Influence of Dendritic Cells on B-Cell Responses during HIV Infection

Dendritic cells (DCs) modulate B-cell differentiation, activation, and survival mainly through production of growth factors such as B lymphocyte stimulator (BLyS/BAFF). DC populations have been reported to be affected in number, phenotype and function during HIV infection and such alterations may contribute to the dysregulation of the B-cell compartment. Herein, we reflect on the potential impact of DC on the pathogenesis of HIV-related B cell disorders, and how DC status may modulate the outcome of mucosal B cell responses against HIV, which are pivotal to the control of disease. A concept that could be extrapolated to the overall outcome of HIV disease, whereby control versus progression may reside in the host's capacity to maintain DC homeostasis at mucosal sites, where DC populations present an inherent capacity of modulating the balance between tolerance and protection, and are amongst the earliest cell types to be exposed to the virus

High Level of Soluble HLA-G in the Female Genital Tract of Beninese Commercial Sex Workers Is Associated with HIV-1 Infection

Most HIV infections are transmitted across mucosal epithelium. Understanding the role of innate and specific mucosal immunity in susceptibility or protection against HIV infection, as well as the effect of HIV infection on mucosal immunity, are of fundamental importance. HLA-G is a powerful modulator of the immune response. The aim of this study was to investigate whether soluble HLA-G (sHLA-G) expression in the female genital tract is associated with HIV-1 infection.Genital levels of sHLA-G were determined in 52 HIV-1-uninfected and 44 antiretroviral naïve HIV-1-infected female commercial sex workers (CSWs), as well as 71 HIV-1-uninfected non-CSW women at low risk of exposure, recruited in Cotonou, Benin. HIV-1-infected CSWs had higher genital levels of sHLA-G compared with those in both the HIV-1-uninfected CSW (P = 0.009) and non-CSW groups (P = 0.0006). The presence of bacterial vaginosis (P = 0.008), and HLA-G*01:01:02 genotype (P = 0.002) were associated with higher genital levels of sHLA-G in the HIV-1-infected CSWs, whereas the HLA-G*01:04:04 genotype was also associated with higher genital level of sHLA-G in the overall population (P = 0.038). When adjustment was made for all significant variables, the increased expression of sHLA-G in the genital mucosa remained significantly associated with both HIV-1 infection (P = 0.02) and bacterial vaginosis (P = 0.03).This study demonstrates that high level of sHLA-G in the genital mucosa is independently associated with both HIV-1 infection and bacterial vaginosis

Contact events in T help for B cell activation

The generation of an Ab response is modulated by contact and cytokine mediated T help for B cells. Here we show that murine splenic small resting B cells do not express mRNA for, or bear IL-2R. Accordingly, these cells do not respond to IL-2. T- contact events induce IL-2R expression on B cells and this is inhibited by blocking of CD40, MHC II or CD54. Although CD40 ligation on its own induces B cell proliferation, it does not confer IL-2 responsiveness. In contrast, signalling through MHC II and CD54 synergizes with IL-5 to induce functional IL-2R on B cells. Moreover, physiological, gp39$rm sp{low},$ T help for B cell IL-2 responsiveness is equivalently dependent on ligation of CD40, CD54 and MHC II, and requires prior sIg signalling. IL-5 synergizes with either LPS or Th to render B cell responses to IL-2 autonomous of further stimulus. Thus, expression of a functional IL-2R is a marker of B cell activation which appears to be tightly regulated through sIg signals and T-contact events and can be modulated by cytokines

Natural Immunity to HIV: A Delicate Balance between Strength and Control

Understanding how the mucosal immune system in the human female reproductive tract might prevent or facilitate HIV infection has important implications for the design of effective interventions. We and others have established cohorts of highly-exposed, HIV-seronegative individuals, such as HIV-uninfected commercial sex workers, who have remained HIV-negative after more than 5 years of active prostitution. Observations obtained in studies of such individuals, who represent a model of natural immunity to HIV, indicate that HIV resistance may be associated with the host’s capacity to preserve systemic integrity by constraining immune activity and controlling inflammatory conditions at the mucosal point of entry. This likely necessitates the orchestration of balanced, first-line and adaptive immune responses

Natural Immunity to HIV: A Template for Vaccine Strategies

Africa accounts for the majority of global human immunodeficiency virus (HIV) infections, most of which affect women through heterosexual intercourse. Currently, there is no cure for HIV and the development of vaccines and microbicides remains the best solution to eradicate the pandemic. We and others have identified HIV highly-exposed seronegative (HESN) individuals among African female commercial sex workers (CSWs). Analyses of genital samples from HESNs have demonstrated potent innate and anti-inflammatory conditions, HIV-specific CD4+ and CD8+ T-cells as well as immunoglobulins (Igs), and increased regulatory cell populations, all of which support a delicate balance between strength and control against HIV intrusion. Moreover, we have recently shown that frequencies of innate marginal zone (MZ) B-cells are decreased in the blood of HESNs when compared to HIV-uninfected non-CSW women, suggesting their recruitment to peripheral sites. This coincides with the fact that levels of B lymphocyte stimulator (BLyS/BAFF), known to shape the MZ pool and whose overexpression leads to MZ deregulation in HIV-infected progressors, are significantly lower in the blood of HESNs when compared to both HIV-infected CSWs and HIV-uninfected non-CSW women. Interestingly, MZ B-cells can bind HIV gp120 and produce specific IgG and IgA, and have a propensity for B regulatory potential, which could help both the fight against HIV and maintenance of low inflammatory conditions in HESNs. HESN individuals provide an exceptional opportunity to identify important clues for the development of protective devices, and efforts should aim at soliciting immune responses observed in the context of their natural immunity to HIV

The capacity to control immune homeostasis at mucosal sites, where the main battle against HIV takes place, is reflected by a normal “non-inflammatory” BLyS/BAFF expression status.

<p>This is likely modulated through efficient epithelial cell:DC cross talk, subsequently allowing for the generation of highly protective HIV-specific B and T cell responses. In contrast, establishment of an imbalance at the level of mucosal immune homeostasis will allow the excess “inflammatory” BLyS/BAFF expression status to lead to dysregulated B and T cell responses, impairing the generation of highly protective HIV-specific immunity. (Graphic art: Christian Charbonneau.)</p