Host-directed approaches in the pursuit of a cure for HIV.

The success of antiretroviral therapy (ART) for people with HIV has been a result of direct acting antiviral small molecules that target key components of the viral life cycle, however ART must be taken life long and there is no cure. The major barrier to a cure for HIV is the persistence of a long lived and proliferating reservoir of latently infected cells that persist on ART. Cure strategies for HIV currently target host proteins to either reduce the size of the reservoir or enhance HIV-specific immunity.

Antibody prophylaxis may mask subclinical SIV infections in macaques.

Broadly neutralizing antibodies (bNAbs) show potential to prevent human immunodeficiency virus (HIV-1) infection in humans. However, there are limited data on the antibody concentrations required to prevent infection. Clinical trials of bNAb prophylaxis have demonstrated partial efficacy, but the sampling frequency typically does not allow precise timing of infection events and concurrent antibody levels.

SIV monoclonal antibody administration spanning treatment interruption in macaques delays viral rebound and selects escape variants.

HIV-1 envelope broadly neutralizing antibodies represent a promising component of HIV-1 cure strategies. To evaluate the therapeutic efficacy of combination monoclonal antibodies (mAbs) in a rigorous nonhuman primate model, we tested different combinations of simian immunodeficiency virus (SIV) neutralizing mAbs in SIVmac251-infected rhesus macaques. Antiretroviral therapy-suppressed animals received anti-SIV mAbs targeting multiple Env epitopes spanning analytical treatment interruption (ATI) in 3 groups (n = 7 each): i) no mAb; ii) 4-mAb combination; and iii) 2-mAb combination.

Isolation and structure of broad SIV-neutralizing antibodies reveal a proximal helical MPER epitope recognized by a rhesus multi-donor class.

The membrane-proximal external region (MPER) of the HIV-1 envelope is a target for broadly neutralizing antibodies (bnAbs), and vaccine-elicited MPER-directed antibodies have recently been reported from a human clinical trial. In this study, we sought to identify MPER-directed nAbs in simian immunodeficiency virus (SIV)-infected rhesus macaques. We isolated four lineages of SIV MPER-directed nAbs from two SIV-infected macaques.

Immune checkpoint inhibitors in infectious disease.

Following success in cancer immunotherapy, immune checkpoint blockade is emerging as an exciting potential treatment for some infectious diseases, specifically two chronic viral infections, HIV and hepatitis B. Here, we will discuss the function of immune checkpoints, their role in infectious disease pathology, and the ability of immune checkpoint blockade to reinvigorate the immune response. We focus on blockade of programmed cell death 1 (PD-1) to induce durable immune-mediated control of HIV, given that anti-PD-1 can restore function to exhausted HIV-specific T cells and also reverse HIV latency, a long-lived form of viral infection.

Immune Activation Profiles Elicited by Distinct, Repeated TLR Agonist Infusions in Rhesus Macaques.

TLR agonists are a promising class of immune system stimulants investigated for immunomodulatory applications in cancer immunotherapy and viral diseases. In this study, we sought to characterize the safety and immune activation achieved by different TLR agonists in rhesus macaques (Macaca mulatta), a useful preclinical model of complex immune interactions. Macaques received one of three TLR agonists, followed by plasma cytokine, immune cell subset representation, and blood cell activation measurements.

AZD5582 plus SIV-specific antibodies reduce lymph node viral reservoirs in antiretroviral therapy-suppressed macaques.

The main barrier to HIV cure is a persistent reservoir of latently infected CD4 T cells harboring replication-competent provirus that fuels rebound viremia upon antiretroviral therapy (ART) interruption. A leading approach to target this reservoir involves agents that reactivate latent HIV proviruses followed by direct clearance of cells expressing induced viral antigens by immune effector cells and immunotherapeutics. We previously showed that AZD5582, an antagonist of inhibitor of apoptosis proteins and mimetic of the second mitochondrial-derived activator of caspases (IAPi/SMACm), induces systemic reversal of HIV/SIV latency but with no reduction in size of the viral reservoir.

Convalescent human IgG, but not IgM, from COVID-19 survivors confers dose-dependent protection against SARS-CoV-2 replication and disease in hamsters.

Introduction: Antibody therapeutic strategies have served an important role during the COVID-19 pandemic, even as their effectiveness has waned with the emergence of escape variants. Here we sought to determine the concentration of convalescent immunoglobulin required to protect against disease from SARS-CoV-2 in a Syrian golden hamster model.

Methods: Total IgG and IgM were isolated from plasma of SARS-CoV-2 convalescent donors.

Broad coverage of neutralization-resistant SIV strains by second-generation SIV-specific antibodies targeting the region involved in binding CD4.

Both SIV and SHIV are powerful tools for evaluating antibody-mediated prevention and treatment of HIV-1. However, owing to a lack of rhesus-derived SIV broadly neutralizing antibodies (bnAbs), testing of bnAbs for HIV-1 prevention or treatment has thus far been performed exclusively in the SHIV NHP model using bnAbs from HIV-1-infected individuals. Here we describe the isolation and characterization of multiple rhesus-derived SIV bnAbs capable of neutralizing most isolates of SIV.

A SARS-CoV-2 Spike Ferritin Nanoparticle Vaccine Is Protective and Promotes a Strong Immunological Response in the Cynomolgus Macaque Coronavirus Disease 2019 (COVID-19) Model.

The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery that will improve vaccination compliance and demonstrate efficacy against emerging variants.

A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in nonhuman primates. High-dose (50 μg) SpFN vaccine, given twice 28 days apart, induced a Th1-biased CD4 T cell helper response and elicited neutralizing antibodies against SARS-CoV-2 wild-type and variants of concern, as well as against SARS-CoV-1.

Protective Efficacy of Gastrointestinal SARS-CoV-2 Delivery against Intranasal and Intratracheal SARS-CoV-2 Challenge in Rhesus Macaques.

Live oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge.

Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques.

Emergence of novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean serum neutralizing antibody titers of 14,000 to 21,000.

Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques.

Unlabelled: Emergence of novel variants of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean neutralizing antibody titers of 14,000-21,000.

Immunogenicity of HIV-1-Based Virus-Like Particles with Increased Incorporation and Stability of Membrane-Bound Env.

An optimal prophylactic vaccine to prevent human immunodeficiency virus (HIV-1) transmission should elicit protective antibody responses against the HIV-1 envelope glycoprotein (Env). Replication-incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present virion-associated Env with a native-like structure during vaccination that closely resembles that encountered on infectious virus. Here, we optimized the incorporation of Env into previously designed mature-form VLPs (mVLPs) and assessed their immunogenicity in mice.

Efficacy of a Broadly Neutralizing SARS-CoV-2 Ferritin Nanoparticle Vaccine in Nonhuman Primates.

Unlabelled: The emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine in nonhuman primates (NHPs). High-dose (50 g) SpFN vaccine, given twice within a 28 day interval, induced a Th1-biased CD4 T cell helper response and a peak neutralizing antibody geometric mean titer of 52,773 against wild-type virus, with activity against SARS-CoV-1 and minimal decrement against variants of concern.

Distinct functions for the membrane-proximal ectodomain region (MPER) of HIV-1 gp41 in cell-free and cell-cell viral transmission and cell-cell fusion.

HIV-1 is spread by cell-free virions and by cell-cell viral transfer. We asked whether the structure and function of a broad neutralizing antibody (bNAb) epitope, the membrane-proximal ectodomain region (MPER) of the viral gp41 transmembrane glycoprotein, differ in cell-free and cell-cell-transmitted viruses and whether this difference could be related to Ab neutralization sensitivity. Whereas cell-free viruses bearing W666A and I675A substitutions in the MPER lacked infectivity, cell-associated mutant viruses were able to initiate robust spreading infection.