Regulation of Retroviral Infections / Research / Research groups / Natural mechanisms of control of HIV/SIV viremia

Unité de Régulation des Infections Rétrovirales

Natural mechanisms of control of HIV/SIV viremia

TEAM MEMBERS
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

HIV-controllers (HIC) (also called “elite controllers” or “elite suppressors”) are rare (less than 1%) HIV-infected patients who control viral replication to undetectable levels in the absence of antiretroviral treatment. In the context of the ANRS-CO21 cohort coordinated by Dr. Olivier Lambotte and Pr. Brigitte Autran, we investigated parameters of control in HICs. Our results support the fact that most HICs are infected with fully replicative-competent HIV-1, implying an active host restraint of viremia. The control of HIV-1 replication in HICs has indeed been associated with a strong, multifunctional specific CD8+ T cell response. Interestingly, we observed that HIV-specific CD8+ T cells expressed the activation marker HLA-DR but not CD38. This unique activation phenotype was associated with a high potential to proliferate upon exposure to antigen. Remarkably, CD8+ T cells from HIV controllers ex vivo effectively suppressed HIV-1 infection without prior stimulation through the elimination of infected CD4+ T cells (Saez-Cirion et al. PNAS 2007; Nat Prot 2010). Our data suggest that the constitutive antiviral capacity of CD8+ T cells could account for the control of viral replication in these patients (Lecuroux et al PLoS One 2013). This CD8 T cell anti-viral activity correlated strongly with the frequency of Gag-specific CD8+ T cells (Saez-Cirion et al. J Immunol 2009). The remarkable spontaneous viral control in these individuals offers a unique model to explore efficient in vivo mechanisms of CD8+ T cell-mediated HIV-1 control and may serve to a better design of vaccination or immune-based therapies. Therefore, we are undertaking new studies with the aim of characterizing the virological, immunological and mechanistic parameters of HIV-1 suppression mediated by HIC CD8+ T cells. This study should bring new information on the function and the persistence of the CD8 T cell response in the HIC patients and on its protective role in vivo.

Our studies have also shown that control of viral reservoirs is a key aspect to achieve spontaneous control of infection. We showedthat weak reservoirs in HIC were associated to lower susceptibility to HIV infection of the main target cells in these patients (Saez-Cirion et al Blood 2011). Overall, controlling the dynamics of viral replication during the early phase of infection is critical to limit the establishment of viral reservoirs and allowing an optimal induction of immunity against HIV. To be able to explore these early times we work in collaboration with the CEA to study models of natural control of SIV 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,
visconti@anrs.fr.

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

Cell susceptibility to HIV infection is a key modulator of HIV pathogenesis. Cellular susceptibility to HIV infection impacts not only the level of viral replication, but also viral cell-to-cell transmission, viral dissemination and cellular homeostasis. Resistance of the main HIV-target cells to infection has been associated with protection from infection, spontaneous control of viremia or reduced viral reservoirs. Cell infectability depends on the balance between facilitating and impairing host factors. Indeed, the virus relies on numerous cellular factors to complete each step of its replication cycle and it needs to altogether overcome intrinsic cell factors that are devised to hinder viral replication. Our objective is to better understand these mechanisms.

p21Waf1/CIP1 as a key regulator of HIV replication
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.