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Unité de Régulation des Infections Rétrovirales
Natural mechanisms of HIV-1 control in humans
CD8 T CELL-MEDIATED HIV-1 SUPPRESSION IN HIV CONTROLLERS
Asier Sáez-Cirión, PhD
Chiraz Hamimi
Pierre Versmisse
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. The control of HIV-1 replication in HICs has been associated with a strong, multifunctional specific CD8+ T cell response. In the context of the ANRS-EP36 study group (http://gazette.kb.inserm.fr/hic/garde.html), constituted by immunologists, virologists, epidemiologists and clinicians and coordinated by Dr. Olivier Lambotte, we investigated parameters of control in HICs. It has been suggested that infection with replication-defective virus may explain the absence of detectable circulating virus in HICs. We investigated the replicative potential of HIV-1 strains in a group of 8 HICs. Our results (Lamine et al. 2007. AIDS. 21:1043-1045) support the fact that at least some HICs are infected with fully replicative-competent HIV-1. Therefore, although in some cases HICs may be infected with defective virus, our results clearly show that HICs can harbor replication-competent HIV. CD4+ T cells from HIC were fully permissive to HIV-1 replication, discarding intracellular restriction as the mechanism of viral control. Accordingly to other studies, we found high frequencies of HIV-specific CD8+ T cells that were restricted in most cases by the HLA class I molecules B57 and B27. 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). Our data suggest that the constitutive antiviral capacity of CD8+ T cells could account for the control of viral replication in these patients. 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.
Chiraz Hamimi
Pierre Versmisse
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. The control of HIV-1 replication in HICs has been associated with a strong, multifunctional specific CD8+ T cell response. In the context of the ANRS-EP36 study group (http://gazette.kb.inserm.fr/hic/garde.html), constituted by immunologists, virologists, epidemiologists and clinicians and coordinated by Dr. Olivier Lambotte, we investigated parameters of control in HICs. It has been suggested that infection with replication-defective virus may explain the absence of detectable circulating virus in HICs. We investigated the replicative potential of HIV-1 strains in a group of 8 HICs. Our results (Lamine et al. 2007. AIDS. 21:1043-1045) support the fact that at least some HICs are infected with fully replicative-competent HIV-1. Therefore, although in some cases HICs may be infected with defective virus, our results clearly show that HICs can harbor replication-competent HIV. CD4+ T cells from HIC were fully permissive to HIV-1 replication, discarding intracellular restriction as the mechanism of viral control. Accordingly to other studies, we found high frequencies of HIV-specific CD8+ T cells that were restricted in most cases by the HLA class I molecules B57 and B27. 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). Our data suggest that the constitutive antiviral capacity of CD8+ T cells could account for the control of viral replication in these patients. 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.
REGULATION OF VIRAL REPLICATION BY CELLULAR RESTRICTION MECHANISMS
Annie David, PhD
Macrophages are key actors of host innate defenses against pathogens, but they are also a major target of HIV and other lentiviruses and play a crucial role in the persistence and pathogenesis of infection (Verani et al. 2005). Modulation of HIV replication in these cells may influence both the host susceptibility to infection and the viral dissemination in infected individuals. We investigate HIV-1 and HIV-2 interactions with human macrophages with the aim to identify host factors involved in the control of viral replication.
p21Waf1/CIP1 inhibits the replication of HIV and SIV in human macrophages
We have shown that the aggregation of the receptors for the Fc portion of immunoglobulin G (FcγR) by immune complex (IC) inhibits HIV-1 replication, independently of viral tropism (Perez-Bercoff D. et al, 2003). Two steps of the viral replication cycle are affected, the reverse transcription and the integration of viral cDNA in host genome (David A. et al., 2006). Other primate lentiviruses (HIV-2, SIVmac and SIVagm), are also affected suggesting that the restriction targets either a protein conserved among these retroviruses or a common function. We have identified the cyclin-dependent kinase inhibitor p21Waf1/CIP1 (p21) as a key factor involved in the FcγR-mediated restriction (Bergamaschi A. et al, 2009). p21 expression is induced upon FcγR aggregation and siRNA-mediated knock-down of p21 rescues the replication of HIV-1 and related primate lentiviruses in IC-activated macrophages, increasing the levels of reverse transcripts and of integrated proviruses (Bergamaschi 2009).
HIV-2 Vpx overcomes an early post-entry block to viral replication in macrophages
Our studies on the replication of HIV-2 in macrophages, in collaboration with F. Margottin, Cochin Institute, have shown that the Vpx protein of HIV-2 and SIV recruits a Cul4a- DDB1 ubiquitin ligase complex through DCAF1 to overcome an early block of reverse transcription in macrophages (Bergamaschi A., Ayinde D. et al, J Virol 2009).
p21Waf1/CIP1 inhibits the replication of HIV and SIV in human macrophages
We have shown that the aggregation of the receptors for the Fc portion of immunoglobulin G (FcγR) by immune complex (IC) inhibits HIV-1 replication, independently of viral tropism (Perez-Bercoff D. et al, 2003). Two steps of the viral replication cycle are affected, the reverse transcription and the integration of viral cDNA in host genome (David A. et al., 2006). Other primate lentiviruses (HIV-2, SIVmac and SIVagm), are also affected suggesting that the restriction targets either a protein conserved among these retroviruses or a common function. We have identified the cyclin-dependent kinase inhibitor p21Waf1/CIP1 (p21) as a key factor involved in the FcγR-mediated restriction (Bergamaschi A. et al, 2009). p21 expression is induced upon FcγR aggregation and siRNA-mediated knock-down of p21 rescues the replication of HIV-1 and related primate lentiviruses in IC-activated macrophages, increasing the levels of reverse transcripts and of integrated proviruses (Bergamaschi 2009).
HIV-2 Vpx overcomes an early post-entry block to viral replication in macrophages
Our studies on the replication of HIV-2 in macrophages, in collaboration with F. Margottin, Cochin Institute, have shown that the Vpx protein of HIV-2 and SIV recruits a Cul4a- DDB1 ubiquitin ligase complex through DCAF1 to overcome an early block of reverse transcription in macrophages (Bergamaschi A., Ayinde D. et al, J Virol 2009).