Altered distribution of mucosal NK cells during HIV infection

Abstract

The human gut mucosa is a major site of HIV infection and infection-associated pathogenesis. Increasing evidence shows that natural killer (NK) cells play an important role in control of HIV infection but the mechanism(s) by which they mediate antiviral activity in the gut is unclear. Here we show two distinct subsets of NK cells exist in the gut, one localized to intraepithelial spaces (IEL) and the other to the lamina propria (LP). The frequency of both subsets of NK cells was reduced in chronic infection, whereas IEL NK cells remained stable in spontaneous controllers with protective KIR/HLA genotypes. Both IEL and LP NK cells were significantly expanded in immunologic non-responsive (INR) patients, who incompletely recovered CD4+ T cells on HAART. These data suggest that both IEL and LP NK cells may expand in the gut in an effort to compensate for compromised CD4+ T cell recovery, but that only IEL NK cells may be involved in providing durable control of HIV in the gut,

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 + T Cells

“…Over the past decade, the importance of NK cells in controlling human immunodeficiency virus type 1 (HIV-1) infection in vivo has become increasingly clearer (1)(2)(3). In response, novel approaches to induce NK cell-directed enhancement of immune function are being developed (4).…”

Mucosal Immune Regulation: Does it Help Thwart HIV?

“…Combinations of KIR and HLA alleles have been associated with HIV disease outcome, with enhanced NK cell function delaying AIDS progression (reviewed by [71]). A recent study has observed the presence of two distinct NK cell subsets residing in the gut with altered frequencies during HIV-infection [72]. Using immunochemistry of gut biopsies, Sip et al [72] demonstrated that intraepithelial and lamina propria NK cells express two different isoforms of Nkp46, a natural cytotoxicity receptor expressed on all NK cells.…”

“…A recent study has observed the presence of two distinct NK cell subsets residing in the gut with altered frequencies during HIV-infection [72]. Using immunochemistry of gut biopsies, Sip et al [72] demonstrated that intraepithelial and lamina propria NK cells express two different isoforms of Nkp46, a natural cytotoxicity receptor expressed on all NK cells. In addition to harbouring a more terminally differentiated phenotype (CD57 + ), intraepithelial NK subset were observed more frequently among individuals with the protective KIR/HLA genotype associated with spontaneous control of HIV replication, implying a potential implication for intraepithelial NK in the control of viremia.…”

“…In addition to harbouring a more terminally differentiated phenotype (CD57 + ), intraepithelial NK subset were observed more frequently among individuals with the protective KIR/HLA genotype associated with spontaneous control of HIV replication, implying a potential implication for intraepithelial NK in the control of viremia. Moreover, the fact that both subsets expanded in the gastro-intestinal tract of HAART treated HIV-positive subsets with incomplete CD4 + reconstitution has led to the suggestion that these cells accumulate in absence of viral replication to potentially compensate for the GALT compromised immunity [72].…”

Exploring the Potential of Monoclonal Antibody Therapeutics for HIV-1 Eradication

“…[85][86][87][88] FccRIIIa is mostly expressed on NK cells and neutrophils, but other cell types such as macrophages, and eosinophils also express this receptor at low levels. 89,90 As NK cells are mostly present in the circulatory system, they may play a critical role in killing recently reactivated CD4 T cells in the blood, while tissue-specific killing may rely on other mechanisms. Several neutralizing and non-neutralizing HIV-specific mAbs have been tested in various ADCC assays.…”