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Background: People living with HIV (PWH) are susceptible to high-risk human papillomavirus (HPV) infection of the anal canal owing to their immunocompromised status. The virus can transform anal squamous epithelia to low-grade squamous intraepithelial lesions (LSILs) and further to high-grade squamous intraepithelial lesions (HSILs). HSILs are well-defined cancer precursors that can progress to invasive cancer if left untreated. HPV-associated cancers commonly carry genomic abnormalities, specifically, a gain of chromosome 3q26 (PIK3CA), 20q13, 5p15 (TERT) and 7 centromere (cen7). We aimed to determine whether HPV-associated anal precancers carry similar genomic abnormalities and if so, to analyze their associations with histological severity and specific HPV types. Methods: Anal lesions from 63 unique patients (36 HSIL, 27 LSIL) were obtained via high-resolution anoscopy (HRA)-directed biopsy. Anal swabs were performed at the time of HRA to collect samples for cytological diagnosis and HPV DNA testing of HPV16, 18, and other (12) high-risk types. FISH-based HPV-associated Cancer Test (FHACT) was performed on the biopsy samples using four-color probes to detect any gain of chromosome 3q, 20q, 5p, and 7. The associations between genomic alterations, histological severity and HPV types were analyzed. Results: Our cohort had a median age of 50, was predominantly (70%) of Black and Hispanic race/ethnicity and 95% had suppressed HIV viral loads. Genomic abnormalities were detected in 47% of anal HSILs and 7% of LSILs (p=0.002). A gain of 3q, 20q, 5p, and cen7 was detected in 42%, 31%, 31%, and 19% of HSILs and 7%, 4%, 0%, and 0% of LSILs, respectively. Genomic abnormalities were more frequent in lesions associated with HPV16/18 infection, compared with those associated with non-16/18 types and negative HPV (42% vs. 24% vs. 9% ; p=0.06). 91% of lesions with 5p gain had gain in 20q. Cen7 gains were only detected in lesions with a gain of 20q13, suggesting a possible sequential order in development of chromosomal gains: 3q26 first, followed by 20q13 or 5p15, and then cen7. Conclusion: Anal precancers frequently demonstrate genomic abnormalities found in other HPV-associated cancers. The most common abnormality was the amplification of chromosome 3q, the location of PIK3CA gene. Our results suggest that PI3- kinase/AKT signaling pathway may play an important role in anal cancer development in PWH.

Background: There are limited data regarding the clinical impact of coronavirus disease 2019 (COVID-19) on people living with human immunodeficiency virus (PLWH). In this study, we compared outcomes for PLWH with COVID-19 to a matched comparison group. Methods: We identified 88 PLWH hospitalized with laboratory-confirmed COVID-19 in our hospital system in New York City between 12 March and 23 April 2020. We collected data on baseline clinical characteristics, laboratory values, HIV status, treatment, and outcomes from this group and matched comparators (1 PLWH to up to 5 patients by age, sex, race/ethnicity, and calendar week of infection). We compared clinical characteristics and outcomes (death, mechanical ventilation, hospital discharge) for these groups, as well as cumulative incidence of death by HIV status. Results: Patients did not differ significantly by HIV status by age, sex, or race/ethnicity due to the matching algorithm. PLWH hospitalized with COVID-19 had high proportions of HIV virologic control on antiretroviral therapy. PLWH had greater proportions of smoking (P < .001) and comorbid illness than uninfected comparators. There was no difference in COVID-19 severity on admission by HIV status (P = .15). Poor outcomes for hospitalized PLWH were frequent but similar to proportions in comparators; 18% required mechanical ventilation and 21% died during follow-up (compared with 23% and 20%, respectively). There was similar cumulative incidence of death over time by HIV status (P = .94). Conclusions: We found no differences in adverse outcomes associated with HIV infection for hospitalized COVID-19 patients compared with a demographically similar patient group.

Background There have been limited data regarding the clinical impact of COVID-19 disease on people with HIV (PWH). In this study we compared outcomes for PWH with COVID-19 disease to a matched comparison group. Design We identified 88 PWH hospitalized with laboratory confirmed COVID-19 in our hospital system in New York between March 12 and April 23, 2020. We collected data on baseline clinical characteristics, laboratory values, HIV infection status, COVID-19 treatment, and outcomes from this group and matched comparators (one PWH to up to five patients by age, sex, race/ethnicity and calendar week of infection). We compared baseline clinical characteristics and outcomes (death, mechanical ventilation, hospital discharge) for these two groups, as well as cumulative incidence of death by HIV status. Results Patients did not differ significantly by HIV status by age, sex or race/ethnicity due to the matching algorithm. PWH hospitalized with COVID-19 had high proportions of HIV virologic control on antiretroviral therapy. PWH had greater proportions of smoking (p

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades antiviral immunity through the expression of viral proteins that block detection, signaling, interferon (IFN) induction, and IFN-stimulated gene (ISG) expression 1, 2 . Weak induction of type I IFNs is associated with a hyperinflammatory response in patients that develop severe COVID-19 3, 4, 5 . Here we uncover a role for cellular nucleic acid-binding protein (CNBP) in restricting SARS-CoV-2. Typically, CNBP resides in the cytosol and, in response to RNA sensing pathways, undergoes phosphorylation, nuclear translocation, and IFNβ enhancer DNA binding to turn on IFNβ gene transcription. In SARS-CoV-2-infected cells CNBP coordinates IFNβ gene transcription. In addition, CNBP binds SARS-CoV-2 viral RNA directly. CNBP competes with the nucleocapsid (N) protein and prevents viral RNA and nucleocapsid protein from undergoing liquid-liquid phase separation (LLPS) forming condensates critical for viral replication. Consequently, cells and animals lacking CNBP have higher viral loads and CNBP-deficient mice succumb rapidly to infection. Altogether, these findings identify CNBP as a key antiviral factor for SARS-CoV-2, functioning both as a regulator of antiviral IFN gene expression and a cell intrinsic restriction factor that disrupts LLPS to limit viral replication and spread., Competing Interests: Competing Interest Statement: The authors declare no competing financial interests.

A well-tolerated and cost-effective oral drug that blocks SARS-CoV-2 growth and dissemination would be a major advance in the global effort to reduce COVID-19 morbidity and mortality. Here, we show that the oral FDA-approved drug nitazoxanide (NTZ) significantly inhibits SARS-CoV-2 viral replication and infection in different primate and human cell models including stem cell-derived human alveolar epithelial type 2 cells. Furthermore, NTZ synergizes with remdesivir, and it broadly inhibits growth of SARS-CoV-2 variants B.1.351 (beta), P.1 (gamma), and B.1617.2 (delta) and viral syncytia formation driven by their spike proteins. Strikingly, oral NTZ treatment of Syrian hamsters significantly inhibits SARS-CoV-2-driven weight loss, inflammation, and viral dissemination and syncytia formation in the lungs. These studies show that NTZ is a novel host-directed therapeutic that broadly inhibits SARS-CoV-2 dissemination and pathogenesis in human and hamster physiological models, which supports further testing and optimization of NTZ-based therapy for SARS-CoV-2 infection alone and in combination with antiviral drugs.