Preclinical Safety and Biodistribution of CRISPR Targeting SIV in Non-Human Primates
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Nonhuman primates have served as a valuable resource to evaluate novel eradication and cure strategies for HIV infection. Using a male rhesus macaque model, researchers demonstrated the safety and utility of CRISPR gene-editing technology for targeting integrated simian immunodeficiency virus (SIV). Their work suggests that a single intravenous inoculation for HIV gene editing can be utilized to reach viral reservoirs throughout the body. Additionally, no off-target effects or abnormal pathology were observed.
A Germ-Free Humanized Mouse Model Shows the Contribution of Resident Microbiota to Human-Specific Pathogen Infection
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Germ-free (GF) mice are of limited value in the study of human-specific pathogens because they do not support their replication. In this report, investigators developed a GF humanized mouse model using the bone marrow–liver–thymus platform to provide a robust and flexible in vivo model that can be used to study the role of resident microbiota in human health and disease. They demonstrated that resident microbiota promote viral acquisition and pathogenesis by using two human-specific pathogens, Epstein–Barr virus and HIV.
Allogeneic Immunity Clears Latent Virus Following Allogeneic Stem Cell Transplantation in SIV-Infected ART-Suppressed Macaques
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Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been documented as curative for HIV, but the mechanisms are not yet known. Using Mauritian cynomolgus macaques of both sexes, researchers performed reduced-intensity alloHSCT experiments to define the individual contributions of allogeneic immunity and CCR5 deficiency to an alloHSCT-mediated HIV cure. They reported that allogeneic immunity was the major driver of reservoir clearance, mediating graft-versus-reservoir effects in HIV infection.
Osteopontin Is an Integral Mediator of Cardiac Interstitial Fibrosis in Models of Human Immunodeficiency Virus Infection
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HIV infection is associated with increased risk of cardiovascular disease. Plasma osteopontin (Opn) is correlated with cardiac pathology, but more work is needed to understand the underlying mechanisms driving cardiac fibrosis. Researchers explored this topic using mouse embryonic fibroblasts, male macaques, and humanized mice of both sexes. They reported the accumulation of Opn in the heart with simian immunodeficiency virus infection. Systemic inhibition of Opn can prevent HIV-associated interstitial fibrosis in the left ventricle.
Brain Microglia Serve as a Persistent HIV Reservoir Despite Durable Antiretroviral Therapy
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Brain microglia are likely to play a role in rebound viremia following the cessation of antiretroviral therapy, but more work is needed to fully understand HIV persistence in the central nervous system (CNS). The investigators developed a protocol to isolate highly pure populations of brain myeloid cells and microglia from the tissues of male rhesus macaques, as well as from rapid autopsies of men and women with HIV. Their observations support the concept that brain microglia are a stable reservoir of quiescent infection.
Lymph-Node-Based CD3+ CD20+ Cells Emerge From Membrane Exchange Between T Follicular Helper Cells and B Cells and Increase Their Frequency Following Simian Immunodeficiency Virus Infection
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CD4+ T follicular helper cells are known to persist during antiretroviral therapy (ART) and have been identified as key targets for viral replication and persistence. Researchers identified a lymphocyte population that expresses CD3 (i.e., T cell lineage marker) and CD20 (i.e., B cell lineage marker) on the cellular surface in lymphoid tissues from rhesus macaques of both sexes and humans of male and female sexes. In macaques, the cells increased following simian immunodeficiency virus infection, were reduced with ART, and increased in frequency after ART interruption.
Antibody-Dependent Cellular Cytotoxicity, Infected Cell Binding and Neutralization by Antibodies to the SIV Envelope Glycoprotein
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Antibodies that bind to the envelope glycoprotein (Env) on the surface of virus-infected cells can recruit cells from the immune system to kill infected cells by antibody-dependent cellular cytotoxicity (ADCC). Researchers characterized ADCC, Env binding, and neutralization in rhesus macaque antibodies that were specific for diverse epitopes of the simian immunodeficiency virus (SIV) envelope glycoprotein. They found that most antibodies that inhibit SIV infectivity also bind to Env on infected cells and mediate ADCC, but this trend was not observed in select instances.
Efficient Ex Vivo Expansion of Conserved Element Vaccine-Specific CD8+ T Cells from SHIV-Infected, ART-Suppressed Nonhuman Primates
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HIV-specific T cells are necessary for control of HIV-1 replication but are largely insufficient for viral clearance. Using male rhesus macaques, investigators sought to increase the frequency of specific T cell responses in vivo using an ex vivo cell manufacturing approach. The resulting products contained high frequencies of specific, polyfunctional T cells, but no significant differences in T cell persistence were observed, nor was acquisition of simian–human immunodeficiency virus (SHIV).
Complement Contributes to Antibody-Mediated Protection Against Repeated SHIV Challenge
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The first clinical efficacy trials of a broadly neutralizing antibody (bNAb) resulted in less benefit than expected and suggested that improvements are needed to prevent HIV infection. Using rhesus macaques of both sexes, investigators sought to further investigate the contribution of antibody-mediated activation of complement to the protective potency of an HIV bNAb in passive transfer and simian–human immunodeficiency virus (SHIV) challenge experiments.
Probiotic Therapy During Vaccination Alters Antibody Response to Simian-Human Immunodeficiency Virus Infection But Not to Commensals
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Strategies to boost vaccine-induced mucosal humoral responses are critical to developing an HIV-1 vaccine, and probiotic supplementation could help boost antibody responses. Researchers analyzed antibody titers to explore this topic in rhesus macaques (sex not specified) infected with simian–human immunodeficiency virus (SHIV). They reported that probiotic treatment during vaccination led to delayed kinetics in the circulating HIV-specific IgA response after breakthrough SHIV infection.