ABSTRACT
The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cross-reactive with the HIV broadly neutralizing Ab (bnAb) 2F5. Molecular mimicry of host proteins by pathogens can lead to autoimmune disease. In this article, we demonstrate that neither the 2F5 bnAb nor HIV MPER-KYNU cross-reactive Abs elicited by immunization with an MPER peptide-liposome vaccine in 2F5 bnAb VHDJH and VLJL knock-in mice and rhesus macaques modified KYNU activity or disrupted tissue tryptophan metabolism. Thus, molecular mimicry by HIV-1 Env that promotes the evasion of host anti-HIV-1 Ab responses can be directed toward nonfunctional host protein epitopes that do not impair host protein function. Therefore, the 2F5 HIV Env gp41 region is a key and safe target for HIV-1 vaccine development.
Subject(s)
AIDS Vaccines/immunology , HIV Envelope Protein gp41/metabolism , HIV Infections/immunology , HIV-1/immunology , Hydrolases/metabolism , Peptides/metabolism , Tryptophan/metabolism , Animals , Antibodies, Neutralizing/metabolism , Cross Reactions , HIV Antibodies/metabolism , HIV Envelope Protein gp41/genetics , HIV Envelope Protein gp41/immunology , Host-Pathogen Interactions , Humans , Hydrolases/genetics , Hydrolases/immunology , Immune Evasion , Macaca mulatta , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Mimicry , Peptides/genetics , Peptides/immunology , Vaccination , Vaccines, SubunitABSTRACT
The use of TLR agonists as an anti-cancer treatment is gaining momentum given their capacity to activate various host cellular responses through the secretion of inflammatory cytokines and type-I interferons. It is now also recognized that the perioperative period is a window of opportunity for various interventions aiming at reducing the risk of cancer metastases-the major cause of cancer related death. However, immune-stimulatory approach has not been used perioperatively given several contraindications to surgery. To overcome these obstacles, in this study, we used the newly introduced, fully synthetic TLR-4 agonist, Glucopyranosyl Lipid-A (GLA-SE), in various models of cancer metastases, and in the context of acute stress or surgery. Without exerting evident adverse effects, a single systemic administration of GLA-SE rapidly and dose dependently elevated both innate and adaptive immunity in the circulation, lungs and the lymphatic system. Importantly, GLA-SE treatment led to reduced metastatic development of a mammary adenocarcinoma and a colon carcinoma by approximately 40-75% in F344 rats and BALB/c mice, respectively, at least partly through elevating marginating-pulmonary NK cell cytotoxicity. GLA-SE is safe and well tolerated in humans, and currently is used as an adjuvant in phase-II clinical trials. Given that the TLR-4 receptor and its signaling cascade is highly conserved throughout evolution, our current results suggest that GLA-SE may be a promising immune stimulatory agent in the context of oncological surgeries, aiming to reduce long-term cancer recurrence.
Subject(s)
Adjuvants, Immunologic/pharmacology , Antineoplastic Agents/pharmacology , Glucosides/pharmacology , Lipid A/pharmacology , Neoplasm Metastasis/drug therapy , Neoplasms, Experimental/pathology , Toll-Like Receptor 4/agonists , Animals , Cell Line, Tumor , Female , Flow Cytometry , Male , Mice , Mice, Inbred BALB C , Perioperative Period , Rats , Rats, Inbred F344ABSTRACT
Two well-defined synthetic peptides TcD and PEP² were used in a sero-epidemiological study for detection of Trypanosoma cruzi infections in an indigenous group in the Amazon region of Ecuador. Of the 18 communities studied along the Rio Napo, province of Napo, 15 (83.3 per cent) were found to be positive for T. cruzi infection. Of the 1,011 individuals examined 61 (6.03 per cent) resulted positive. A prevalence of infection of 4.8 per cent was found in children aged 1-5 years. The prevalence of infection increased with age, with adults 50 years or older showing a maximum prevalence of 18.8 per cent. Autochthonous transmission of T. cruzi is present among this isolated indigenous population.