Deciphering the role of Th17 cells in HIV infection

The mechanisms by which some individuals are able to control HIV infection and progression (HIV elite controllers or long-term non progressors [LTNPs]) in contrast to rapidly progressing individuals are poorly understood. Various viral or host genetic factors, i.e. viral nef- or cellular CCR5 deletions, may explain part of the observed differences. HIV elite controllers persistently have viral loads below 400 HIV RNA copies/ml without undergoing antiretroviral therapy, they stably express lower HIV-DNA in mononuclear cells and the majority of HIV elite controllers exert efficient CD8+ T cell responses. Viral control in LTNPs occurs early during infection and the viral load remains low also during acute phase of HIV infection. A study in SIV-infected rhesus macaques recently illustrated, that not only cytotoxic T cells (CTLs), but also the pre-existing T helper 17 (Th17) cell size contributes to lower peak and set-point viral loads. Therefore, to improve the care of HIV-infected individuals, it is crucial to identify additional host immune functions which contribute to restrict disease progression. In this context, our group recently illustrated that complement-opsonisation of HIV significantly enhanced the CTL-stimulatory capacity of dendritic cells (DC) both in vitro and in vivo. In preliminary experiments we now observed that not only CTLs are more efficiently activated by DC when virus is coated with complement fragments, but also Th17 cell differentiation was initiated by DC exposed to complement-opsonised HIV. In contrast, no Th17 cell induction was observed when DC were loaded with non-opsonised HIV. Additionally, we showed by ex vivo analyses using plasma samples from HIV elite controllers that high levels of complement and low levels of specific IgGs are coating the surface of HIV-1 preparations following opsonisation, which could contribute to the enhancement of cellular immune responses seen in these individuals. Complement activation occurs immediately after entry of HIV via mucosal surfaces. Interindividual differences regarding this step might provide another missing piece of the puzzle that allows resistance to retroviral disease progression during the very early steps of HIV infection. Thus, I plan to decipher the role of T helper cell differentiation, especially Th17/Treg balance, following viral infections as a function of the opsonisation pattern of the virus during the project period. The results might provide a new mechanism for understanding interindividual variation, and at best will lead to an improved DC-based immunotherapeutical vaccination strategy against HIV.

The immune system comprises complex cellular and humoral responses, which form an interactive network to recognize and eradicate invading pathogens. Among the first components activated during the innate immune response is the systemic complement system. It consists of various fluid-phase and cell membrane-bound proteins and acts as a tightly regulated cascade of enzymatic reactions to defend the host against pathogens. Thus, the complement system represents a first line of host defense by covalently coating (opsonization) and subsequently lysing pathogens, inducting pro-inflammatory cytokines and thereby maintaining homeostasis. In our studies, we described that complement-opsonized HIV-1 in contrast to non-opsonized virus is clearly sensed by dendritic cells, the sentinels and most important antigen-presenting cells of our immune system. This recognition goes along with higher activation and maturation of dendritic cells and therefore leads to stronger induction of T helper cells, cytotoxic T cells as well as humoral antiviral immune responses. In the project Deciphering the role of Th17 cells in HIV infection we investigated the activation and differentiation of T helper cells upon stimulation with dendritic cells exposed to various conditions. Prior to co-culture with autologous nave CD4+ T cells, dendritic cells were loaded with differentially opsonized HIV particles. We could demonstrate that complement-opsonization of HIV triggered an efficient antiviral immune response in dendritic cells and simultaneously polarized nave T cells into the T helper 17 lineage. The balance between T helper 17 cell and regulatory T cell is of utmost importance for immune defense in mucosal tissues, but during HIV-1 pathogenesis this balance is destroyed. In this study we could show that opsonization of HIV has a severe effect on the differentiation of nave T helper cell responses and that complement-opsonization of HIV, which is mainly detected in the acute phase of HIV infection, is favoring the induction of Th17 immune responses. To clearly identify the mechanism that explains the observed loss of Th17 cells in HIV pathogenesis, further studies need to be performed.