV (WLWH) as they navigate menopause and the intersections with HIV and aging stigma. As a woman living with HIV, I also intend to briefly touch on the clinical care experience from the patient perspective and its impact on engagement in care. WLWH have the double stigma that surrounds both HIV and aging. Feelings of shame, reduced sense of worth, loss of vitality, and reduction in sexual attractiveness and desire are common, and multiplied in both populations. The desired outcome of this talk is the intentional investment of clinicians and researchers in exploring the quality of life of the women they serve as it relates to menopause. There must be research in all aspects of women’s health as it relates to HIV and the transitions that women experience aging with the disease process. Quality of life can only be achieved when women are given the tools and information to make informed decisions about their health. Shared decision making which is a critical component of quality care can only be effective when comfortability and willingness to engage exist. Background: Menopause represents a highly vulnerable time for women physically, mentally, and socially. The growing body of menopause research among women living with HIV (WLWH) demonstrates that this vulnerable population experiences greater mood and vasomotor symptom burden, which adversely impacts adherence to clinic visits and antiretroviral therapy. Estrogen loss associated with menopause may further enhance the risk for cardiometabolic, cognitive, and bone comorbidities in WLWH. Although there are still more questions than answers in the context of the clinical management of menopause in WLWH, research in this field is evolving, and clinical prevention along with clinician and patient education on this topic can enhance clinical outcomes and quality of life in WLWH globally. Clinical Management of Women With HIV in Menopause Sara Looby Massachusetts General Hospital, Boston, MA, USA

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Influence of Hormone Changes on Physiology, Virology, and Immunology Eileen Scully The Johns Hopkins University School of Medicine, Baltimore, MD, USA

Background: Disentangling the unique impacts of aging and reproductive aging through menopause may identify novel features of the pathogenesis of HIV that will inform strategies to manage longterm complications and achieve an HIV cure. Early data indicate that menopause and declining levels of estradiol are associated with increased inflammation and changes in HIV viral dynamics. Further work is needed to define the mechanisms of estradiol impacts on both HIV and the immune system.

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CROI 2025