Increased plasmacytoid dendritic cell maturation and natural killer cell activation in HIV-1 exposed, uninfected intravenous drug users

Abstract

Background Increased NK activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected subjects. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1high) has also been observed in a subset of HIV-1 exposed, uninfected subjects. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intra-venous drug users (EU-IDU) remains to be elucidated. Objective We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU subjects and 15 control, uninfected donors from Philadelphia. Design We assessed the activation status of NK cells and Dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU subjects. Results As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU subjects compared to control uninfected donors (p=0.0056, n=13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*80I ligands was not enriched in our cohort of EU-IDU subjects. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared to control uninfected donors (p=0.0011, n=12). When stimulated in vitro, both PDCs and NK cells from EU-IDU subjects maintained strong effector cell function and did not exhibit signs of exhaustion. Conclusion Increased maturation of PDCs is associated with heightened NK activation in EU-IDU subjects suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU.

Differences in HIV-Specific T Cell Responses between HIV-Exposed and -Unexposed HIV-Seronegative Individuals

“…These include commercial sex workers living within regions of HIV-1 endemicity (2,26,39,40,63,64,72), HIV-1-serodiscordant couples practicing unprotected sex (7,31,41,58,71,74), intravenous drug users (50,67,76,77), men who have sex with men who engage in unsafe sex practices (13,23,31,34,42), hemophiliacs exposed to contaminated blood products (4,24,75), and newborn HIVnegative babies whose mothers are HIV positive (65). From these studies has come one clear genetic protective factor, the ⌬32 deletion in the CCR5 gene, which, in homozygotes, results in nonexpression of this HIV-1 coreceptor (18,46).…”

Increased Activity of NK Cells and Plasmacytoid Dendritic Cells in HIV-Exposed Seronegative (ESN) Individuals

“…Most of the reports on ESNs so far, have compared them with chronically infected HIV positives [18,25,29] or healthy controls only [4], which may not actually present the true picture considering the long term effects of HIV infection on the immune system The reduced CD4 cell count during progressive stages of disease as observed in our study is a hallmark of HIV infection. Individuals who maintain the CD4 count due to many different mechanisms which may be intrinsic to the individual, are resistant to disease progression as seen in LTNPs.…”

“…While the IRF7 gene expression was assessed in terms of its mRNA abundance in the peripheral blood of the subjects, the IFNα levels were based on an in vitro stimulation assay, the two parameters could not be correlated and may be the reason of this discrepancy. Retention of PDC function in EUIDUs without an increase in PDC numbers as reported by Tomescu et al [4] suggests that exposure route may also play an important role and calls for further evaluation.…”

“…The role of innate immunity in the modulation of susceptibility to HIV infection is unclear and only a few recent reports describe a possible role for this arm of the immune response [3][4][5]. We had earlier reported that Human immunodeficiency virus (HIV) gag antigen-specific T-helper and granule-dependent CD8 T-cell have enhanced activities in exposed but uninfected (ESN) heterosexual partners of HIV type 1-infected individuals in North India [6].…”

Mucosal Immune Regulation: Does it Help Thwart HIV?

“…Immature DCs (iDC) from HESNs induced higher IFN-g production from NK cells that become more potent in eliminating autologous iDCs upon in vitro isolation or differentiation [101]. In addition to altered NK-DC cross-talk, several studies looking at KIR genotypes or NK activities have linked increased NK activity to protection against sexually and intravenously acquired HIV infection [102][103][104] (reviewed by [33]). Recently, we've developed a model of protection termed Immune Quiescence (IQ) to explain HIV resistance [105] among the Pumwani cohort of CSWs in Nairobi, Kenya.…”