Unité de Régulation des Infections Rétrovirales
Research
Recent achievements and current projects
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 vitro or 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 FcgammaR-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-alpha production, 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 vitro to HIV-1 infection. Together with the low rate of in utero mother-to-child transmission, this suggests that a natural control occurs in vivo limiting the infection of the fetus. We are currently investigating the 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
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 vitro or 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 FcgammaR-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-alpha production, 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 vitro to HIV-1 infection. Together with the low rate of in utero mother-to-child transmission, this suggests that a natural control occurs in vivo limiting the infection of the fetus. We are currently investigating the 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