| 1. |
- Borggren, Marie, et al.
(författare)
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Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-I variants emerging during AIDS progression
- 2008
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Ingår i: Retrovirology. - : Springer Science and Business Media LLC. - 1742-4690. ; 5:28
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Tidskriftsartikel (refereegranskat)abstract
- Background: At early stages of infection CCR5 is the predominant HIV-1 coreceptor, but in approximately 50% of those infected CXCR4-using viruses emerge with disease progression. This coreceptor switch is correlated with an accelerated progression. However, those that maintain virus exclusively restricted to CCR5 (R5) also develop AIDS. We have previously reported that R5 variants in these "non-switch virus" patients evolve during disease progression towards a more replicative phenotype exhibiting altered CCR5 coreceptor interactions. DC-SIGN is a C-type lectin expressed by dendritic cells that HIV-1 may bind and utilize for enhanced infection of T cells in trans. To further explore the evolution of the R5 phenotype we analyzed sequential R5 isolates obtained before and after AIDS onset, i.e. at the chronic stage and during end-stage disease, with regard to efficiency of DC-SIGN use in trans-infections. Results: Results from binding and trans-infection assays showed that R5 viruses emerging during end-stage AIDS disease displayed reduced ability to use DC-SIGN. To better understand viral determinants underlying altered DC-SIGN usage by R5 viruses, we cloned and sequenced the HIV-1 env gene. We found that end-stage R5 viruses lacked potential N-linked glycosylation sites (PNGS) in the gp120 V2 and V4 regions, which were present in the majority of the chronic stage R5 variants. One of these sites, amino acid position 160 (aa160) in the V2 region, also correlated with efficient use of DC-SIGN for binding and trans-infections. In fitness assays, where head-to-head competitions between chronic stage and AIDS R5 viruses were setup in parallel direct and DCSIGN-mediated infections, results were further supported. Competitions revealed that R5 viruses obtained before AIDS onset, containing the V2 PNGS at aa160, were selected for in the transinfection. Whereas, in agreement with our previous studies, the opposite was seen in direct target cell infections where end-stage viruses out-competed the chronic stage viruses. Conclusion: Results of our study suggest R5 virus variants with diverse fitness for direct and DCSIGN-mediated trans-infections evolve within infected individuals at end-stage disease. In addition, our results point to the importance of a glycosylation site within the gp120 V2 region for efficient DC-SIGN use of HIV-1 R5 viruses.
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| 2. |
- Borggren, Marie, et al.
(författare)
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Increased Sensitivity to Broadly Neutralizing Antibodies of End-Stage Disease R5 HIV-1 Correlates with Evolution in Env Glycosylation and Charge.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Induction of broadly neutralizing antibodies, such as the monoclonal antibodies IgGb12, 2F5 and 2G12, is the objective of most antibody-based HIV-1 vaccine undertakings. However, despite the relative conserved nature of epitopes targeted by these antibodies, mechanisms underlying the sensitivity of circulating HIV-1 variants to broadly neutralizing antibodies are not fully understood. Here we have studied sensitivity to broadly neutralizing antibodies of HIV-1 variants that emerge during disease progression in relation to molecular alterations in the viral envelope glycoproteins (Env), using a panel of primary R5 HIV-1 isolates sequentially obtained before and after AIDS onset.
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| 3. |
- Borggren, Marie
(författare)
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Intrahost evolution of HIV-1 phenotypes
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HIV-1 evolves constantly within an infected individual, due to its mutation-prone viral enzyme, high viral turnover and pressure from the host immune system. Therefore, viruses isolated at different time points from the same individual are never exactly the same and, accordingly, rarely function the same way. However, if we can understand how HIV-1 phenotypically evolves in the newly infected host and during disease progression, we may develop better therapeutics and perhaps halt the spread of the virus. This thesis is based on studies in which we have investigated how HIV-1 phenotypically evolves within infected individuals. We studied viruses emerging in infected adults, during late stage disease, and in vertically infected children, from shortly after birth until immunodeficiency. Some patients maintained viruses that exclusively used CC chemokine receptor 5 (CCR5) as coreceptor, R5 HIV-1, throughout the infection. Others had viruses whose coreceptor use was altered to include CXC chemokine receptor 4 (CXCR4). We analyzed sequentially obtained viruses from both groups of patients and studied phenotypic features in relation to molecular alterations in the viral envelope glycoproteins (Env). We found that the virus evolution at late stage disease toward increased infectivity and replicative capacity was fairly similar within patients harboring R5 or CXCR4-using HIV-1. The R5 HIV-1 also showed a decrease in trans-infection ability, mediated by the C-type lectin DC-SIGN, at end-stage disease. In addition, end-stage R5 HIV-1 were more sensitivity to certain broadly neutralizing antibodies. Furthermore, phenotypic alterations correlated with the decline in CD4+ T cell count during development of immunodeficiency. The observed evolution in phenotypic features also correlated with molecular alterations of the viral envelope glycoprotein gp120, with an increase in net positive charge and a loss of potential N-linked glycosylation sites (PNGS) at the end-stage of the disease. In addition, the efficiency of HIV-1 DC-SIGN use correlated with the presence of a specific glycan site in gp120. Studies on R5 HIV-1 from vertically infected children and their mothers demonstrated that efficient use of DC-SIGN for trans-infection do not appear to be a benefit for newly transmitted virus variants. Instead, the efficiency of virus DC-SIGN use increased during disease progression, from early after birth until immunodeficiency. These studies reveal that the phenotypes of R5 and CXCR4-using HIV-1 may evolve in an adaptive manner during disease progression and transmission.
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| 4. |
- Borggren, Marie, et al.
(författare)
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Neutralizing Antibody Response and Antibody-Dependent Cellular Cytotoxicity in HIV-1-Infected Individuals from Guinea-Bissau and Denmark
- 2016
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Ingår i: AIDS Research and Human Retroviruses. - : Mary Ann Liebert Inc. - 0889-2229 .- 1931-8405. ; 32:5, s. 434-442
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Tidskriftsartikel (refereegranskat)abstract
- The development of therapeutic and prophylactic HIV vaccines for African countries is urgently needed, but the question of what immunogens to use needs to be answered. One approach is to include HIV envelope immunogens derived from HIV-positive individuals from a geographically concentrated epidemic with more limited viral genetic diversity for a region-based vaccine. To address if there is a basis for a regional selected antibody vaccine, we have screened two regionally separate cohorts from Guinea-Bissau and Denmark for neutralizing antibody activity and antibody-dependent cellular cytotoxicity (ADCC) against local and nonlocal circulating HIV-1 strains. The neutralizing activity did not demonstrate higher potential against local circulating strains according to geography and subtype determination, but the plasma from Danish individuals demonstrated significantly higher inhibitory activity than that from Guinea-Bissau individuals against both local and nonlocal virus strains. Interestingly, an opposite pattern was observed with ADCC activity, where Guinea-Bissau individual plasma demonstrated higher activity than Danish plasma and was specifically against the local circulating subtype. Thus, on basis of samples from these two cohorts, no local-specific neutralizing activity was detected, but a local ADCC response was identified in the Guinea-Bissau samples, suggesting potential use of regional immunogens for an ADCC-inducing vaccine.
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| 5. |
- Borggren, Marie, et al.
(författare)
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R5 human immunodeficiency virus type 1 with efficient DC-SIGN use is not selected for early after birth in vertically infected children
- 2013
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Ingår i: The Journal of general virology. - : Microbiology Society. - 1465-2099 .- 0022-1317. ; 94:Pt 4, s. 767-773
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Tidskriftsartikel (refereegranskat)abstract
- The binding of human immunodeficiency virus (HIV) to C-type lectin receptors may result in either enhanced trans-infection of T-cells or virus degradation. We have investigated the efficacy of HIV-1 utilization of DC-SIGN, a C-type lectin receptor, in the setting of intrauterine or intrapartum mother-to-child transmission (MTCT). Viruses isolated from HIV-1-infected mothers at delivery and from their vertically infected children both shortly after birth and later during the progression of the disease were analysed for their use of DC-SIGN, binding and ability to trans-infect. DC-SIGN use of a child’s earlier virus isolate tended to be reduced as compared with that of the corresponding maternal isolate. Furthermore, the children’s later isolate displayed enhanced DC-SIGN utilization compared with that of the corresponding earlier virus. These results were also supported in head-to-head competition assays and suggest that HIV-1 variants displaying efficient DC-SIGN use are not selected for during intrauterine or intrapartum MTCT. However, viruses with increased DC-SIGN use may evolve later in paediatric HIV-1 infections.
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| 6. |
- Borggren, Marie, et al.
(författare)
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The Evolution of HIV-1 Interactions with Coreceptors and Mannose C-Type Lectin Receptors.
- 2015
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Ingår i: Progress in Molecular Biology and Translational Science. - : Elsevier. - 1877-1173 .- 1878-0814. ; 129, s. 109-140
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Tidskriftsartikel (refereegranskat)abstract
- The phenotype of human immunodeficiency virus type 1 (HIV-1) commonly evolves between and within infected individuals, at virus transmission, and during disease progression. This evolution includes altered interactions between the virus and its coreceptors, i.e., chemokine receptors, as well as mannose C-type lectin receptors (CLRs). Transmitted/founder viruses are predominantly restricted to CCR5, whereas the subsequent intrapatient evolution of HIV-1 coreceptor use during progressive disease can be subdivided into two distinct pathways. Accordingly, the CCR5-restricted virus population is either gradually replaced by virus variants able to use CXCR4 or evolves toward an altered, more flexible use of CCR5. Despite a strong dependency on these coreceptors for host cell entry, HIV-1 also interacts with other cell surface molecules during target cell attachment, including the CLRs. The virus interaction with the CLRs may result either in the efficient transfer of virus to CD4(+) T cells or in the degradation of the virus in endosomal compartments. The determinants of the diverse outcomes depend on which CLR is engaged and also on the glycan makeup of the envelope glycoproteins, which may evolve with the strength of the immune pressure during the disease course. With the current clinical introduction of CCR5 antagonists and the development of additional entry inhibitors, knowledge on the evolution and baseline characteristics of HIV-1 interactions with coreceptor and CLR interactions may play important roles for individualized and optimized treatment strategies. This review summarizes our current understanding of the evolution of HIV-1 interactions with these receptors.
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| 7. |
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| 8. |
- Ruffin, Nicolas, et al.
(författare)
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Rational design of HIV vaccines and microbicides: report of the EUROPRISE annual conference 2011
- 2012
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Europrise is a Network of Excellence supported by the European Commission within the 6th Framework programme from 2007 to 2012. The Network has involved over 50 institutions from 13 European countries together with 3 industrial partners and 6 African countries. The Network encompasses an integrated program of research, training, dissemination and advocacy within the field of HIV vaccines and microbicides. A central and timely theme of the Network is the development of the unique concept of co-usage of vaccines and microbicides. Training of PhD students has been a major task, and some of these post-graduate students have here summarized novel ideas emanating from presentations at the last annual Europrise meeting in Prague. The latest data and ideas concerning HIV vaccine and microbicide studies are included in this review; these studies are so recent that the majority have yet to be published. Data were presented and discussed concerning novel immunisation strategies; microbicides and PrEP (alone and in combination with vaccines); mucosal transmission of HIV/SIV; mucosal vaccination; novel adjuvants; neutralizing antibodies; innate immune responses; HIV/SIV pathogenesis and disease progression; new methods and reagents. These-necessarily overlapping topics-are comprehensively summarised by the Europrise students in the context of other recent exciting data.
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| 9. |
- Vinner, Lasse, et al.
(författare)
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Sequence analysis of HIV-1 isolates from Guinea-Bissau: selection of vaccine epitopes relevant in both West African and European countries.
- 2011
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Ingår i: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. - : Wiley. - 1600-0463. ; 119:8, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- For a CD8 epitope-based vaccine to match different geographic locations, the targeted epitopes for cytotoxic T-lymphocytes (CTLs) must be present in the local circulating HIV-1 strains. Secondly, the vaccine epitopes should match the host population HLA types. We characterized two new HIV-1 isolates from Guinea-Bissau. Also, we have identified 15 subdominant CD8 epitopes representing common HLA super-types theoretically covering most HLA alleles in any population. Herein we demonstrate that the selected vaccine epitopes are well conserved and simultaneously present in sequences from West Africa and Denmark. Use of the selected epitopes will likely ensure 10 immune targets in the majority of candidates for experimental therapeutic vaccination in both geographic regions. Our results warrant testing of the selected vaccine epitopes in both geographic locations.
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| 10. |
- Wahren, Britta, et al.
(författare)
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Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference
- 2010
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 8
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Forskningsöversikt (refereegranskat)abstract
- EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials. The Network is composed of 58 partners representing more than 65 institutions from 13 European countries; it also includes three major pharmaceutical companies (GlaxoSmithKline, Novartis and Sanofi-Pasteur) involved in HIV microbicide and vaccine research. The Network displays a dedicated and informative web page: http://www.europrise.org. Finally, a distinguishing trait of EUROPRISE is its PhD School of students from across Europe, a unique example in the world of science aimed at spreading excellence through training. EUROPRISE held its second annual conference in Budapest in November, 2009. The conference had 143 participants and their presentations covered aspects of vaccine and microbicide research, development and discovery. Since training is a major task of the Network, the students of the EUROPRISE PhD program summarized certain presentations and their view of the conference in this paper.
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