HIV-1 progressively destroys the immune system, resulting in AIDS by complex mechanisms, which are not yet entirely elucidated. Our laboratory is conducting research on the mechanisms underlying host control of HIV/SIV replication and pathogenesis. We specifically investigate the features of efficient anti-HIV/AIDS immunity, including innate defenses as well as innate and adaptive immune responses. With these aims, we are studying models of natural or induced protection against infection and against disease.

The long-term goal is to identify correlates of protection against HIV/AIDSand to be able to induce such protective responses in humans.

1. Cell restriction of HIV replication.

Some innate host factors can restrict intracellular HIV-1 replication impeding HIV-1 infection of target cells. We investigate mechanisms of restriction of HIV replication in human macrophages, which play a crucial role in the spread of HIV-1 infection and the establishment of viral reservoirs. We have shown that the induction of the cyclin-dependent kinase inhibitor p21^Waf-1/Cip1by FcγR-aggregation and other stimuli inhibits the reverse transcription and integration of HIV-1 and related primate lentiviruses in monocyte-derived macrophages.

2. Control of HIV infection by innate immune responses

Natural Killer (NK) cell are a crucial component of early antiviral responses.We showed that the NK cell CD85j subset is able to control HIV-1 replication in dendritic cells (DC) by a natural anti-HIV activity via specific ligand receptor interactions. We identified a new ligand for the CD85j NK cell receptor that may be implicated in HIV control. We also found that NK cell activation by DC loaded with HIV-1 antigens (ANRS vaccine candidates) control in vitroHIV-1 infection of DC.

To identify correlates of protection against HIV-1 infection in a mucosa, we are studying innate immunity at the materno-fetal interface in the decidua (uterine mucosa during pregnancy) since early in uterotransmission is rare. We have shown that CD14+ dAPC are the main target of R5 HIV-1. The receptor repertoire of dNK cells is distinct from the one of the periphery and evolves during the first trimester of pregnancy. The natural control of in uteroHIV transmission might involve dAPC/dNK cell interactions via direct contact or soluble factors.

3. Control of HIV infection by adaptive immune responses

We are studying patients who efficiently control viremia for long periods of time in the absence of therapy: the HIV controllers (HIC). We have shown that, in many HIC, this control is associated with the capacity of their HIV-specific CD8⁺T cells, and mainly of Gag-specific cells, to kill HIV-1 infected CD4+T cells. However, we also found weak CD8⁺T cell responses in a group of HIC suggesting the existence of other mechanisms of viral control.

4. Role of regulatory T cells (Treg) in HIV infection

Tregs are subsets of T cells with immunosuppressive capacities. In HIV-1 infection, Tregs may be harmful by suppressing HIV-specific immune responses. In contrast, they may also contribute to the control of the generalized T cell activation occurring very early during primary HIV infection. We are currently studying the impact of the different subsets of regulatory T cells (natural Tregs, Tr1 and Th3 cells, double negative perforin+ T cells) and of the balance between effector and regulatory T-cell responses on disease progression in patients with primary HIV infection.

5. Protection mechanisms against chronic immune activation and AIDS

SIV-infected African Green monkeys (AGM) do not progress to AIDS despite high level of viral replication. This resistance to AIDS is associated with the lack of chronic T cell activation. We have shown that AGM, early after infection, are able to rapidly sense the virus and to mount a robust innate response. However, inflammation is resolved by the end of the acute infection, avoiding chronic immune activation. The down-regulation of the inflammatory response including expression of IFN inducible genes implies active regulatory mechanisms that are under investigation.

Keywords: HIV, SIV, AIDS, innate Immunity, CD8+ T lymphocyte, natural killer cell, dendritic cell, macrophage, control of mother-to-child transmission, mucosal immunity, HIV controllers, natural hosts, immune activation, IFN, regulatory T cells

1 - Marlin R, Nugeyre M-T, de Truchis C, Berkane N, Gervaise A, Barré-Sinoussi F, Menu E, 2009, Antigen-Presenting Cells represent targets for R5 HIV-1 infection in the first trimester pregnancy uterine mucosa, PloS One, 4(6):e5971.PMID: 19543402

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, 2009, Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response, J Clin Invest, 119(12):3544-55. PMID: 19959873.

3 - Sáez-Cirión A, Shin SY, Versmisse P, Barré-Sinoussi F, Pancino G, 2010, Ex vivo T cell-based HIV suppression assay to evaluate HIV-specific CD8+ T-cell responses.Nat Protoc. 5(6):1033-41. Epub 2010 May 13.PMID: 20539279

4 - Bergamaschi A, David A, Le Rouzic E, Nisole S, Barré-Sinoussi F, Pancino G., 2009, 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. 83(23):12253-65, PMID: 19759136

5 - Scott-Algara D, Arnold V, Didier C, Kattan T, Pirozzi G, Barré-Sinoussi F, Pancino G, 2008, The CD85J+ NK cell subset potently controls HIV-1 replication in autologous dendritic cells, PLoS One, 3(4):e1975, PMID: 18398485