HIV-2 infection is associated with preserved GALT homeostasis and epithelial integrity despite ongoing mucosal viral replication.

The mechanisms that enable preservation of gut mucosal integrity during persistent viral replication and inherent inflammation remain unclear. Here, we investigated, for the first time, gut homeostasis in HIV-2 infection, a naturally occurring form of attenuated HIV disease. We found viral replication in both sigmoid and ileum of asymptomatic HIV-2+ patients (range: 240-851 circulating CD4+T-cells per µl) despite their undetectable viremia, accompanied by interferon-γ-producing CD8 T-cell expansion, irrespective of antiretroviral treatment. Nevertheless, there was no CD4 T-cell depletion, and Foxp3+ and IL-17- or IL-22-producing CD4 T-cell numbers were unaffected. Moreover, IL-22-producing innate lymphoid cells and IL-22-induced antimicrobial peptides and mucins were maintained. In agreement, the epithelium histology was preserved, including tight junction protein zonula occludens (ZO-1) levels. Furthermore, in vitro infection of colon epithelia with primary isolates revealed no HIV-2 impact on ZO-1 expression. Notably, sigmoid transcriptional levels of CCL20 and CCL28 were significantly increased, in direct correlation with GM-CSF, indicating a local response able to enhance CD4 T-cell recruitment. In conclusion, maintenance of mucosal integrity in HIV-2 infection was associated with T-cell recruitment responses, potentially counteracting CD4 T-cell depletion due to HIV-2 replication. These data have unique implications for the design of therapies targeting gut homeostasis in HIV-1 infection and other chronic inflammatory settings.

Colonic patch and colonic SILT development are independent and differentially regulated events.

Intestinal lymphoid tissues have to simultaneously ensure protection against pathogens and tolerance toward commensals. Despite such vital functions, their development in the colon is poorly understood. Here, we show that the two distinct lymphoid tissues of the colon-colonic patches and colonic solitary intestinal lymphoid tissues (SILTs)-can easily be distinguished based on anatomical location, developmental timeframe, and cellular organization. Furthermore, whereas colonic patch development depended on CXCL13-mediated lymphoid tissue inducer (LTi) cell clustering followed by LTα-mediated consolidation, early LTi clustering at SILT anlagen did not require CXCL13, CCR6, or CXCR3. Subsequent dendritic cell recruitment to and gp38(+)VCAM-1(+) lymphoid stromal cell differentiation within SILTs required LTα; B-cell recruitment and follicular dendritic cell differentiation depended on MyD88-mediated signaling, but not the microflora. In conclusion, our data demonstrate that different mechanisms, mediated mainly by programmed stimuli, induce the formation of distinct colonic lymphoid tissues, therefore suggesting that these tissues may have different functions.

Response of naïve and memory CD8+ T cells to antigen stimulation in vivo.

We studied the influence of memory T cell properties on the efficiency of secondary immune responses by comparing the in vivo immune response of the same numbers of T cell receptor (TCR) transgenic (Tg) naïve and memory T cells. Compared to naïve Tg cells, memory cells divided after a shorter lag time; had an increased division rate; a lower loss rate; and showed more rapid and efficient differentiation to effector functions. We found that initial naïve T cell priming resulted in cells expressing mutually exclusive effector functions, whereas memory T cells were multifunctional after reactivation, with each individual cell expressing two to three different effector functions simultaneously. These special properties of memory T cells ensure the immediate control of reinfection.