Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice

The emerging SARS-CoV-2 variants of concern (VOCs) may display enhanced transmissibility, more severity and/or immune evasion; however, the pathogenesis of these new VOCs in experimental SARS-CoV-2 models or the potential infection of other animal species is not completely understood. Here we infected K18-hACE2 transgenic mice with B.1, B.1.351/Beta, B.1.617.2/Delta and BA.1.1/Omicron isolates and demonstrated heterogeneous infectivity and pathogenesis. B.1.351/Beta variant was the most pathogenic, while BA.1.1/Omicron led to lower viral RNA in the absence of major visible clinical signs. In parallel, we infected wildtype (WT) mice and confirmed that, contrary to B.1 and B.1.617.2/Delta, B.1.351/Beta and BA.1.1/Omicron can infect them. Infection in WT mice coursed without major clinical signs and viral RNA was transient and undetectable in the lungs by day 7 post-infection. In silico modeling supported these findings by predicting B.1.351/Beta receptor binding domain (RBD) mutations result in an increased affinity for both human and murine ACE2 receptors, while BA.1/Omicron RBD mutations only show increased affinity for murine ACE2

Case report: mechanisms of HIV elite control in two African women

Background The majority of people living with HIV require antiretroviral therapy (ART) for controlling viral replication, however there are rare HIV controllers who spontaneously and durably control HIV in the absence of treatment. Understanding what mediates viral control in these individuals has provided us with insights into the immune mechanisms that may be important to induce for a vaccine or functional cure for HIV. To date, few African elite controllers from high incidence settings have been described. We identified virological controllers from the CAPRISA 002 cohort of HIV-1 subtype C infected women in KwaZulu Natal, South Africa, two (1%) of whom were elite controllers. We examined the genetic, clinical, immunological and virological characteristics of these two elite HIV controllers in detail, to determine whether they exhibit features of putative viral control similar to those described for elite controllers reported in the literature. Case presentation In this case report, we present clinical features, CD4+ T cell and viral load trajectories for two African women over 7 years of HIV infection. Viral load became undetectable 10 months after HIV infection in Elite Controller 1 (EC1), and after 6 weeks in Elite Controller 2 (EC2), and remained undetectable for the duration of follow-up, in the absence of ART. Both elite controllers expressed multiple HLA Class I and II haplotypes previously associated with slower disease progression (HLA-A*74:01, HLA-B*44:03, HLA-B*81:01, HLA-B*57:03, HLA-DRB1*13). Fitness assays revealed that both women were infected with replication competent viruses, and both expressed higher mRNA levels of p21, a host restriction factor associated with viral control. HIV-specific T cell responses were examined using flow cytometry. EC1 mounted high frequency HIV-specific CD8+ T cell responses, including a B*81:01-restricted Gag TL9 response. Unusually, EC2 had evidence of pre-infection HIV-specific CD4+ T cell responses. Conclusion We identified some features typical of elite controllers, including high magnitude HIV-specific responses and beneficial HLA. In addition, we made the atypical finding of pre-infection HIV-specific immunity in one elite controller, that may have contributed to very early viral control. This report highlights the importance of studying HIV controllers in high incidence settings

New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains

We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = <0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N–Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N–Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N–Y181C RTs to binary and ternary complexes, respectively

Indolylarylsulfones carrying a heterocyclic tail as very potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors

We synthesized new indolylarylsulfone (IAS) derivatives carrying a heterocyclic tail at the indole-2-carboxamide nitrogen as potential anti-HIV/AIDS agents. Several new IASs yielded EC50 values <1.0 nM against HIV-1 WT and mutant strains in MT-4 cells. The (R)-11 enantiomer proved to be exceptionally potent against the whole viral panel; in the reverse transcriptase (RT) screening assay, it was remarkably superior to NVP and EFV and comparable to ETV. The binding poses were consistent with the one previously described for the IAS non-nucleoside reverse transcriptase inhibitors. Docking studies showed that the methyl group of (R)-11 points toward the cleft created by the K103N mutation, different from the corresponding group of (S)-11. By calculating the solvent-accessible surface, we observed that the exposed area of RT in complex with (S)-11 was larger than the area of the (R)-11 complex. Compounds 6 and 16 and enantiomer (R)-11 represent novel robust lead compounds of the IAS class

Deletion of LCE3C and LCE3B is a susceptibility factor for psoriatic arthritis: A study in Spanish and Italian populations and meta-analysis

Objective The LCE3C-LCE3B-del variant is associated with psoriasis and rheumatoid arthritis. Its role in psoriatic arthritis (PsA) is unclear, however, as shown by 3 recent studies with contradictory results. In order to investigate whether LCE3C-LCE3B-del constitutes a risk factor for PsA susceptibility, we first tested this variant in patients with PsA from Spanish and Italian populations and then performed a meta-analysis including the previous case-control studies. Methods We genotyped LCE3C-LCE3B-del and its tag single-nucleotide polymorphism (SNP), rs4112788, in an original discovery cohort of 424 Italian patients with PsA and 450 unaffected control subjects. A Spanish replication cohort consisting of 225 patients with PsA and 469 control subjects was also genotyped. A meta-analysis considering 7,758 control subjects and 2,325 patients with PsA was also performed. Results We observed a significant association between PsA and the LCE3C-LCE3B-del tag SNP in the Italian and Spanish cohorts, with an overall corrected P value of 0.00019 and a corresponding odds ratio of 1.35 (95% confidence interval 1.14-1.59). Stratified analyses by subphenotype indicated a stronger association for patients with oligoarticular disease. Meta-analysis including data from all previous published studies confirmed an association of PsA with the LCE3C-LCE3B-del tag SNP. Conclusion LCE3C-LCE3B-del is a susceptibility factor for PsA, confirming the existence of a shared risk factor involving the epidermal skin barrier in autoimmune disorders. Copyright © 2011 by the American College of Rheumatology.Peer Reviewe

Increased SAMHD1 transcript expression correlates with interferon-related genes in HIV-1-infected patients

PURPOSE: To investigate the contribution of SAMHD1 to HIV-1 infection in vivo and its relationship with IFN response, the expression of SAMHD1 and IFN-related pathways was evaluated in HIV-1-infected patients. METHODS: Peripheral blood mononuclear cells (PBMC) from 388 HIV-1-infected patients, both therapy naïve (n = 92) and long-term HAART treated (n = 296), and from 100 gender and age-matched healthy individuals were examined. CD4+ T cells, CD14+ monocytes and gut biopsies were also analyzed in HIV-1-infected subjects on suppressive antiretroviral therapy. Gene expression levels of SAMDH1, ISGs (MxA, MxB, HERC5, IRF7) and IRF3 were evaluated by real-time RT-PCR assays. RESULTS: SAMHD1 levels in HIV-1-positive patients were significantly increased compared to those in healthy donors. SAMHD1 expression was enhanced in treated patients compared to naïve patients (p &lt; 0.0001) and healthy donors (p = 0.0038). Virologically suppressed treated patients exhibited higher SAMHD1 levels than healthy donors (p = 0.0008), viraemic patients (p = 0.0001) and naïve patients (p &lt; 0.0001). SAMHD1 levels were also increased in CD4+ T cells compared to those in CD14+ monocytes and in PBMC compared to those of GALT. Moreover, SAMHD1 was expressed more strongly than ISGs in HIV-1-infected patients and positive correlations were found between SAMHD1, ISGs and IRF3 levels. CONCLUSIONS: SAMHD1 is more strongly expressed than the classical IFN-related genes, increased during antiretroviral therapy and correlated with ISGs and IRF3 in HIV-1-infected patients