Unité de Régulation des Infections Rétrovirales
Natural mechanisms of control of HIV/SIV viremia
Annie David, Research Engineer
Pierre Versmisse, Technician
Caroline P. Passaes, Post doc (CEA/IP)
Jose Carlos Valle-Casuso, Post doc
Mathieu Angin, Post doc
Gianfranco Pancino, Emeritus Research Director
NATURAL CONTROL OF INFECTION
For more information see:
Sáez-Cirión A, Pancino G. HIV controllers: a genetically determined or inducible phenotype? Immunol Rev. 2013 Jul;254(1):281-94.
THE VISCONTI STUDY
The possibility to translate the mechanisms of control observed in HIV controllers to other patients is uncertain. Starting antiretroviral therapy during primary infection may provide significant benefits to HIV-infected patients (i.e. reduction of viral reservoirs, preservation of immune responses, protection from chronic immune activation). Indeed, we have observed that some HIV-infected patients interrupting a prolonged antiretroviral therapy initiated close to primary infection are able to control viremia afterwards. In the ANRS EP47 VISCONTI study, we identified and characterized a group of 14 post-treatment controllers (PTCs) in long term remission (more than 8 years in median) of HIV infection. PTCs achieved control of infection through mechanisms that are, at least in part, different from those commonly observed in HICs and their capacity to control is likely related to early therapeutic intervention (which occurred within 10 weeks following primary infection). We found that PTCs were able, after therapy interruption, to keep, and in some cases further reduce, a weak viral reservoir. This might be related to the low contribution of long-lived cells to the HIV-reservoir in these patients. Finally, we estimated the probability of maintaining viral control at 24 months post-early treatment interruption to be between 5 and 15%, which is significantly higher than the one expected for spontaneous control of infection.
Our current efforts are focused in understanding the mechanisms underlying control of infection in PTC and in identifying the parameters that explain why only a minority of early treated patients are able to achieve HIV remission. The final objective is to identify parameters that will help us to anticipate which patients are more likely to control infection after treatment interruption. In the absence of such parameters, treatment interruption may be harmful and is not recommended outside structured clinical protocols.
The VISCONTI study is a multidisciplinar collaborative consortium including clinicians, virologists, immunologists, geneticists and epidemiologists coordinated by Prof. Christine Rouzioux, Dr. Laurent Hocqueloux and Dr. Asier Sáez-Cirión. An international cohorte of Post-treatment controllers is being established to study this phenomenon, firstname.lastname@example.org.
Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, Potard V, Versmisse P, Melard A, Prazuck T, Descours B, Guergnon J, Viard JP, Boufassa F, Lambotte O, Goujard C, Meyer L, Costagliola D, Venet A, Pancino G, Autran B, Rouzioux C; ANRS VISCONTI Study Group. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013 Mar;9(3):e1003211
REGULATION OF VIRAL REPLICATION BY CELLULAR RESTRICTION MECHANISMS
We have identified the cyclin-dependent kinase inhibitor p21Waf1/CIP1 (p21) as a key factor involved in restriction of HIV and SIV replication in human macrophages (Bergamaschi A. et al, 2009). p21 expression impairs the reverse transcription of HIV-1 and other primate lentiviruses, including the simian immunodeficiency virus (SIV)mac, by blocking the synthesis of cellular deoxynucleotides (dNTP) that are used by retroviral reverse transcriptase for viral DNA synthesis. p21 represses the expression of a key enzyme of the dNTP biosynthesis pathway, the RNR2 subunit of the ribonucleotide reductase. p21 RNR2-related activiy is independent of SAMHD1, another cellular factor that restricts HIV by decreasing the pool of dNTP. Our findings point to new potential cellular targets for antiretroviral strategies.
For more information see:
Allouch A, David A, Amie SM, Lahouassa H, Chartier L, Margottin-Goguet F, Barré-Sinoussi F, Kim B, Sáez-Cirión A, Pancino G. p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway. Proc Natl Acad Sci U S A. 2013 110(42):E3997-4006.