Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants

Closely related HLA alleles presenting similar HIV-1 epitopes can be associated with variable clinical outcome. Here the authors report their findings on CD8+ T cell responses to the HIV-1 Gag-p24 TL9 immunodominant epitope in the context of closely related protective and less protective HLA alleles, and their differential effect on viral contro

Post-treatment control or treated controllers? Viral remission in treated and untreated primary HIV infection

OBJECTIVE(S): An HIV cure will impose aviraemia which is sustained following the withdrawal of antiretroviral therapy (ART). Understanding the efficacy of novel interventions aimed at curing HIV requires characterisation of both natural viral control and the effect of ART on viral control after treatment interruption. DESIGN: Analysis of transient viral control in recent seroconverters in the SPARTAC trial. METHODS: We compared untreated and treated HIV seroconverters (n = 292) and identified periods of control (plasma VL<400 copies/mL for ≥16 weeks off therapy) in 7.9% of ART-naive participants, and in 12.0% overall. HIV DNA was measured by qPCR and HIV-specific CD8 responses were measured by ELISpot. T cell activation and exhaustion were measured by flow cytometry. RESULTS: At baseline, future controllers had lower HIV DNA, lower plasma VLs, higher CD4:CD8 ratios (all p < 0.001), and higher CD4 counts (p < 0.05) than non-controllers. Among controllers, the only difference between the untreated and those who received ART was higher baseline VLs in the latter (p = 0.003), supporting an added ART effect. CONCLUSIONS: Consideration of spontaneous remission in untreated individuals will be critical to avoid overestimating the effect size of new interventions used in HIV cure studies

Lobster Fishery Management in the Marine Ecosystem Approach at Simeulue Island Waters (Wpp-nri 572)

The lobster fishery is one of the leading fisheries commodity on Simeulue Regency so that local government must manage wisely in order to maintain the sustainability of the lobster fishery. Aceh Government Regulation namely Qanun Aceh No. 7 of 2010 concerning fisheries already in effect. However, the institutional system has not functioned optimally in the management of lobster fisheries. The purpose this study is to examine the domain of fishing techniques, socio-economic and institutional management of lobster fisheries with ecosystem approaches in Simeulue waters. Research method using qualitative research. The method of data collection is survey method which is done by purposive sampling approach that is by doing depth responder interview which is considered informative and wide knowledge about the institute. Data analysis using EAFM analysis done with Flag Modeling technique. Based on the results of the study that the assessment of the fishing domain techniques and economic domains in aggregate showed bad category. Meanwhile, social domains and institutional domains show moderate categories so aggregate composites overall show fewer categories. It is therefore necessary to make a tactical decision from the bad to be better in accordance with the category of each EAFM domain

Non-human TRIM5 variants enhance recognition of HIV-1-infected cells by CD8+ T cells

Tripartite motif-containing protein 5 (TRIM5) restricts human immunodeficiency virus type-1 (HIV-1) in a species-specific manner by uncoating viral particles while activating early innate responses. Although the contribution of TRIM5 proteins to cellular immunity has not yet been studied, their interactions with the incoming viral capsid and the cellular proteasome led us to hypothesize a role for them. Here, we investigate whether the expression of two non-human TRIM5 orthologs, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), both of which are potent restrictors of HIV-1, could enhance immune recognition of infected cells by CD8+ T cells. We illustrate how TRIM5 restriction improves CD8+ T cell-mediated HIV-1 inhibition. Moreover, when TRIM5 activity was blocked by the non-immunosuppressive analog of cyclosporin A, SmBz-CsA, we found a significant reduction in CD107a/MIP1β expression in HIV-1-specific CD8+ T cells. This finding underscores the direct link between TRIM5 restriction and activation of CD8+ T-cell responses. Interestingly, cells expressing RhT5 induced stronger CD8+ T-cell responses through the specific recognition of the HIV-1 capsid by the immune system. The underlying mechanism of this process may involve TRIM5-specific capsid recruitment to cellular proteasomes and increase peptide availability for loading and presentation of HLA class I antigens. In summary, we identified a novel function for non-human TRIM5 variants in cellular immunity. We hypothesise that TRIM5 can couple innate viral sensing and CD8+ T-cell activation to increase species barriers against retrovirus infection. IMPORTANCE: New therapeutics to tackle HIV-1 infection should aim to combine rapid innate viral sensing and cellular immune recognition. Such strategies could prevent seeding of the viral reservoir and the immune damage that occurs during acute infection. The non-human TRIM5 variants, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), are attractive candidates owing to their potency in sensing HIV-1 and blocking its activity. Here, we show that expression of RhT5 and TCyp in HIV-1-infected cells improves CD8+ T cell-mediated inhibition through the direct activation of HIV-1-specific CD8+ T-cell responses. We found that the potency in CD8+ activation was stronger for RhT5 variants and capsid-specific CD8+ T-cells in a mechanism that relies on TRIM5-dependent particle recruitment to cellular proteasomes. This novel mechanism couples innate viral sensing with cellular immunity in a single protein and could be exploited to develop innovative therapeutics for control of HIV-1 infection

Host genotype and time dependent antigen presentation of viral peptides: predictions from theory

The rate of progression of HIV infected individuals to AIDS is known to vary with the genotype of the host, and is linked to their allele of human leukocyte antigen (HLA) proteins, which present protein degradation products at the cell surface to circulating T-cells. HLA alleles are associated with Gag-specific T-cell responses that are protective against progression of the disease. While Pol is the most conserved HIV sequence, its association with immune control is not as strong. To gain a more thorough quantitative understanding of the factors that contribute to immunodominance, we have constructed a model of the recognition of HIV infection by the MHC class I pathway. Our model predicts surface presentation of HIV peptides over time, demonstrates the importance of viral protein kinetics, and provides evidence of the importance of Gag peptides in the long-term control of HIV infection. Furthermore, short-term dynamics are also predicted, with simulation of virion-derived peptides suggesting that efficient processing of Gag can lead to a 50% probability of presentation within 3 hours post-infection, as observed experimentally. In conjunction with epitope prediction algorithms, this modelling approach could be used to refine experimental targets for potential T-cell vaccines, both for HIV and other viruses

Investment Incentives Under Emission Trading: An Experimental Study

This paper presents the results of an experimental investigation on incentives to adopt advanced abatement technology under emissions trading. Our experimental design mimics an industry with small asymmetric polluting firms regulated by different schemes of tradable permits. We consider three allocation/auction policies: auctioning off (costly) permits through an ascending clock auction, grandfathering permits with re-allocation through a single-unit double auction, and grandfathering with re-allocation through an ascending clock auction. Our results confirm both dynamic and static theoretical equivalence of auctioning and grandfathering. We nevertheless find that although the market institution used to reallocate permits does not impact the dynamic efficiency from investment, it affects the static efficiency from permit trading

Technological Change in Economic Models of Environmental Policy: A Survey

This paper provides an overview of the treatment of technological change in economic models of environmental policy. Numerous economic modeling studies have confirmed the sensitivity of mid- and long-run climate change mitigation cost and benefit projections to assumptions about technology costs. In general, technical progress is considered to be a noneconomic, exogenous variable in global climate change modeling. However, there is overwhelming evidence that technological change is not an exogenous variable but to an important degree endogenous, induced by needs and pressures. Hence, some environmenteconomy models treat technological change as endogenous, responding to socio-economic variables. Three main elements in models of technological innovation are: (i) corporate investment in research and development, (ii) spillovers from R&D, and (iii) technology learning, especially learning-by-doing. The incorporation of induced technological change in different types of environmental-economic models tends to reduce the costs of environmental policy, accelerates abatement and may lead to positive spillover and negative leakage