HIV infection causes B cell activation and dysfunction that deplete memory B cells and impair isotype diversification of IgG antibodies. Cytokines are critical for B cell activation (e.g. interleukin (IL)-6, interferon (IFN)-γ, IFN-α) and immunoglobulin isotype diversification (e.g. IL-21). As aberrant expression of cytokine receptors, such as the IL-7 receptor, is a characteristic abnormality of CD4+ T cells in HIV patients, we have examined cytokine receptor expression on B cells to gain further insights into B cell dysfunction.
Methods: Expression of receptors for IL-6, IFN-γ (IFNGR1 and IFNGR2), IFN-α (IFNAR1 and IFNAR2) and IL-21 was examined on B cell subpopulations (naïve, switched memory and marginal-zone-like (MZL)), defined by expression of IgD and CD27, in cryopreserved peripheral blood mononuclear cells from HIV patients who were ART naïve (n=10) or ART-treated (n=10) and non-HIV controls (n=10). results: IFNAR1 was increased on naïve (IgD+, CD27-), switched memory (IgD-, CD27+) and marginal zone-like (IgD+, CD27+) B cells (p<0.008) and did not decline on ART. IFNAR2 was also increased on switched memory B cells (p=0.04) but was lower on MZL B cells (p=0.01), returning to normal on ART. IFNGR1 and IFNGR2 were lower on MZL B cells alone (p=0.02 and p=0.005, respectively) and normalised with ART, whereas IFNGR2 was increased on switched memory B cells. IL-21R was increased on all B cell subpopulations (p<0.03) while IL-6R was increased only on switched memory B cells (p=0.04).
Conclusions: B cells of HIV patients exhibit aberrant expression of IFN-α receptors to a greater extent than the IL-6R, suggesting that IFN-α may be more significant than IL-6 in B cell activation. Impaired isotype diversification of IgG antibodies is not associated with decreased IL-21R expression on B cells. Aberrant expression of some receptors persists on ART and might be used as a marker of ongoing B cell dysfunction.
REACH was a collaborative research and practice initiative to develop evidence building frameworks, capacity, tools and resources with the Victorian HIV community partnership.
HIV disease is associated with chronic inflammation and activation of the innate immune system. This state, as measured using plasma markers of inflammation, persists following suppression of HIV viremia using antiretroviral therapy, and may increase risk of non-AIDS co-morbidities. The causes of innate immune activation in the setting of virological suppression are unclear. Natural killer (NK) cells are innate immune cells that kill virus-infected and transformed cells without prior sensitization. We have shown that NK cells are activated both phenotypically (elevated expression of HLA-DR) and functionally (increased spontaneous degranulation measured by CD107a surface expression) in virologically suppressed (VS) HIV+ individuals. NK cells also lose expression of CD16, the receptor which mediates antibody-dependent cellular cytotoxicity.
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