The crease is most often referred to as a single palmar crease. The older term "simian crease" is not used much anymore, since it tends to have a negative meaning (The word "simian" refers to a monkey or ape).
Simian 22 PRO
Gag peptide, derived from the simian immunodeficiency virus (SIV), is a homologue of the human immunodeficiency virus (HIV) gag protein which interacts with viral components in order to induce the infectious form of the virus. SIV can be used to model HIV.
Citation: Chang XL, Reed JS, Webb GM, Wu HL, Le J, Bateman KB, et al. (2022) Suppression of human and simian immunodeficiency virus replication with the CCR5-specific antibody Leronlimab in two species. PLoS Pathog 18(3): e1010396.
Macaques (Macaca mulatta) used in this study were housed at the ONPRC in Animal Biosafety level (ABSL)-2+ rooms with autonomously controlled temperature, humidity, and lighting. At assignment, macaques were free of Cercopithecine herpesvirus 1, D-type simian retrovirus, simian T-lymphotrophic virus type 1, and Mycobacterium tuberculosis. Macaques were typed for the MHC alleles Mamu-B*17, and Mamu-B*08. Macaques positive for Mamu-B*17 and/or B*08 were excluded when possible or placed into the control group when it was not possible to exclude biased results. All attempts were made to pair house macaques during the study period by gender and treatment group. When compatible partners were not available, macaques had auditory, visual, and olfactory contact with neighboring macaques and were provided with an enhanced enrichment plan designed and overseen by a macaque behavioral specialist. Macaques were fed Purina LabDiet 5000 (Purina Mills International, St. Louis, MO) twice daily and received daily food enrichment (e.g., fresh fruit, vegetables). Automatic water systems provided fresh and potable water. Ketamine HCl (Ketathesia, Henry Schein Animal Health) with or without Dexmedetomidine (Dexmedesed, Dechra, Overland Park, KS) was used to sedate macaques for procedures, including subcutaneous injections of Leronlimab, venipuncture, tissue biopsy, and SHIV challenge. At the study endpoint, macaques were euthanized with sodium pentobarbital overdose (>50 mg/kg) and exsanguinated via the distal aorta. Aboard certified veterinary pathologist performed and collected tissues at necropsy.
CCR5, a chemokine receptor central for orchestrating lymphocyte/cell migration to the sites of inflammation and to the immunosurveillance, is involved in the pathogenesis of a wide spectrum of health conditions, including inflammatory diseases, viral infections, cancers and autoimmune diseases. CCR5 is also the primary coreceptor for the human immunodeficiency viruses (HIVs), supporting its entry into CD4+ T lymphocytes upon transmission and in the early stages of infection in humans. A natural loss-of-function mutation CCR5-Δ32, preventing the mutated protein expression on the cell surface, renders homozygous carriers of the null allele resistant to HIV-1 infection. This phenomenon was leveraged in the development of therapies and cure strategies for AIDS. Meanwhile, over 40 African nonhuman primate species are long-term hosts of simian immunodeficiency virus (SIV), an ancestral family of viruses that give rise to the pandemic CCR5 (R5)-tropic HIV-1. Many natural hosts typically do not progress to immunodeficiency upon the SIV infection. They have developed various strategies to minimize the SIV-related pathogenesis and disease progression, including an array of mechanisms employing modulation of the CCR5 receptor activity: (i) deletion mutations abrogating the CCR5 surface expression and conferring resistance to infection in null homozygotes; (ii) downregulation of CCR5 expression on CD4+ T cells, particularly memory cells and cells at the mucosal sites, preventing SIV from infecting and killing cells important for the maintenance of immune homeostasis, (iii) delayed onset of CCR5 expression on the CD4+ T cells during ontogenetic development that protects the offspring from vertical transmission of the virus. These host adaptations, aimed at lowering the availability of target CCR5+ CD4+ T cells through CCR5 downregulation, were countered by SIV, which evolved to alter the entry coreceptor usage toward infecting different CD4+ T-cell subpopulations that support viral replication yet without disruption of host immune homeostasis. These natural strategies against SIV/HIV-1 infection, involving control of CCR5 function, inspired therapeutic approaches against HIV-1 disease, employing CCR5 coreceptor blocking as well as gene editing and silencing of CCR5. Given the pleiotropic role of CCR5 in health beyond immune disease, the precision as well as costs and benefits of such interventions needs to be carefully considered.
Non-human primates (NHP) have been indispensable to the study of simian immunodeficiency (SIV)/human immunodeficiency (HIV) infection, pathogenesis, and the development of prophylactic and therapeutic interventions to prevent transmission and progression to disease. A number of SIV and chimeric simian-human immunodeficiency virus (SHIV) challenge stocks have significantly advanced the NHP model, making it possible to identify and better understand factors that influence virus transmission, acute infection, pathogenesis and the eventual progression to AIDS. The development of SHIV recombinant viruses, in particular, has been especially advantageous in that it provides a more relevant research tool for studying properties of HIV-1 infection in a NHP setting. These include HIV-1 envelope characteristics that affect transmission and pathogenesis. SHIV constructs also allow for the evaluation of the efficacy of anti-HIV microbicide formulations and vaccines that are directed against envelope and other critical virus components such as reverse transcriptase. While beneficial, the vast number of virologically-distinct challenge stocks and the growth of the NHP challenge model repertoire to now include rhesus, pigtail and cynomolgus macaques, have collectively introduced an increased level of complexity with regard to experimental design and data interpretation. Furthermore, some virus stocks have virological properties that limit applications in novel areas of drug discovery, prompting the development of new generation SHIV challenge stocks. The purpose of this chapter is to therefore summarize efforts that have been made to characterize both SIV/SHIV challenge stocks and NHP hosts, to highlight the development of new generation SHIV, and how these novel challenge stocks have advanced the SHIV NHP challenge model and anti-HIV drug and vaccine development.
Thus, while there is a fairly broad repertoire of macaques as animal models for AIDS research, their distinct pathogenic outcomes and innate physiological and biological makeup have to be carefully accounted for prior to selection for experimental studies. There is healthy skepticism regarding the extent to which macaques can accurately reflect HIV pathogenesis and predict efficacy of vaccines or other prophylactic tools in humans, and this is especially highlighted by negative results of the vaccine clinical trials AIDSVAX and STEP [49]. However, NHP macaques continue to be the best available model that researchers can utilize to study in vivo host-virus interactions in a system that is similar to HIV infected individuals. Furthermore, macaque models can be utilized to conduct retrospective studies to recapitulate vaccine clinical trials that have been conducted in humans. The most recent Phase IIb vaccine clinical trial, RV144, demonstrated a modest level of protection (31.2%) with a prime-boost platform involving ALVAC HIV (vCP1521) and AIDSVAX B/E gp120 candidate vaccines, and a working group has been set up to identify correlates of protection conferred by this vaccination in macaques in order to compare and contrast degrees of protection and associated protective immune responses. Drawing parallels between macaque models and vaccine trial participants may inform the design of future clinical trials as well as guide the choice of NHP model for prospective pre-clinical studies. The nature of the challenge virus itself has to also be considered. Indeed, as reviewed below, virus stocks utilized in NHP research have grown past SIV to include chimeric SHIV strains as well as simian-tropic HIV-1 strains, to better reflect properties of HIV-1 specific transmission and associated immune responses, and to facilitate experimental studies on anti-retroviral treatments and anti-HIV vaccines in NHP models. The selection of a NHP model will also require careful thought of the scientific questions being evaluated, the impact of these studies on the design of clinical trials in humans, as well as the cost and availability associated with each macaque species. These considerations are detailed below and are summarized in Table 1.
While SIV strains have a wide range of applications in NHP macaque models of AIDS, the genetic, structural and antigenic differences between SIV and HIV-1, particularly in the virus envelope (Env), pose limitations in areas addressing cellular tropism or co-receptor affinity, antibody neutralization, and immune-driven evolution and adaptation of Env. These differences in Env and other viral components can restrict the utility of SIV challenge models when evaluating Env-based vaccine strategies, or when testing methods of PrEP that employ entry inhibitors and/or post-entry inhibitors. To circumvent this issue, chimeric simian/human immunodeficiency viruses have been developed to create challenge stocks that better mimic the infectivity and pathogenic properties of HIV-1 in a macaque model setting.
The similarity in the genetic organization and composition of HIV-1 and SIV make it possible to construct replication-competent recombinant viruses that exhibit properties of both lineages. The genetic backbone of the majority of SHIV strains is SIVmac239. These viruses have been engineered to contain not only HIV-1 env, but also genes encoding Tat, Rev, Vpu, Vpr, Nef, integrase and/or reverse transcriptase. Initial SHIV constructs were found to have attenuated pathogenesis in macaques compared to parental SIVmac strains. However, the isolation of variants obtained from serial passage and in vivo adaptation in macaques yielded challenge stocks that variably increased their pathogenicity. The dual-tropic chimera SHIV89.6 that was originally developed by Reimann et al, contains the env gene from cytopathic primary patient isolate HIV-1 89.6, and although CD4+ T-cell loss and some degree of persistent infection was observed following intravenous inoculation in rhesus macaques, no disease developed [84]. In contrast, serial transfusion of peripheral blood from a rhesus macaque infected with SHIV89.6 yielded more pathogenic variants, SHIV89.6P (isolated from PBMC, LN and spleen) and SHIV89.6PD (plasma-derived), that had primarily CXCR4-tropism and resulted in higher viral loads and CD4+ T-cell decline, as well as simian AIDS [84, 122]. This SHIV construct and its derivatives have since been utilized to decipher host and virus factors influencing transmission and early T-cell and antibody responses following intravenous and intravaginal inoculation in macaques, and have also been applied in a number of pre-clinical vaccine trials. However, the suitability of HIV89.6P as a challenge virus in rhesus macaque models, particularly when evaluating vaccine candidates, has been called into question given their CXCR4-tropism. The affinity for the CXCR4 co-receptor allows for infection of naïve CD4+ T-cells which has a major impact on the kinetics of CD4+ T-cell depletion, resulting in rates of lymphopenia that are not reflective of that caused by HIV-1 and most SIV strains that are CCR5-tropic. 2ff7e9595c
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