L'impact des cellules dendritiques dans la dérégulation des cellules B dans un contexte d'infection au virus d'immunodéficience humaine

In the context of HIV-1 infection, DC are amongst the first cells to encounter the virus at the mucosal surfaces, and are directly and indirectly affected by the virus or its components. The fact that DC are altered in number, phenotype and function in the context of HIV, suggest they may be involved in driving B cell dysregulations, which occur as early as in the acute phase of HIV-infection and are not fully restored by therapy. As such, in recent longitudinal studies involving HIV-infected individuals with different rates of disease progression, we have shown that B cell dysregulations were associated with increased BLyS/BAFF expression in plasma and by blood myeloid DC (mDC). In previous work with HIV-transgenic mice, B cell dysregulations involved DC, excess BLyS/BAFF and were dependant on the HIV negative factor (Nef). We therefore aim to investigate the impact of HIV-Nef in modulating DC phenotype and B cell dysregulations. Blood samples from the same HIV-infected individuals as mentioned above were studied, following the identical longitudinal scheme. HIV-Nef was detected in plasma and beared by blood mDC and mDC precursors of all viremic HIV-infected patients, throughout follow-up and beyond therapy. Detection of HIV-Nef in mDC and their precursors was associated with BLyS/BAFF over-expression. In vitro, soluble HIV-Nef drove monocyte-derived mDC towards a pro-inflammatory phenotype by increasing the expression of BLyS/BAFF and TNF-α. Futhermore, this effect was blocked by the addition of retinoic acid. These data suggest that HIV-Nef is involved in the driving and persistence of B cell dysregulations in HIV-infected individuals. Based on our observations, therapeutic blocking of BLyS/BAFF and/or Nef could help control inflammation and B cell disorders. Moreover, measurement of HIV-Nef post-therapy may be useful in assessing reservoir status. We have previously shown that B cell dysregulations in the blood of HIV-infected rapid and classic progressors were accompanied by the increased frequency of a population presenting characteristics of both transitional immature (TI) and marginal zone (MZ) B cells, which we have termed “MZ-like precursors”. However, this population was unaltered in ELITE controllers (EC), even though we found significantly lower frequencies of more mature MZ-like B cells. These results suggest that such first line B cell populations may be involved in the battle against HIV-1. Interestingly, MZ-like B cell populations have recently been associated with Breg potential. As such, we found that as for HIV negative individuals, mature MZ-like B cells control their capacity of IL-10 production in EC. In contrast, HIV-1-infected rapid and classic progressors presented increased relative frequencies of MZ-like B cells expressing IL-10. Interestingly, in EC, blood MZ-like precursors provided substantial LT-α expression when compared to HIV negative individuals, and in contrast to that found in rapid and classic progressors, where significant LT-α expression was provided by TI B cells. In fact, the degree of control of disease progression seems associated with greater LT-α to IL-10 ratio within the MZ-like precursors population. Our results therefore suggest that maintenance of Breg integrity and increased LT-α expression by first line B cells, such as MZ-like populations, is involved in the control of HIV-1 disease progression, possibly trough contribution to immune modulation and homeostasis. Soliciting such populations should be beared in mind in the design of vaccine strategies aiming at generating both first line and adaptive protective responses.

Keyphrases: Nef, BLyS, BAFF, inflammation, Human immunodeficiency virus, dendritic cells, B cells, IL-10, clinical progression, marginal zone