High genomic stability of Andes virus following successive passage in Syrian hamsters.

Andes virus (ANDV) is a South American hantavirus that causes hantavirus cardiopulmonary syndrome (HCPS), a severe respiratory infection with a case fatality rate as high as 40%. A critical model for studying HCPS is the Syrian hamster model, which faithfully recapitulates key aspects of the disease. Recent studies have shown that strains of ANDV from different origins, i.

The significance of studying high-consequence pathogens in their natural reservoirs.

Concern over spillover events caused by high-consequence pathogens has grown in recent years due to the increased occurrence of such events, and because the COVID-19 pandemic demonstrated how severe the consequences of spillover events can be. As such, there is escalading interest in uncovering the factors that make spillover events more likely, specifically for high-consequence pathogens. An important aspect of this work involves researching how high-consequence pathogens interact with their reservoir hosts.

Assessing the Potential of Sexual Transmission of Lassa Virus in a Natural Rodent Reservoir.

Lassa virus (LASV) is maintained in and transmitted by Mastomys natalensis across West Africa. To date, few studies have addressed transmission of LASV between rodents. Here, we experimentally assessed the potential for sexual transmission of LASV in Mastomys.

Molecular detection and isolation of clade Ib monkeypox virus, Canada, November 2024.

In November 2024, a case of clade Ib mpox was confirmed in Canada. Here, we describe the events that led to laboratory confirmation of clade Ib monkeypox virus (MPXV) and the public health response. Genomic analysis of the Canadian clade Ib MPXV revealed a number of APOBEC3-related mutations suggesting sustained human-to-human transmission.

The HIV-1 envelope cytoplasmic tail protects infected cells from ADCC by downregulating CD4.

Unlabelled: HIV-1-mediated CD4 downregulation is a well-known mechanism that protects infected cells from antibody-dependent cellular cytotoxicity (ADCC). While CD4 downregulation by HIV-1 Nef and Vpu proteins has been extensively studied, the contribution of the HIV-1 envelope glycoprotein (Env) in this mechanism is less understood. While Env is known to retain CD4 in the endoplasmic reticulum (ER) through its CD4-binding site (CD4bs), little is known about the mechanisms underlying this process.

Safety, pharmacokinetics, and biological activity of CD4-mimetic BNM-III-170 in SHIV-infected rhesus macaques.

Anti-HIV-1 antibodies capable of mediating ADCC are elicited by the majority of people with HIV-1 and preferentially target the "open," CD4-bound conformation of HIV-1 envelope glycoproteins (Env). However, due to the "closed" conformation sampled by unliganded HIV-1-Envs, these antibodies are ineffective at eliminating infected cells. BNM-III-170 is a small-molecule CD4-mimetic compound that binds the Phe43 cavity of the gp120 subunit of Env, forcing Env to "open up," thus exposing epitopes targeted by CD4-induced (CD4i), ADCC-mediating antibodies.

A gp41 HR2 residue modulates the susceptibility of HIV-1 envelope glycoproteins to small molecule inhibitors targeting gp120.

One characteristic of the HIV-1 CRF01_AE strain is that it contains a bulkier histidine residue at position 375 (H375) in its envelope glycoproteins (Env). This residue is part of the Phe43 cavity, where residue 43 of CD4 engages with gp120. It has been shown that H375 contributes to resistance against small molecule inhibitors targeting gp120.

Sin Nombre Virus as Unlikely Reverse Zoonotic Threat.

We inoculated clinical materials into deer mice to attempt isolation of Sin Nombre virus. We did not observe productive infection in the natural rodent reservoir. Genomic comparisons between rodent reservoirs and human disease may provide insight into hantavirus evolution and genetic determinants, but reverse zoonosis of Sin Nombre virus appears unlikely.

Dissecting immunological mechanisms underlying influenza viral nucleoprotein-induced mucosal immunity against diverse viral strains.

The nucleoprotein (NP) of type A influenza virus (IAV) is highly conserved across all virus strains, making it an attractive candidate antigen for universal vaccines. While various studies have explored NP-induced mucosal immunity, here we interrogated the mechanistic differences between intramuscular (IM) and intranasal (IN) delivery of a recombinant adenovirus carrying NP fused with a bifunctional CD40 ligand. Despite being less effective than IM delivery in inducing systemic cellular immune responses and antibody-dependent cellular cytotoxicity (ADCC), IN immunization elicited superior antigen-specific recall humoral and cellular response in the nasal associated lymphoid tissue (NALT) of the upper respiratory tract, the initial site of immune recognition and elimination of inhaled pathogens.

The combination of three CD4-induced antibodies targeting highly conserved Env regions with a small CD4-mimetic achieves potent ADCC activity.

The majority of naturally elicited antibodies against the HIV-1 envelope glycoproteins (Env) are non-neutralizing (nnAbs) because they are unable to recognize the Env trimer in its native "closed" conformation. Nevertheless, it has been shown that nnAbs have the potential to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) provided that Env is present on the cell surface in its "open" conformation. This is because most nnAbs recognize epitopes that become accessible only after Env interaction with CD4 and the exposure of epitopes that are normally occluded in the closed trimer.

Treatment efficacy of cidofovir and brincidofovir against clade II Monkeypox virus isolates.

While historically confined to endemic areas, Monkeypox virus (MPXV) infection has increasingly garnered international attention due to sporadic outbreaks in non-endemic countries in the last two decades and its potential for human-to-human transmission. In 2022, a multi-country outbreak of mpox disease was declared by the World Health Organization (WHO) and nearly 100 000 mpox cases have been reported since the beginning of this pandemic. The clade II variant of the virus appears to be responsible for the vast majority of these infections.

Three families of CD4-induced antibodies are associated with the capacity of plasma from people living with HIV to mediate ADCC in the presence of CD4-mimetics.

Unlabelled: CD4-mimetics (CD4mcs) are small molecule compounds that mimic the interaction of the CD4 receptor with HIV-1 envelope glycoproteins (Env). Env from primary viruses normally samples a "closed" conformation that occludes epitopes recognized by CD4-induced (CD4i) non-neutralizing antibodies (nnAbs). CD4mcs induce conformational changes on Env resulting in the exposure of these otherwise inaccessible epitopes.

Conformational dynamics of the HIV-1 envelope glycoprotein from CRF01_AE is associated with susceptibility to antibody-dependent cellular cytotoxicity.

The HIV-1 envelope glycoprotein (Env) is expressed at the surface of infected cells and as such can be targeted by non-neutralizing antibodies (nnAbs) that mediate antibody-dependent cellular cytotoxicity (ADCC). Previous single-molecule Förster resonance energy transfer (smFRET) studies demonstrated that Env from clinical isolates predominantly adopt a "closed" conformation (State 1), which is resistant to nnAbs. After interacting with the cellular receptor CD4, the conformational equilibrium of Env shifts toward States 2 and 3, exposing the coreceptor binding site (CoRBS) and permitting binding of antibodies targeting this site.

Structure and inhibition of SARS-CoV-2 spike refolding in membranes.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the receptor angiotensin converting enzyme 2 (ACE2) and drives virus-host membrane fusion through refolding of its S2 domain. Whereas the S1 domain contains high sequence variability, the S2 domain is conserved and is a promising pan-betacoronavirus vaccine target. We applied cryo-electron tomography to capture intermediates of S2 refolding and understand inhibition by antibodies to the S2 stem-helix.

The combination of three CD4-induced antibodies targeting highly conserved Env regions with a small CD4-mimetic achieves potent ADCC activity.

The majority of naturally-elicited antibodies against the HIV-1 envelope glycoproteins (Env) are non-neutralizing (nnAbs), because they are unable to recognize the Env timer in its native "closed" conformation. Nevertheless, it has been shown that nnAbs have the potential to eliminate HIV-1-infected cells by Antibody-Dependent Cellular Cytotoxicity (ADCC) provided that Env is present on the cell surface in its "open" conformation. This is because most nnAbs recognize epitopes that become accessible only after Env interaction with CD4 and the exposure of epitopes that are normally occluded in the closed trimer.

Three families of CD4-induced antibodies are associated with the capacity of plasma from people living with HIV to mediate ADCC in presence of CD4-mimetics.

CD4-mimetics (CD4mcs) are small molecule compounds that mimic the interaction of the CD4 receptor with HIV-1 envelope glycoproteins (Env). Env from primary viruses normally samples a "closed" conformation which occludes epitopes recognized by CD4-induced (CD4i) non-neutralizing antibodies (nnAbs). CD4mcs induce conformational changes on Env resulting in the exposure of these otherwise inaccessible epitopes.

Plasma Human Immunodeficiency Virus 1 Soluble Glycoprotein 120 Association With Correlates of Immune Dysfunction and Inflammation in Antiretroviral Therapy-Treated Individuals With Undetectable Viremia.

Background: Chronic inflammation persists in some people living with human immunodeficiency virus (HIV) during antiretroviral therapy and is associated with premature aging. The glycoprotein 120 (gp120) subunit of HIV-1 envelope sheds and can be detected in plasma, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasma soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, linked to CD4 depletion in vitro, contribute to chronic inflammation, immune dysfunction, and subclinical cardiovascular disease in participants of the Canadian HIV and Aging Cohort Study with undetectable viremia.

Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir.

The HIV-1 entry inhibitor temsavir prevents the viral receptor CD4 (cluster of differentiation 4) from interacting with the envelope glycoprotein (Env) and blocks its conformational changes. To do this, temsavir relies on the presence of a residue with small side chain at position 375 in Env and is unable to neutralize viral strains like CRF01_AE carrying His375. Here we investigate the mechanism of temsavir resistance and show that residue 375 is not the sole determinant of resistance.

Plasmatic HIV-1 soluble gp120 is associated with immune dysfunction and inflammation in ART-treated individuals with undetectable viremia.

Background: Chronic inflammation persists in some people living with HIV (PLWH), even during antiretroviral therapy (ART) and is associated with premature aging. The gp120 subunit of the HIV-1 envelope glycoprotein can shed from viral and cellular membranes and can be detected in plasma and tissues, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasmatic soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, which were previously linked to CD4 depletion , could contribute to chronic inflammation, immune dysfunction, and sub-clinical cardiovascular disease in participants of the Canadian HIV and Aging cohort (CHACS) with undetectable viremia.

Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity.

HIV-1 evades antibody-dependent cellular cytotoxicity (ADCC) responses not only by controlling Env conformation and quantity at the cell surface but also by altering NK cell activation via the downmodulation of several ligands of activating and co-activating NK cell receptors. The signaling lymphocyte activation molecule (SLAM) family of receptors, which includes NTB-A and 2B4, act as co-activating receptors to sustain NK cell activation and cytotoxic responses. These receptors cooperate with CD16 (FcγRIII) and other activating receptors to trigger NK cell effector functions.

Structure-function Analyses Reveal Key Molecular Determinants of HIV-1 CRF01_AE Resistance to the Entry Inhibitor Temsavir.

The HIV-1 entry inhibitor temsavir prevents CD4 from interacting with the envelope glycoprotein (Env) and blocks its conformational changes. To do this temsavir relies on the presence of a residue with small side chain at position 375 in Env and is unable to neutralize viral strains like CRF01_AE carrying His375. Here we investigate the mechanism of temsavir-resistance and show that residue 375 is not the sole determinant of resistance.

Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120.

While HIV-1-mediated CD4 downregulation protects infected cells from antibody-dependent cellular cytotoxicity (ADCC), shed gp120 binds to CD4 on uninfected bystander CD4 T cells, sensitizing them to ADCC mediated by HIV plasma. Soluble gp120-CD4 interaction on multiple immune cells also triggers a cytokine burst. The small molecule temsavir acts as an HIV-1 attachment inhibitor by preventing envelope glycoprotein (Env)-CD4 interaction and alters the overall antigenicity of Env by affecting its processing and glycosylation.