Regulation of Retroviral Infections  


  HEADProfessor Françoise BARRE-SINOUSSI / francoise.barre-sinoussi@pasteur.fr
  MEMBERSARNOLD Vincent PhD student / BARRE-SINOUSSI Françoise PhD, Head of Unit (IP, INSERM) / BERGAMASCHI Anna PhD, Post-doc / CANNOU Claude Technician, Laboratory assistant (IP) / CUMMINGS Jean Saville PhD, Post-doc / DAVID Annie PhD, Engineer (IP) / DELAIRE Marie-Claire Laboratory assistant (IP) / DIDIER Céline Senior Technician (IP) / HAMINI Chiraz PhD student / JACQUELIN Béatrice PhD, Engineer (IP)
OULLIE Magali Executive Secretary (IP) / LIOVAT Anne-Sophie PhD student / MARLIN Romain PhD student / MENU Elisabeth PhD, Assistant Professor (INSERM) / MULLER-TRUTWIN Michaela PhD, Associate Professor (IP) / NUGEYRE Marie-Thérèse Engineer (IP) / PANCINO Gianfranco MD, PhD, Research Director (INSERM)
PETITJEAN Gaël PhD, Post-doc / RESCANIERE Olivier, Scientific assistant (IP) / ROSS Anna-Laura PhD, Post-doc / SAEZ-CIRION Asier PhD, Assistant Professor (IP) / SCOTT-ALGARA Daniel MD, PhD, Associate Professor (IP) / VERSMISSE Pierre Senior Technician (IP) / WEISS Laurence MD, PhD, Professor (Paris V University)


  Annual Report

Unlike most other persistent viruses, HIV-1 progressively destroys the immune system, resulting in AIDS by very complex mechanisms that remain to be elucidated. Our laboratory is conducting research on the mechanisms underlying the control of HIV/SIV replication and pathogenesis. We specifically investigate cellular restriction mechanisms that may limit viral replication, innate immune mechanisms that regulate the induction of harmful versus protective immune responses, and the specific features of efficient immune anti-viral responses, using different models either in vitroor in human and non-human primates.

1. Regulation of viral replication by cellular restriction mechanisms.

Our investigations on host cells permissive or not to HIV-1 infection demonstrated that:

- The cyclin-dependent kinase inhibitor p21Waf-1/Cip1 is induced by FcγR-aggregation and inhibits the reverse transcription and integration of HIV-1 and related primate lentiviruses in human macrophages

- The DCAF1 ubiquitin ligase is a critical host effector of Vpx to mediate macrophage infection by HIV-2. Vpx assembly with the CUL4A-DDB1 ubiquitin ligase complex through DCAF1 recruitment may lead to the inactivation of an HIV-2 restriction factor in macrophages.

- Cell-free HIV-1 infection encounters a surface block in trophoblast cells from the placenta leading to a non-productive entry route, which either actively targets incoming virions for non-proteasomal degradation, and impedes their release into the cytoplasm, or causes the inactivation of mechanisms essential for viral replication.

2. Protection against AIDS by Innate immune mechanisms

African Green monkeys (AGM) infected by SIV are protected against AIDS because they manage to avoid the harmful chronic T cell activation. We have shown that AGM first mount an innate immune response to the virus (PDC homing to lymph nodes, IFN-αproduction, expression of IFN-stimulated genes), but that this pro-inflammatory response is resolved by the end of the acute infection. Thus, chronic T cell activation is not avoided by ignorance of the virus, but interestingly through the induction of an active regulatory mechanism.

3. Protective innate or specific anti-viral responses

- Antigen presenting cells from the decidua (uterine mucosa during pregnancy) are permissive in vitroto HIV-1 infection. Together with the low rate of in uteromother-to-child transmission,this suggests that a natural control occurs in vivolimiting the infection of the fetus. We are currently investigatingthe role of the mucosal maternal innate immunity in this control.

Natural Killer (NK) cell subsets are able to control HIV-1 replication in infected dendritic cells (DC) either by a natural anti HIV activity (CD85j NK cell subset) or after specific activation of DC loaded with HIV antigens.

- CD8+T cells from HIV controllers (HICs) suppress ex vivo HIV-1 infection of autologous CD4+T cells, suggesting a crucial role of this response in the control of HIV replication in vivo. This anti-viral capacity correlates with the frequency of HIV-specific CD8+T cells, in particular of Gag specific response. However, some HICs have weak HIV-specific CD8+T cell responses, suggesting that other host mechanisms may contribute to controlling HIV infection.

Keywords: HIV, SIV, Innate Immunity, CD8+ T lymphocyte, natural killer cell, dendritic cell, macrophage, mother-to-child transmission, mucosal immunity, HIV controllers, immune activation, protection



  Publications

1 - Marlin R, NugeyreM-T, de TruchisC, BerkaneN, GervaiseA, Barré-SinoussiF,MenuE. Antigen-Presenting Cells represent targets for R5 HIV-1 infection in the first trimester pregnancy uterine mucosa.PloSOne, 2009, 4(6):e5971.

2 - Jacquelin B, Mayau V, Targat B, Liovat AS, Kunkel D, Petitjean G, Dillies MA, Roques P, Butor C, Silvestri G, Giavedoni LD, Lebon P, Barré-Sinoussi F, Benecke A, Müller-Trutwin MC. Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response.J Clin Invest. 2009 Dec;119(12):3544-55.

3- Sáez-Cirión A, Sinet M, Shin SY, Urrutia A, Versmisse P, Lacabaratz C, Boufassa F, Avettand-Fènoël V, Rouzioux C, Delfraissy JF, Barré-Sinoussi F, Lambotte O, Venet A, Pancino G; ANRS EP36 HIV Controllers Study Group. Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses.J Immunol. 2009 ;182(12):7828-37

4- Bergamaschi A, David A, Le Rouzic E, Nisole S, Barré-Sinoussi F, Pancino G. The CDK inhibitor p21Cip1/WAF1 is induced by Fc{gamma}R activation and restricts the replication of HIV-1 and related primate lentiviruses in human macrophages.J Virol. 2009 Dec;83(23):12253-65.

5-Scott-Algara D, Arnold V, Didier C, Kattan T, Pirozzi G, Barré-Sinoussi F, Pancino G. The CD85J+ NK cell subset potently controls HIV-1 replication in autologous dendritic cells.PLoS One. 2008, 3(4):e1975.



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Activity Reports 2009 - Institut Pasteur
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