Oliver Hartley
University of Geneva
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Featured researches published by Oliver Hartley.
Nature Reviews Immunology | 2006
Michael M. Lederman; Robin E. Offord; Oliver Hartley
The HIV epidemic is, by many criteria, the worst outbreak of infectious disease in history. The rate of new infections is now ∼5 million per year, mainly in the developing world, and is increasing. Women are now substantially more at risk of infection with HIV than men. With no cure or effective vaccine in sight, a huge effort is required to develop topical agents (often called microbicides) that, applied to the vaginal mucosa, would prevent infection of these high-risk individuals. We discuss the targets for topical agents that have been identified by studies of the biology of HIV infection and provide an overview of the progress towards the development of a usable agent.
Proceedings of the National Academy of Sciences of the United States of America | 2008
Hubert Gaertner; Fabrice Cerini; Jean-Michel Escola; Gabriel Kuenzi; Astrid Melotti; Robin E. Offord; Irène Rossitto-Borlat; Rebecca Nedellec; Janelle R. Salkowitz; Guy Gorochov; Donald E. Mosier; Oliver Hartley
New prevention strategies for use in developing countries are urgently needed to curb the worldwide HIV/AIDS epidemic. The N-terminally modified chemokine PSC-RANTES is a highly potent entry inhibitor against R5-tropic HIV-1 strains, with an inhibitory mechanism involving long-term intracellular sequestration of the HIV coreceptor, CCR5. PSC-RANTES is fully protective when applied topically in a macaque model of vaginal HIV transmission, but it has 2 potential disadvantages related to further development: the requirement for chemical synthesis adds to production costs, and its strong CCR5 agonist activity might induce local inflammation. It would thus be preferable to find a recombinant analogue that retained the high potency of PSC-RANTES but lacked its agonist activity. Using a strategy based on phage display, we set out to discover PSC-RANTES analogs that contain only natural amino acids. We sought molecules that retain the potency and inhibitory mechanism of PSC-RANTES, while trying to reduce CCR5 signaling to as low a level as possible. We identified 3 analogues, all of which exhibit in vitro potency against HIV-1 comparable to that of PSC-RANTES. The first, 6P4-RANTES, resembles PSC-RANTES in that it is a strong agonist that induces prolonged intracellular sequestration of CCR5. The second, 5P12-RANTES, has no detectable G protein-linked signaling activity and does not bring about receptor sequestration. The third, 5P14-RANTES, induces significant levels of CCR5 internalization without detectable G protein-linked signaling activity. These 3 molecules represent promising candidates for further development as topical HIV prevention strategies.
Journal of Virology | 2000
Vincent S. Torre; Andre J. Marozsan; Jamie L. Albright; Kalonji R. Collins; Oliver Hartley; Robin E. Offord; Miguel E. Quiñones-Mateu; Eric J. Arts
Aminooxypentane (AOP)-RANTES efficiently and specifically blocks entry of non-syncytium-inducing (NSI), CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1) into host cells. Inhibition appears to be mediated by increased intracellular retention of the CCR5 coreceptor- AOP-RANTES complex and/or competitive binding of AOP-RANTES with NSI R5 HIV-1 isolates for CCR5. Although AOP-RANTES and other beta-chemokine analogs are potent inhibitors, the extreme heterogeneity of the HIV-1 envelope glycoproteins (gp120 and gp41) and variable coreceptor usage may affect the susceptibility of variant HIV-1 strains to these drugs. Using the same peripheral blood mononuclear cells (PBMC) with all isolates, we observed a significant variation in AOP-RANTES inhibition of 13 primary NSI R5 isolates; 50% inhibitory concentrations (IC(50)) ranged from 0.04 nM with HIV-1(A-92RW009) to 1.3 nM with HIV-1(B-BaL). Experiments performed on the same isolate (HIV-1(B-BaL)) with PBMC from different donors revealed no isolate-specific variation in AOP-RANTES IC(50) values but did show a considerable difference in virus replication efficiency. Exclusive entry via the CCR5 coreceptor by these NSI R5 isolates suggests that variable inhibition by AOP-RANTES is not due to alternative coreceptor usage but rather differential CCR5 binding. Analysis of the envelope V3 loop sequence linked a threonine or arginine at position 319 (numbering based on the HXB2 genome) with AOP-RANTES resistance. With the exception of one isolate, A319 was associated with increased sensitivity to AOP-RANTES inhibition. Distribution of AOP-RANTES IC(50) values with these isolates has promoted ongoing screens for new CCR5 agonists that show broad inhibition of HIV-1 variants.
Antimicrobial Agents and Chemotherapy | 2003
Cristina Pastore; Gaston Picchio; Francesco Galimi; Richard J. Fish; Oliver Hartley; Robin E. Offord; Donald E. Mosier
ABSTRACT C-C chemokine receptor 5 (CCR5) is the primary coreceptor for human immunodeficiency virus type 1 (HIV-1) infection. Native chemokines that bind to CCR5 inhibit HIV-1 infection, albeit weakly, but chemically modified chemokines inhibit infection more efficiently. We have investigated the inhibitory mechanism of three N-terminally modified RANTES variants (AOP-, NNY-, and PSC-RANTES) with the MT-2 human T-cell line stably expressing either native or mutated CCR5. The RANTES analogues showed the same rank order (PSC > NNY > AOP) in their capacity to induce prolonged CCR5 internalization, inhibit surface reexpression, and prevent HIV-1 infection on MT-2 cells expressing wild-type CCR5 or CCR5 with four C-terminal serine phosphorylation sites mutated to alanine. None of the RANTES analogues caused internalization of a C-terminal cytoplasmic domain deletion mutant of CCR5, and each derivative had equal potency in inhibiting HIV-1 infection of MT-2 cells expressing this mutant. We conclude that the C-terminal cytoplasmic residues of CCR5 are necessary for receptor sequestration by RANTES analogues but that the process and the relative activity of each derivative are not dependent upon phosphorylation of the C-terminal serine residues. Two mechanisms of antiviral activity are demonstrated: receptor blockade and receptor sequestration. Potency correlates with the ability to induce CCR5 sequestration but not with receptor binding, suggesting that sequestration may make the greater contribution to antiviral activity.
The Journal of Infectious Diseases | 2009
Ronald S. Veazey; Binhua Ling; Linda C. Green; Erin P. Ribka; Jeffrey D. Lifson; Michael Piatak; Michael M. Lederman; Donald E. Mosier; Robin E. Offord; Oliver Hartley
Effective strategies for preventing human immunodeficiency virus infection are urgently needed, but recent failures in key clinical trials of vaccines and microbicides highlight the need for new approaches validated in relevant animal models. Here, we show that 2 new chemokine (C-C motif) receptor 5 inhibitors, 5P12-RANTES (regulated on activation, normal T cell expressed and secreted) and 6P4-RANTES, fully protect against infection in the rhesus vaginal challenge model. These highly potent molecules, which are amenable to low-cost production, represent promising new additions to the microbicides pipeline.
Journal of Virology | 2004
Tatsuyoshi Kawamura; Shannon E Bruce; Awet Abraha; Makoto Sugaya; Oliver Hartley; Robin E. Offord; Eric J. Arts; Peter A. Zimmerman; Andrew Blauvelt
ABSTRACT Topical microbicides that effectively block interactions between CCR5+ immature Langerhans cells (LC) residing within genital epithelia and R5 human immunodeficiency virus (HIV) may decrease sexual transmission of HIV. Here, we investigated the ability of synthetic RANTES analogues (AOP-, NNY-, and PSC-RANTES) to block R5 HIV infection of human immature LC by using a skin explant model. In initial experiments using activated peripheral blood mononuclear cells, each analogue compound demonstrated marked antiviral activity against two R5 HIV isolates. Next, we found that 20-min preincubation of skin explants with each RANTES analogue blocked R5 HIV infection of LC in a dose-dependent manner (1 to 100 nM) and that PSC-RANTES was the most potent of these compounds. Similarly, preincubation of LC with each analogue was able to block LC-mediated infection of cocultured CD4+ T cells. Competition experiments between primary R5 and X4 HIV isolates showed blocking of R5 HIV by PSC-RANTES and no evidence of increased propagation of X4 HIV, data that are consistent with the specificity of PSC-RANTES for CCR5 and the CCR5+ CXCR4− phenotype of immature LC. Finally, when CCR5 genetic polymorphism data were integrated with results from the in vitro LC infection studies, PSC-RANTES was found to be equally effective in inhibiting R5 HIV in LC isolated from individuals with CCR5 diplotypes known to be associated with low, intermediate, and high cell surface levels of CCR5. In summary, PSC-RANTES is a potent inhibitor of R5 HIV infection in immature LC, suggesting that it may be useful as a topical microbicide to block sexual transmission of HIV.
Journal of Leukocyte Biology | 2009
Karim Dorgham; Ata Ghadiri; Patricia Hermand; Mathieu P. Rodero; Lucie Poupel; Mutsumori Iga; Oliver Hartley; Guy Gorochov; Christophe Combadière; Philippe Deterre
Chemokines are mainly involved in the recruitment of leukocytes into tissues, a key feature of inflammation. Through its unique receptor CX3CR1, the chemokine CX3CL1 participates in diverse inflammatory processes including arterial atherosclerosis and cerebral or renal inflammation. Using a phage display strategy, we engineered a hCX3CL1 analog (named F1) with a modified N terminus. F1 bound specifically to cells expressing hCX3CR1 and had a Kd value close to that of native CX3CL1. F1 was not a signaling molecule and did not induce chemotaxis, calcium flux, or CX3CR1 internalization. However, it potently inhibited the CX3CL1‐induced calcium flux and chemotaxis in CX3CR1‐expressing primary cells of human and murine origin with an IC50 of 5–50 nM. It also efficiently inhibited the cell adhesion mediated by the CX3CL1‐CX3CR1 axis. Finally, in a noninfectious murine model of peritonitis, F1 strongly inhibited macrophage accumulation. These data reveal a prototype molecule that is the first bona fide antagonist of hCX3CR1. This molecule could be used as a lead compound for the development of a novel class of anti‐inflammatory substances that act by inhibiting CX3CR1.
Journal of Virology | 2001
Rebecca Sabbe; Gaston Picchio; Cristina Pastore; Olivier Chaloin; Oliver Hartley; Robin E. Offord; Donald E. Mosier
ABSTRACT N-terminal modifications of the chemokine RANTES bind to C-C chemokine receptor 5 (CCR5) and block human immunodeficiency virus type 1 (HIV-1) infection with greater efficacy than native RANTES. Modified RANTES compounds induce rapid CCR5 internalization and much slower receptor reexpression than native RANTES, suggesting that receptor sequestration is one mode of anti-HIV activity. The rates of CCR5 internalization and reexpression were compared using the potentn-nonanoyl (NNY)-RANTES derivative and CD4+ T cells derived from donors with different CCR5 gene polymorphisms. NNY-RANTES caused even more rapid receptor internalization and slower reexpression than aminooxypentane (AOP)-RANTES. Polymorphisms in the promoter and coding regions of CCR5 significantly affected the receptor reexpression rate after exposure of cells to NNY-RANTES. These observations may be relevant for understanding the protective effects of different CCR5 genotypes against HIV-1 disease progression.
The Journal of Physiology | 2003
Aaron P. Russell; Emmanuel Somm; Manu Praz; Antoinette Crettenand; Oliver Hartley; Astrid Melotti; Jean-Paul Giacobino; Patrick Muzzin; Charles Gobelet; Olivier Dériaz
It has been proposed that mitochondrial uncoupling protein 3 (UCP3) behaves as an uncoupler of oxidative phosphorylation. In a cross‐sectional study, UCP3 protein levels were found to be lower in all fibre types of endurance‐trained cyclists as compared to healthy controls. This decrease was greatest in the type I oxidative fibres, and it was hypothesised that this may be due to the preferential recruitment of these fibres during endurance training. To test this hypothesis, we compared the effects of 6 weeks of endurance (ETr) and sprint (STr) running training on UCP3 mRNA expression and fibre‐type protein content using real‐time PCR and immunofluorescence techniques, respectively. UCP3 mRNA and protein levels were downregulated similarly in ETr and STr (UCP3 mRNA: by 65 and 50 %, respectively; protein: by 30 and 27 %, respectively). ETr significantly reduced UCP3 protein content in type I, IIa and IIx muscle fibres by 54, 29 and 16 %, respectively. STr significantly reduced UCP3 protein content in type I, IIa and IIx muscle fibres by 24, 31 and 26 %, respectively. The fibre‐type reductions in UCP3 due to ETr, but not STr, were significantly different from each other, with the effect being greater in type I than in type IIa, and in type IIa than in type IIx fibres. As a result, compared to STr, ETr reduced UCP3 expression significantly more in fibre type I and significantly less in fibre types IIx. This suggests that the more a fibre is recruited, the more it adapts to training by a decrease in its UCP3 expression. In addition, the more a fibre type depends on fatty acid β oxidation and oxidative phosphorylation, the more it responds to ETr by a decrease in its UCP3 content.
Journal of Virology | 2003
Oliver Hartley; Karim Dorgham; Danielle Perez-Bercoff; Fabrice Cerini; Anouk Heimann; Hubert Gaertner; Robin E. Offord; Gianfranco Pancino; Patrice Debré; Guy Gorochov
ABSTRACT The chemokine receptors CCR5 and CXCR4 are promising non-virus-encoded targets for human immunodeficiency virus (HIV) therapy. We describe a selection procedure to isolate mutant forms of RANTES (CCL5) with antiviral activity considerably in excess of that of the native chemokine. The phage-displayed library of randomly mutated and N-terminally extended variants was screened by using live CCR5-expressing cells, and two of the selected mutants, P1 and P2, were further characterized. Both were significantly more potent HIV inhibitors than RANTES, with P2 being the most active (50% inhibitory concentration of 600 pM in a viral coat-mediated cell fusion assay, complete protection of target cells against primary HIV type 1 strains at a concentration of 10 nM). P2 resembles AOP-RANTES in that it is a superagonist of CCR5 and potently induces receptor sequestration. P1, while less potent than P2, has the advantage of significantly reduced signaling activity via CCR5 (30% of that of RANTES). Additionally, both P1 and P2 exhibit not only significantly increased affinity for CCR5 but also enhanced receptor selectivity, retaining only trace levels of signaling activity via CCR1 and CCR3. The phage chemokine approach that was successfully applied here could be adapted to other chemokine-chemokine receptor systems and used to further improve the first-generation mutants reported in this paper.