Overview: Scott M. Hammer Workshop for New Investigators and Trainees

Over the past four decades, remarkable progress has been made in understanding HIV epidemiology, pathogenesis, treatment, and prevention from the combined efforts of community members, clinicians, investigators, and funding agencies worldwide. Yet more work and new approaches are needed to achieve the ambitious goal of ending the epidemic and ensuring optimal quality of life for those living with HIV. To encourage and stimulate the next generation of investigators, the CROI Program Committee organizes an annual Workshop for New Investigators and Trainees comprised of expert and comprehensible talks to cover current knowledge and controversies in basic, clinical, and public health investigation into HIV and related infections, and to highlight relevant work to be presented over the ensuing days at CROI. This year, the program will begin with a presentation by Dr Stuart Neil on novel aspects of the molecular virology of HIV-1 and SARS-CoV-2. Following this, Dr Guido Silvestri will cover the immune responses against HIV and SARS-CoV-2. Ms Dawn Averitt, an HIV treatment policy advocate and activist will provide a community perspective on the power of community engagement in research. In the following presentation, Dr Monica Gandhi will review novel therapeutic strategies for HIV. Dr Raphael Landovitz will address advances in different strategies for preventing HIV transmission. Dr John Mellors will review advances in preclinical and clinical approaches for functional or sterilizing HIV-1 cure. The workshop will end with an intervention by Dr Rochelle Walensky, who will discuss career opportunities in research and public health. By completing the workshop, attendees will have achieved a head start toward maximizing the knowledge gained and research ideas arising from CROI 2022.

SCOTT M. HAMMER WORKSHOP for NEW INVESTIGATORS and TRAINEES

Over the past four decades, remarkable progress has been made in understanding HIV epidemiology, pathogenesis, treatment, and prevention from the combined efforts of community members, clinicians, investigators, and funding agencies worldwide. Yet more work and new approaches are needed to achieve the ambitious goal of ending the epidemic and ensuring optimal quality of life for those living with HIV. To encourage and stimulate the next generation of investigators, the CROI Program Committee organizes an annual Workshop for New Investigators and Trainees comprised of expert and comprehensible talks to cover current knowledge and controversies in basic, clinical, and public health investigation into HIV and related infections, and to highlight relevant work to be presented over the ensuing days at CROI. This year, the presentations will cover HIV and SARS-CoV-2. The program will begin with a presentation by Dr Theodora Hatziioannou on novel aspects of the HIV-1 and SARS-CoV-2 replication cycles, with an emphasis on the similarities and differences between the two viruses. Following this, Dr Penny Moore will cover the immune responses against HIV and SARS-CoV-2. Dr Carlos del Rio will outline the most efficient prevention measures for controlling the COVID-19 pandemic and will review therapeutic strategies and currently available SARS-CoV-2 vaccines. In the next presentation, Dr Adaora Adimora will address advances in different biomedic strategies for the prevention of HIV transmission. Finally, Dr Peter W. Hunt will review advances in preclinical and clinical approaches for functional or sterilizing HIV-1 cure. By the completion of the workshop, attendees will have achieved a head start toward maximizing the knowledge gained and research ideas arising from CROI 2022.

CSF and BLOOD ANALYSES in PARTICIPANTS with POST-COVID-19 NEUROPSYCHIATRIC SYMPTOMS

Background: The pathogenesis of neuropsychiatric symptoms persisting months after acute SARS-CoV-2 infection is poorly understood. We examined clinical and laboratory parameters in participants with post-acute COVID-19 neuropsychiatric symptom to assess for systemic and nervous system immune perturbations. Methods: Participants with a history of laboratory confirmed COVID-19 and ongoing neurologic symptoms were enrolled in an observational study that collected medical history;detailed post-COVID symptom survey;and paired cerebrospinal fluid (CSF) and blood. In addition to standard clinical labs, neopterin and anti-SARS-CoV-2 antibodies (anti-spike, RBD, and nucleocapsid) were measured by ELISA. Non-parametric tests were used to compare CSF and blood findings between the post-COVID participants and pre-COVID-19 era healthy controls. Results: Post-COVID participants (n=27) and controls (n=21) were similar in age (median 51 and 46 years), but there was a greater proportion of females (67% vs 24%;p=0.004) and white participants in the post-COVID cohort (63% vs 24%;p=0.04). The post-COVID study visit was a median of 264 days (IQR 59-332) after acute COVID-19 symptom onset. 35% were hospitalized during their acute illness;12% required intensive care. 33% had previously been treated with medications for mental health conditions. The most frequent neuropsychiatric symptoms were cognitive impairment (67%), mood symptoms (67%), headache (56%), and neuropathy (41%). Blood c-reactive protein, T cell count, and T cell subset frequency (CD4% and CD8%) were similar between groups, while D-dimer was higher in the post-COVID cohort (median 0.48 vs 0.27 mg/L;p = 0.019) (Figure). CSF WBC, protein, neopterin, and CSF/blood albumin ratio were similar between the groups;the frequency of CSF lymphocytes was lower in the post-COVID cohort (p = 0.05) (Figure 1). Antibodies against at least one SARS-CoV-2 antigen were detected in 7/10 CSF and 8/9 blood samples in the post-COVID CSF (antibody reactivity range 1.5 to 55-fold greater than to control antigens). Conclusion: In this small cohort of post-COVID participants with neurologic symptoms, we found limited differences in CSF and blood markers when compared to pre-pandemic healthy controls. Deeper immunophenotyping in a larger number of participants may provide greater insight into subtle differences. The presence of anti-SARS-CoV-2 antibodies in CSF months after acute infection warrants further investigation.

Program committee workshop for new investigators and trainees: Session overview

Over the past four decades, remarkable progress has been made in understanding HIV epidemiology, pathogenesis, treatment, and prevention from the combined efforts of community members, clinicians, investigators, and funding agencies worldwide. Yet more work and new approaches are needed to achieve the ambitious goal of ending the epidemic and ensuring optimal quality of life for those living with HIV. To encourage and stimulate the next generation of investigators, the CROI Program Committee organizes an annual Workshop for New Investigators and Trainees comprised of expert and comprehensible talks to cover current knowledge and controversies in basic, clinical and public health investigation into HIV and related infections, and to highlight relevant work to be presented over the ensuing days at CROI. This year, the presentations will cover both HIV and SARS-CoV-2. The program will begin with a presentation by Dr Frank Kirchhoff on novel aspects of the HIV-1 and SARS-CoV-2 replication cycles, with an emphasis on the similarities and differences between the two viruses. Following this, Dr Galit Alter will cover the immune responses (with a particular focus on B- and T-cell responses) against HIV and SARS-CoV-2. Dr Jürgen Rockstroh will outline the most efficient prevention measures for controlling the COVID-19 pandemic and will review new testing technologies as well as therapeutic strategies and currently available SARS-CoV-2 vaccines. In the next presentation, Jean-Michel Molina will address advances in different biomedical strategies for prevention of HIV transmission, with an emphasis on the recent development in preexposure prophylaxis (PrEP) but also some of the emerging strategies to limit SARS-CoV-2 transmission. Finally, Dr Katharine Bar will review advances in characterizing the size and composition of the replication- and rebound-competent HIV-1 reservoirs as well as highlight several preclinical and clinical approaches for functional or sterilizing HIV-1 cure. By the completion of the workshop, attendees will have achieved a head start toward maximizing the knowledge gained and research ideas arising from vCROI 2021.

Divergent and self-reactive immune responses in the CNS of COVID-19 patients

Background: One third of COVID-19 patients develop significant neurological symptoms, yet SARS-CoV-2 is rarely detected in central nervous system (CNS) tissue, suggesting a potential role for parainfectious processes, including neuroimmune responses. Methods: We examined immune parameters in CSF and blood samples from a cohort of hospitalized patients with COVID-19 and significant neurological complications (n=6), compared to SARS-CoV-2 uninfected controls (Fig1A). Immune cells were characterized by single cell RNA and repertoire sequencing. Intrathecal antibodies were assessed for anti-viral and auto-reactivity by ELISA, mouse brain immunostaining, phage display, and IP-MS. Results: Through single cell and parallel cytokine analyses of CSF and paired plasma, we found divergent T cell responses in the CNS compartment, including increased levels of IL-1B and IL-12-associated innate and adaptive immune cell activation (Fig1B). We found evidence of clonal expansion of B cells in the CSF, with B cell receptor sequences that were unique from those observed in peripheral blood B cells (Fig1C), suggesting a divergent intrathecal humoral response to SARS-CoV-2. Indeed, all COVID-19 cases examined had anti-SARS-antibodies. Next, we directly examined whether CSF resident antibodies targeted self-antigens and found a significant burden of CNS autoimmunity, with the CSF from most patients recognizing neural self-antigens. COVID-19 CSF produced immunoreactive staining of specific anatomic regions of the brain including cortical neurons, olfactory bulb, thalamus, and cerebral vasculature. Finally, we produced a panel of monoclonal antibodies from patients' CSF and peripheral blood, and show that these target both anti-viral and anti-neural antigens-including one CSF-derived mAb specific for the spike protein that also recognizes neural tissue (Fig1D). Conclusion: This immune survey reveals evidence of a compartmentalized and self-reactive immune response in the CNS in COVID-19 patients with neurologic symptoms. We identified both innate and adaptive anti-viral immune responses, as well as humoral autoimmunity that appears to be unique to the CNS during SARS-CoV-2 infection. These data suggest a potential role for autoimmunity in contributing to neurological symptoms, and merit further investigation to the potential role of autoantibodies in post-acute COVID-19 neurological symptoms.

A survey-based pilot study to assess the effects of covid-19 isolation on older plwh

Background: Public health emergencies increase stress, anxiety, and fear, and older adults and those with pre-existing conditions may be especially vulnerable. We used a survey-based pilot study to explore the psychosocial impact of COVID-19 on older PLWH and correlate the level of COVID-19 related distress with baseline HIV disease metrics. Methods: Participants were PLWH > age 50 who had previously (2017-2020) enrolled in the HARC HIV biorepository study at Yale. 48 PLWH were contacted and 22 participated in this study, conducted Aug-Sep 2020. An 8-part survey was administered to inquire about COVID-19 exposure, financial distress, medication adherence/medical follow-up, social support, substance use, and mood symptoms (Table 1). Cross-sectional analysis was performed on results at the time of survey administration, and longitudinal analysis was performed to compare anxiety (GAD-7), alcohol/drug use (ASSIST), and depression (CES-D) to baseline values obtained pre-pandemic (median 1.3 years prior). Results: Participant demographics are reported in Table 1. 2 participants reported having been diagnosed with COVID-19, 1 of whom had a known COVID-19 positive contact. 68% of participants were retired and reported no changes to their work due to COVID-19, and most reported moderate (4.1 on scale of 0-7) financial distress. Most reported excellent medication adherence, with 77% reporting no missed doses. 95% stated they felt “very well supported” by their primary HIV care providers, with 18% saying their care was improved during COVID-19. Only 18% felt their care was “somewhat worse.” Most participants also scored highly on the social support scale, with an average score of 11 out of 14. There were no significant differences between pre-pandemic and current scores for anxiety, alcohol/drug use, and depression, and there was no correlation between baseline HIV metrics and current level of distress. However, there was an association between COVID-19-associated worsening in GAD-7 score and a history of substance use disorder (p = 0.02). Conclusion: These results suggest that overall, most participants were doing well with excellent medication adherence and no significant changes in scores for anxiety, depression, and substance use, but that older PLWH with a history of substance use disorder had a greater risk for increased anxiety during COVID- 19. These findings can help identify groups who may be the most at-risk to experience distress from a second wave of COVID-19 and put support measures in place.