Unité de Régulation des Infections Rétrovirales
Despite the success of anti-retroviral therapy both as treatment and prevention, novel scalable and low-cost vaccine and therapeutic tools remain the only solutions to definitively stop the global HIV/AIDS epidemic. To achieve this goal, we need to understand better which responses should be elicited, including at the mucosa level, to prevent HIV infection and/or disease progression. Our approaches are to study human cohorts as well as primate and experimental models to decipher mechanisms implicated in the control of HIV infection and immune activation, two critical determinants of HIV/AIDS pathogenesis (Figure 1).
1-Innate mechanisms of defense against HIV infection
In order to better understand the mechanisms of natural control of HIV mucosal transmission at early time points, we are studying the model of uterine mucosa during pregnancy, the decidua. Indeed, 90% of the fetus from HIV-1 positive women are protected from infection, even in the absence of preventive antiretroviral therapy. We found that soluble factors and interactions between Natural Killer (dNK) cells and macrophages (dM) derived from human deciduas result in a negative control of HIV replication in vitro in dM. Furthermore, dM express SAMHD1, a restriction factor, that might be involved in their low permissivity to HIV-1 infection. Together, these mechanisms may contribute to the natural control of HIV transmission at the mucosal level. We also demonstrated that Toll-Like receptors are expressed by dNK cells and dM, are functional and may also participate to the control. In parallel, we are studying the innate immunity of the female reproductive tract in non pregnant women and in particular the impact of TLR activation in the control of HIV-1 infection in the different mucosal compartments.
We also found that a subset of circulating NK cells has a remarkable capacity to control HIV replication in dendritic cells (DCs). We identified a novel NK cell receptor ligand (S100A9) and found that NK cells stimulated by S100A9 ligand are able to control HIV replication on DC and CD4 T cells and to increase cytokine secretion and expression of NK cell receptors, which are implicated in the control of HIV replication. Using an in vitro model setup in our lab, we also showed that peripheral NK cells stimulated by HIV MVA ANRS vaccine candidate are primed to inhibit HIV replication.
Intrinsic immunity of target cells to HIV-1 replication also constitutes an innate mechanism of defense against HIV-1, and has been associated, by us and others, with protection against infection in exposed uninfected individuals and spontaneous control of infection in HIV controllers. We have identified the cellular p21Waf1 as a factor blocking early steps of HIV-1 replication in macrophages, which might constitute a host barrier to HIV-1 integration. We found out that p21 blocks HIV replication by reducing the intracellular deoxyribonucleotide (dNTP) pool to levels below those required for viral cDNA synthesis. p21 inhibits transcription of RNR2, an enzyme essential for the reduction of ribonucleotides to dNTP, by repressing its transcriptional activator E2F1.
2- Protection against AIDS related to a persistent control of HIV-1 reservoirs
Rare individuals, called HIV controllers, are able to naturally control their infection to undetectable levels without therapy. We have studied a cohort (ANRS CO21) of these patients and demonstrated that an efficient HIV suppressive CD8+ T cell response likely contributes to such spontaneous control. We have shown that this efficient CD8+ T cell response was probably due to intrinsic characteristic of these cells defined early during induction of the response. In addition, we found a reduced permissiveness of their CD4 T cells and macrophages to HIV replication. This mechanism may be involved in the limited level of viral reservoirs measured in these particular patients, thus facilitating the control of infection. Seeking whether control of HIV viremia could be induced thanks to therapeutic intervention, we described for the first time a group of 14 adults who, despite a unfavorable MHC background, have achieved a durable remission of HIV infection after interruption of an antiretroviral treatment started very early in primary infection (ANRS VISCONTI Study). These individuals were characterized by a severe primary infection and low levels of immune activation, T cell responses and viral reservoirs during the phase of control.
3- Regulation of immune activation and protection against AIDS
In HIV infection, the level of T cell activation has been demonstrated to be a stronger predictor of disease progression than either viral load or CD4+ T cell counts. Chronic Immune activation is a hallmark of HIV infection and associated with all-cause mortality. In order to decipher the mechanisms that induce and regulate this chronic immune activation, we study the innate response during the early phases of HIV and SIV infection.
African Green monkeys (AGM) are natural carriers of SIV. They do not develop AIDS despite similar high level of viral replication as macaques infected by SIV who progress to AIDS. We have discovered that AGM lack chronic inflammation. Our data revealed that plasmacytoid dendritic cells of AGM rapidly sensor the virus in vivo and that AGM mount a strong inflammation during acute infection, as measured by the presence of interferon-alpha and IP-10. However, this inflammatory response is resolved by the end of the acute infection. This demonstrates that AGMs don’t lack but rather rapidly control inflammation induced by SIV infection despite persistent viremia. This contrasts with HIV infection, where inflammation persists. Based on these findings in the AGM model, we raised the hypothesis that a weak inflammation in acute HIV-1 infection is associated with a better subsequent control of the disease. We demonstrated that the inflammatory profile in the acute phase of HIV-1 infection predicts T cell activation levels at set-point in patients of the ANRS PRIMO Co6 cohort. Moreover, high IP-10 levels in the plasma predicted rapid progression towards AIDS. IP-10 levels are known to be closely associated with monocyte activation. Surprisingly the levels of IP-10 in acute HIV-1 infection revealed to be a better prognostic marker of rapid disease progression than viral load or CD4+ T cell counts.
In HIV/SIV infection, impairment of the intestinal barrier and subsequent microbial translocation (MT) has been involved in chronic immune activation. Th17 cells are critical to prevent MT by maintaining epithelial barrier integrity and a loss of the balance between Th17 and regulatory T cells (Tregs) has been associated with disease progression. We investigated, in patients with acute HIV infection, the early relationship between the Th17/Treg ratio, monocyte activation and microbial translocation and their impact on the T-cell activation levels at set point, known to predict disease progression. Th17 cell frequency and Th17/Treg ratio strongly negatively correlated with CD8 T-cell activation level and viral load. Soluble CD14 and IL-1RA, two markers of monocyte activation, were associated with T-cell activation and negatively correlated with the Th17/Treg ratio in the absence of systemic microbial translocation. Interestingly, we demonstrated that early levels of sCD14 and IL-1RA defining an “innate immune set point” predicted the T-cell activation set point, itself predictive of subsequent CD4 T-cell loss. Altogether, data support the hypothesis that, in acute infection, T-cell and monocyte activation are not primarily driven by systemic MT but rather by viral replication. Levels of IL-1RA and sCD4 might be powerful early surrogate markers for disease progression
Understanding how chronic inflammation could be avoided during HIV infection is a major issue for the patients.
Altogether, our work highlights the role of innate host determinants and the dynamics of early viral replication in shaping innate immune and efficient antiviral responses and the establishment of viral reservoirs. We will thus continue to explore the very early mechanisms of HIV pathogenesis with the aim to identify correlates of protection. Parts of our research are developed within the program of the Vaccine Research Institute (VRI) and the Center of Infectious Disease Models and Innovate Therapies (IDMIT), both recently funded through the National Program of Novel Investments (Labex, INBS), as well as within the International AIDS Society (IAS) Global Scientific Strategy on “Towards an HIV Cure”.