The difficulty in detecting rare infected cells immediately after mucosal HIV transmission has hindered our understanding of the initial cells targeted by the virus. Working with the macaque simian ...immunodeficiency virus (SIV) vaginal challenge model, we developed methodology to identify discrete foci of SIV (mac239) infection 48 hr after vaginal inoculation. We find infectious foci throughout the reproductive tract, from labia to ovary. Phenotyping infected cells reveals that SIV has a significant bias for infection of CCR6+ CD4+ T cells. SIV-infected cells expressed the transcriptional regulator RORγt, confirming that the initial target cells are specifically of the Th17 lineage. Furthermore, we detect host responses to infection, as evidenced by apoptosis, cell lysis, and phagocytosis of infected cells. Thus, our analysis identifies Th17-lineage CCR6+ CD4+ T cells as primary targets of SIV during vaginal transmission. This opens new opportunities for interventions to protect these cells and prevent HIV transmission.
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•Methodology to identify SIV-infected foci 48 hr after vaginal exposure in macaques•Vaginal exposure with SIV causes infection throughout the female reproductive tract•SIV preferentially infects Th17 cells during the first 48 hr after challenge•Host-mediated antiviral measures are observed by day 2 after vaginal exposure
Understanding mucosal transmission of HIV is critical to design effective prevention strategies. Utilizing a rhesus macaque model of SIV infection, Stieh et al. identify CCR6+ RORγt+ Th17 cells throughout the female reproductive tract as being selectively targeted for infection early during transmission.
Simian immunodeficiency viruses of sooty mangabeys (SIVsm) are the source of multiple, successful cross-species transmissions, having given rise to HIV-2 in humans, SIVmac in rhesus macaques, and ...SIVstm in stump-tailed macaques. Cellular assays and phylogenetic comparisons indirectly support a role for TRIM5alpha, the product of the TRIM5 gene, in suppressing interspecies transmission and emergence of retroviruses in nature. Here, we investigate the in vivo role of TRIM5 directly, focusing on transmission of primate immunodeficiency viruses between outbred primate hosts. Specifically, we retrospectively analyzed experimental cross-species transmission of SIVsm in two cohorts of rhesus macaques and found a significant effect of TRIM5 genotype on viral replication levels. The effect was especially pronounced in a cohort of animals infected with SIVsmE543-3, where TRIM5 genotype correlated with approximately 100-fold to 1,000-fold differences in viral replication levels. Surprisingly, transmission occurred even in individuals bearing restrictive TRIM5 genotypes, resulting in attenuation of replication rather than an outright block to infection. In cell-culture assays, the same TRIM5 alleles associated with viral suppression in vivo blocked infectivity of two SIVsm strains, but not the macaque-adapted strain SIVmac239. Adaptations appeared in the viral capsid in animals with restrictive TRIM5 genotypes, and similar adaptations coincide with emergence of SIVmac in captive macaques in the 1970s. Thus, host TRIM5 can suppress viral replication in vivo, exerting selective pressure during the initial stages of cross-species transmission.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
‘Infodemia’ is a portmanteau between ‘information’ and ‘epidemics’, referring to wide and rapid accumulation and dissemination of information, misinformation, and disinformation about a given ...subject, such as a disease. As facts, rumors and fears mix and disperse, the misinfodemic creates loud background noise, preventing the general public from discerning between accurate and false information. We compared and contrasted key elements of the AIDS and COVID-19 misinfodemics, to identify common features, and, based on experience with the AIDS pandemic, recommend actions to control and reverse the SARS-CoV-2 misinfodemic that contributed to erode the trust between the public and scientists and governments and has created barriers to control of COVID-19. As pandemics emerge and evolve, providing robust responses to future misinfodemics must be a priority for society and public health.
Misinfodemics constantly thwart the impact of efficacious responses to emerging pandemics.Infodemics foster serious distrust between the people and medical professionals and the legitimate acts of governments requiring public cooperation for controlling pandemics.Prevention of the misinfodemics by the scientific community is critical for the successful control of emerging pandemics and should be undertaken immediately.Comparison of the HIV and SARS-CoV-2 pandemics is informative for understanding misinfodemics throughout modern history. These comparisons strongly suggest that misinfodemics will certainly be a reoccurring phenomenon with disastrous consequences without decisive actions.
Chronic Chagasic cardiomyopathy is responsible for a large disease burden in the Americas, and a therapeutic vaccine would be highly desirable. We tested the safety and efficacy of a therapeutic DNA ...vaccine encoding antigens TSA-1 and Tc24 for preventing cardiac alterations in experimentally infected macaques. A secondary objective was to evaluate the feasibility of detecting changes in cardiac alterations in these animals.
Naïve rhesus macaques were infected with Trypanosoma cruzi and treated with three doses of DNA vaccines.
Blood cell counts and chemistry indicated that therapeutic vaccination was safe, as hepatic and renal function appeared unaffected by the vaccination and/or infection with T. cruzi. Electrocardiographic (ECG) recordings indicated that no marked arrhythmias developed up to 7 months post-infection. Univariate analysis of ECG parameters found no significant differences in any of these parameters between vaccinated and control macaques. However, linear discriminant analysis revealed that control macaques presented clear alterations in their ECG patterns at 7 months post-infection, indicative of the onset of conduction defects and cardiac alterations, and these changes were prevented in vaccine treated macaques.
This is the first evidence that therapeutic vaccination against T. cruzi can prevent cardiac alterations in non-human primates, strengthening the rationale for developing a human vaccine against Chagas disease.
Neutralizing antibodies are thought to be crucial for HIV vaccine protection, but studies in animal models suggest that high antibody concentrations are required. This is a major potential hurdle for ...vaccine design. However, these studies typically apply a large virus inoculum to ensure infection in control animals in single-challenge experiments. In contrast, most human infection via sexual encounter probably involves repeated exposures to much lower doses of virus. Therefore, animal studies may have provided an overestimate of the levels of antibodies required for protection in humans. We investigated whether plasma concentrations of antibody corresponding to relatively modest neutralization titers in vitro could protect macaques from repeated intravaginal exposure to low doses of a simian immunodeficiency virus-HIV chimera (SHIV) that uses the CC chemokine receptor 5 (CCR5) co-receptor. An effector function-deficient variant of the neutralizing antibody was also included. The results show that a substantially larger number of challenges is required to infect macaques treated with neutralizing antibody than control antibody-treated macaques, and support the notion that effector function may contribute to antibody protection. Overall, the results imply that lower amounts of antibody than previously considered protective may provide benefit in the context of typical human exposure to HIV-1.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Island Biogeography Reveals the Deep History of SIV Worobey, Michael; Telfer, Paul; Souquière, Sandrine ...
Science (American Association for the Advancement of Science),
09/2010, Letnik:
329, Številka:
5998
Journal Article
Recenzirano
Simian immunodeficiency virus (SIV) lineages have been identified that are endemic to Bioko Island. The time the island formed offers a geological time scale calibration point for dating the most ...recent common ancestor of SIV. The Bioko viruses cover the whole range of SIV genetic diversity, and each Bioko SIV clade is most closely related to viruses circulating in hosts of the same genus on the African mainland rather than to SIVs of other Bioko species. Our phylogeographic approach establishes that SIV is ancient and at least 32,000 years old. Our conservative calibration point and analyses of gene sequence saturation and dating bias suggest it may be much older.
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi is one of the most important neglected parasitic diseases in the Americas. Vaccines represent an attractive complementary strategy ...for the control of T. cruzi infection and pre-clinical studies in mice demonstrated that trypomastigote surface antigen (TSA-1) and the flagellar calcium-binding (Tc24) parasite antigens are promising candidates for vaccine development. We performed here the first evaluation of the safety and immunogenicity of two recombinant vaccine antigens (named TSA1-C4 and Tc24-C4) in naïve non-human primates. Three rhesus macaques received 3 doses of each recombinant protein, formulated with E6020 (Eisai Co., Ltd.), a novel Toll-like receptor-4 agonist, in a stable emulsion. All parameters from blood chemistry and blood cell counts were stable over the course of the study and unaffected by the vaccine. A specific IgG response against both antigens was detectable after the first vaccine dose, and increased with the second dose. After three vaccine doses, stimulation of PBMCs with a peptide pool derived from TSA1-C4 resulted in the induction of TSA1-C4-specific TNFα-, IL-2- and IFNγ-producing CD4+ in one or two animals while stimulation with a peptide pool derived from Tc24-C4 only activated IFNγ-producing CD4+T cells in one animal. In two animals there was also activation of TSA1-C4-specific IL2-producing CD8+ T cells. This is the first report of the immunogenicity of T. cruzi-derived recombinant antigens formulated as an emulsion with a TLR4 agonist in a non-human primate model. Our results strongly support the need for further evaluation of the preventive efficacy of this type of vaccine in non-human primates and explore the effect of the vaccine in a therapeutic model of naturally-infected Chagasic non-human primates, which would strengthen the rationale for the clinical development as a human vaccine against Chagas disease.
Chronic Chagasic cardiomyopathy develops years after infection in 20-40% of patients, but disease progression is poorly understood. Here, we assessed
parasite dynamics and pathogenesis over a ...2.5-year period in naturally infected rhesus macaques. Individuals with better control of parasitemia were infected with a greater diversity of parasite strains compared to those with increasing parasitemia over time. Also, the
parasite multiplication rate decreased with increasing parasite diversity, suggesting competition among strains or a stronger immune response in multiple infections. Significant differences in electrocardiographic (ECG) profiles were observed in Chagasic macaques compared to uninfected controls, suggesting early conduction defects, and changes in ECG patterns over time were observed only in macaques with increasing parasitemia and lower parasite diversity. Disease progression was also associated with plasma fibronectin degradation, which may serve as a biomarker. These data provide a novel framework for the understanding of Chagas disease pathogenesis, with parasite diversity shaping disease progression.IMPORTANCEChagas disease progression remains poorly understood, and patients at increased risk of developing severe cardiac disease cannot be distinguished from those who may remain asymptomatic. Monitoring of
strain dynamics and pathogenesis over 2-3 years in naturally infected macaques shows that increasing parasite diversity in hosts is detrimental to parasite multiplication and Chagasic cardiomyopathy disease progression. This provides a novel framework for the understanding of Chagas disease pathogenesis.
Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine. Indeed, passively administered neutralizing antibodies have been shown to ...protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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