Secondary Logo

Journal Logo

Brief Report: Inflammatory Colonic Innate Lymphoid Cells Are Increased During Untreated HIV-1 Infection and Associated With Markers of Gut Dysbiosis and Mucosal Immune Activation

Dillon, Stephanie M. PhD*; Castleman, Moriah J. PhD*; Frank, Daniel N. PhD*,†; Austin, Gregory L. MD, MPH; Gianella, Sara MD§; Cogswell, Andrew C. BA; Landay, Alan L. PhD; Barker, Edward PhD; Wilson, Cara C. MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: December 1, 2017 - Volume 76 - Issue 4 - p 431–437
doi: 10.1097/QAI.0000000000001523
Translational Research

Background: HIV-1 infection is associated with intestinal inflammation, changes in the enteric microbiota (dysbiosis), and intestinal epithelial cell damage. NKp44+ innate lymphoid cells (ILCs) play an important role in epithelial barrier maintenance through the production of interleukin (IL)-22 but also display functional plasticity and can produce inflammatory cytokines [eg, interferon gamma (IFNγ)] in response to cytokine milieu and stimulatory signals. The objective of this pilot study was to enumerate frequencies of IL-22 and IFNγ-expressing colonic NKp44+ ILCs during untreated, chronic HIV-1 infection.

Setting: A cross-sectional study was performed to compare numbers of cytokine-expressing ILCs in colonic biopsies of untreated, chronic HIV-1 infected (n = 22), and uninfected (n = 10) study participants. Associations between cytokine+ ILC and previously established measures of virological, immunological, and microbiome indices were analyzed.

Methods: Multicolor flow cytometry was used to measure the absolute number of colonic CD3NKp44±CD56± ILCs expressing IL-22 or IFNγ after in vitro mitogenic stimulation.

Results: Numbers of colonic NKp44+ ILCs that expressed IFNγ were significantly higher in HIV-1 infected versus uninfected persons and positively correlated with relative abundances of dysbiotic bacterial species in the Xanthomonadaceae and Prevotellaceae bacterial families and with colonic myeloid dendritic cell and T-cell activation.

Conclusion: Higher numbers of inflammatory colonic ILCs during untreated chronic HIV-1 infection that associated with dysbiosis and colonic myeloid dendritic cell and T-cell activation suggest that inflammatory ILCs may contribute to gut mucosal inflammation and epithelial barrier breakdown, important features of HIV-1 mucosal pathogenesis.

Supplemental Digital Content is Available in the Text.

*Department of Medicine, Division of Infectious Diseases, University of Colorado Anschutz Medical Campus, Aurora, CO;

University of Colorado Microbiome Research Consortium, Aurora, CO;

Division of Gastroenterology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO;

§Division of Infectious Diseases, School of Medicine, University of California, San Diego, La Jolla, CA; and

Department of Immunity and Emerging Pathogens, Rush University Medical Center, Chicago, IL.

Correspondence to: Cara C. Wilson, MD, Department of Medicine, Division of Infectious Diseases, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Mail Stop B168, Aurora, CO 80045 (e-mail:

Supported by National Institutes of Health (NIH) Grant R01 DK088663 and RO1 AI118983 and, in part, by NIH/NCATS Colorado CTSI Grant Number UL1 TR000154.

Presented at the Conference on Retroviruses and Opportunistic Infections, February 12–14, 2017, Seattle, WA.

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received April 12, 2017

Accepted July 31, 2017

Back to Top | Article Outline


Disruption of intestinal homeostasis, intestinal epithelial cell (IEC) damage, and changes in the microbiota (dysbiosis)1–5 are associated with HIV-1 infection. IEC damage leads to translocation of dysbiotic microbes,6 and microbial translocation is linked to tissue and systemic immune activation and predicts disease progression in untreated HIV-1–infected persons.7–10 Understanding the mechanisms that drive IEC damage and microbial translocation will be critical to controlling both gut and systemic inflammation during HIV-1 infection.

Maintenance of intestinal barrier integrity and homeostasis relies in part on the presence of interleukin (IL)-22.11,12 Depletion of gut T-helper 22 (Th22) and Th17 cells, subsets of which coproduce IL-22, is considered to be a major contributor to HIV-1 pathogenesis.1,13–15 A pivotal publication by Cella et al described non–T cells capable of producing IL-22 in human mucosa-associated lymphoid tissues.16 These non–T cells identified by the expression of an NK cell activation receptor NKp4417 and the classic NK cell marker CD56 were termed NK22 cells. NK22 cells are now considered members of the recently identified family of Group 3 innate lymphoid cells (ILC3s), which play important and diverse roles in mucosal immunity.18–20 In untreated HIV-infected individuals, frequencies of colonic IL-22–expressing non–T cells that included NKp44+ cells were increased early in infection.13 Furthermore, frequencies of NKp44+ IL-22–producing cells correlated with an intact intestinal barrier in long-term antiretroviral therapy–treated HIV-infected persons.21 Thus, NKp44+ ILCs may also play a critical role in regulating epithelial barrier health during HIV infection.

Multiple studies have suggested that ILCs, including ILC3s, display a degree of functional plasticity and can produce inflammatory cytokines [eg, tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ)] in response to the local cytokine milieu (eg, IL-2, IL-23, IL-12p70, IL-1β, and IL-18) and/or exposure to stimulatory signals (eg, ligation of NKp44).22–25 We have previously demonstrated that colonic myeloid dendritic cells (mDCs) produce IL-23 and IL-1β in response to exogenous exposure to mucosa-associated colonic commensal bacteria that are increased in relative abundance in untreated HIV-1–infected persons.26 Moreover, HIV-1 induces the expression of NKp44L on CD4 T cells both in vitro and in vivo.27–29 These observations raise the possibility that a microenvironment exists in the gut of HIV-1–infected persons that is conducive to IL-22–producing ILCs switching into inflammatory ILCs. Indeed, colonic NKp44+ ILCs demonstrated an altered phenotype by producing IFNγ rather than IL-17/IL-22 during pathogenic Simian Immunodeficiency Virus (SIV) infection.30,31 Therefore, we evaluated the frequencies of IL-22–producing, IL-17–producing, and IFNγ-producing colonic NKp44-expressing ILCs in the setting of untreated chronic HIV-1 infection.

Back to Top | Article Outline


Study Participants

Untreated, chronically HIV-1–infected adults and HIV-1–seronegative (uninfected) controls were enrolled in this cross-sectional study at the University of Colorado Anschutz Medical Campus. Inclusion and exclusion criteria were extensively detailed in previous publications.26,32,33 All study participants voluntarily provided written informed consent. This study was approved by the Colorado Multiple Institutional Review Board (COMIRB).

Back to Top | Article Outline

Surface and Intracellular Flow Cytometry Staining Assays, Acquisition, and Analysis

The collection, processing, and storage of colon biopsies are detailed elsewhere.26,32,33 Colonic cells were cultured in Roswell Park Memorial Institute (RPMI) medium (Invitrogen, Carlsbad, CA) + 10% human AB serum (Gemini Bio Products, West Sacramento, CA) + 1% penicillin/streptomycin/L-glutamine (Invitrogen) and stimulated with phorbol myristate acetate (PMA) (250 ng/mL; Sigma-Aldrich, St. Louis, MO) and ionomycin (1 μg/mL; Sigma-Aldrich) and 0.1% Brefeldin A (Golgi Plug; BD Biosciences, San Jose, CA) for 16 hours. Cells were collected, and frequencies of NKp44+CD56, NKp44+CD56+, and NKp44CD56+ cells and cytokine-expressing NKp44+CD56, NKp44+CD56+, and NKp44CD56+ cells were determined using standard multicolor intracellular cytokine flow cytometry protocols.26,32–36 Cells were stained with viability dye (Aqua, Invitrogen), CD45 (clone: 2D1; PerCp-Cy5.5, eBioscience, San Diego, CA), CD3 (UCHT1; PE Texas Red, Beckman Coulter, Indianapolis, IN), NKp44 (P44-8; APC, Biolegend, San Diego, CA), CD56 (B159; PE-Cy5, BD Biosciences), IL-22 (22URTI; PE, eBioscience), IL-17 (N49-653; V450, BD Biosciences), and IFNγ (B27; AF700, BD Biosciences). All flow cytometry data were acquired on an LSRII Flow Cytometer (BD Biosciences) and analyzed using BD FACSDiva software version 6.1.2 (BD Biosciences)36 (Fig. S1, Supplemental Digital Content, Evaluation of cytokine-expressing ILCs was only performed when there were at least 25 NKp44+CD56, NKp44+CD56+, and NKp44CD56+ events.

Back to Top | Article Outline

Enumeration of Immunological, Virological, and Microbial Parameters

Measurements of plasma IL-6, C-reactive protein, TNFα, IFNγ, IL-10, soluble CD14, lipoteichoic acid, lipopolysaccharide and intestinal fatty acid–binding protein, colonic mucosa levels of HIV-1 RNA, frequencies of colonic mDC, plasmacytoid DC, CD4 and CD8 T cells, measurements of mDC activation/maturation (CD40/CD83) and T-cell activation (CD38+HLA-DR+), and frequencies of IFNγ-expressing, IL-22–expressing, and IL-17–expressing Th cells have been previously published.26,32,33 Laboratory and analytic methods used to profile the intestinal microbiomes were as described.26,32,33,35

Back to Top | Article Outline

Statistical Analysis

Nonparametric statistics were performed with no adjustments for multiple comparisons because of the exploratory nature of this study. Analyses were performed using GraphPad Prism version 6 for Windows (GraphPad Software, San Diego, CA). P value <0.05 was considered statistically significant.

Back to Top | Article Outline


Absolute numbers of colonic ILCs and cytokine-expressing colonic ILCs were determined in a subset of untreated HIV-1–infected (N = 22) and uninfected (N = 10) study participants from a previously detailed clinical study.26,32,33 Study participant characteristics are detailed in Table S1, Supplemental Digital Content,

Back to Top | Article Outline

Absolute Numbers of Colonic ILCs

There were no significant differences in the absolute number of colonic NKp44+CD56 and NKp44+CD56+ ILCs between uninfected and HIV-1–infected subjects (Fig. S2, Supplemental Digital Content, Conversely, HIV-1–infected individuals had significantly fewer NKp44CD56+ cells compared with uninfected controls.

Back to Top | Article Outline

Cytokine Profiles of Colonic ILCs in Healthy Individuals

We first compared absolute numbers of IL-22–expressing, IL-17–expressing, and IFNγ-expressing CD3ILCs in healthy uninfected persons (Fig. 1A). Greater numbers of NKp44+CD56 ILCs expressed IL-22 compared with IFNγ or IL-17, although this latter comparison did not reach statistical significance. Similar numbers of NKp44+CD56+ expressed IL-22 or IFNγ, whereas fewer were capable of producing IL-17. Very few NKp44+CD56+ ILCs coexpressed IL-22 and IFNγ (data not shown), suggesting distinct cytokine-producing populations. The number of NKp44CD56+ cells that expressed IFNγ was significantly greater than IL-22– or IL-17–expressing cells.



Back to Top | Article Outline

Altered ILC Cytokine Profiles in HIV Infection

In HIV-1–infected individuals, comparable numbers of NKp44+CD56 ILCs expressed IL-22 or IFNγ (Fig. 1B) with few NKp44+CD56 ILCs expressing both IL-22 and IFNγ (data not shown). Numbers of IL-22+ and IFNγ+NKp44+CD56 ILCs were significantly greater than IL-17–expressing NKp44+CD56 ILCs. Cytokine profiles of the remaining ILC populations in HIV-1 infected persons were generally reflective of those observed in uninfected persons, with similar numbers NKp44+CD56+ ILCs producing either IL-22 or IFNγ and with NKp44CD56+ ILCs primarily producing IFNγ (Fig. 1B).

We next compared the absolute number of cytokine-producing ILCs between uninfected and HIV-1–infected persons. IFNγ-producing NKp44+CD56 and NKp44+CD56+ ILCs were significantly increased in number in HIV-1–infected relative to uninfected persons (Figs. 2A, C). Absolute numbers of IFNγ+NKp44CD56+ ILCs were not statistically different between the 2 cohorts (data not shown). Numbers of IL-22–expressing NKp44+CD56 or NKp44+CD56+ ILC populations were not significantly different between HIV-1–infected and uninfected study participants (Fig. 2E). Although numbers of IL-22–expressing NKp44CD56+ cells were low compared to IFNγ+NKp44CD56+ cells, significantly fewer of these cells were observed in HIV-1–infected persons (Fig. 2E). No statistical differences between uninfected and HIV-1–infected individuals in the absolute numbers of IL-17–expressing ILC populations were noted (data not shown).



Back to Top | Article Outline

Associations of IFNγ-Expressing Colonic ILCs With Dysbiotic Microbes and Markers of Immune Activation in HIV-1 Infection

Given the finding of increased IFNγ+ ILCs in HIV-infected persons, we next addressed associations of these ILC populations with previously reported measures of clinical, virological, immunological, and microbiome indices for the HIV-1–infected cohort26,32,33 (Table S2, Supplemental Digital Content, Absolute numbers of colonic IFNγ+NKp44+CD56 ILCs significantly correlated with the relative abundance of Xanthomonadaceae and Prevotellaceae families, with the Prevotella genus (Fig. 2B), and with the individual species Prevotella copri and Prevotella stercorea (R = 0.68, P = 0.01; R = 0.63, P = 0.02, respectively; data not shown). Numbers of IFNγ+NKp44+CD56 ILCs inversely correlated with the percentages of CD83+CD1c+ mDC (R = −0.51, P = 0.03) and positively correlated with numbers of IFNγ-producing CD4 T cells (R = 0.53, P = 0.01) (data not shown). IFNγ+ NKp44+CD56+ ILC numbers were not significantly associated with dysbiotic microbes but instead positively correlated with colon CD1c+ mDC activation levels and with absolute numbers of activated colon CD4 and CD8 T cells in HIV-1–infected individuals (Fig. 2D).

Back to Top | Article Outline


This study highlights that untreated, chronic HIV-1 infection is associated with higher numbers of colonic NKp44+ ILCs that express IFNγ. The difference in the number of these cells expressing IFNγ is unlikely related to an increase in the number of NKp44+ ILCs, given that no significant difference in the overall number of each NKp44+ ILC subsets was observed between the 2 cohorts. IFNγ is an inflammatory cytokine that increases intestinal epithelial barrier permeability primarily through alterations in tight junction protein expression and thereby enhances bacterial transcytosis.37–39 Accordingly, the presence of these inflammatory ILCs likely contributes to epithelial barrier breakdown and the resultant microbial translocation.

We, and others, have demonstrated that alterations in intestinal mucosa–associated bacterial communities during HIV-1 infection are associated with indicators of mucosal HIV-1 pathogenesis (reviewed in Ref. 40). In our study, major findings from the microbiome analysis included higher relative abundance of mucosa-associated bacteria belonging to the Proteobacteria phylum (including Xanthomonadaceae) and of Prevotella spp. in HIV-1–infected persons.26,33 Increased relative abundance of P. spp. in HIV-1–infected persons associated with increased colonic mDC and T-cell activation.26,33 Other HIV-associated mucosal abnormalities included decreased percentages of colonic mDC expressing CD83,26 a molecule reported to play a role in intestinal immune regulation.41 In this current study, numbers of IFNγ-expressing NKp44+ ILCs positively correlated with relative abundances of bacterial species in the Xanthomonadaceae and Prevotellaceae families, with colonic mDC and T-cell activation and inversely associated with the fraction of colonic mDCs expressing CD83. We have previously shown that enteric bacterial species found in high abundance in HIV-1–infected persons (eg, Prevotella) are capable of inducing IL-23 and IL-1β from colonic mDC in vitro,26 cytokines that contribute to the induction of inflammatory cytokines such as IFNγ and TNFα by ILCs.25,42 Thus, we hypothesize that in the setting of HIV-1 infection, the shift in the phenotype of primarily IL-22–producing ILCs to IFNγ-producing ILCs is linked to an intricate relationship between translocating bacteria, colonic mDC, and other signals within the inflammatory environment (eg, NKp44L).

In contrast to the dramatic alterations in numbers of IFNγ-expressing NKp44+ ILCs associated with HIV-1 infection, absolute numbers of IL-22–expressing NKp44+ cells were similar in both HIV-1–infected and uninfected individuals, an observation in keeping with a number of other studies investigating gut ILCs during HIV-1 infection.13,21,43,44 Conversely, 1 study which identified colonic tissue ILCs as CD3IL-22+ using immunohistological techniques found decreased numbers of these cells in untreated HIV-1–infected versus uninfected individuals.45 In contrast to HIV-1 infection, both absolute frequencies of ILCs and frequencies of IL-22–/IL-17–producing ILCs were significantly reduced during early and chronic SIV infection.30,31,46–48 Of note, we observed a decrease in frequencies of NKp44CD56+ cells that expressed IL-22, likely related to the overall decrease in absolute numbers of colonic NKp44CD56+ cells as a whole. However, NKp44CD56+ cells do not typically produce IL-22, so the impact of an overall decrease in this small population in untreated, chronic HIV-1–infected persons may be minor in the context of maintenance of IL-22+NKp44+ ILCs.

We acknowledge a number of limitations to this pilot study. The study was not powered to address alterations in numbers of colonic cytokine-producing ILCs in the setting of HIV-1 infection. The 2 study groups were not matched for sexual practice, which has recently been reported to affect the intestinal microbiome independent of HIV-1 infection49,50 and may drive mucosal immune cell activation and inflammation50 and therefore be a contributing factor to our current observations. Enumeration of the specific ILC subsets was based on criteria used to identify NK22 cells.16 Since that time, the field of ILC biology has greatly expanded, and a more rigorous and specific identification paradigm for the various ILC subsets (ie, NK, ILC1s, ILC2, and ILC3s) is being used.19,20,42,51,52 Our ability to determine the composition of the specific ILC subsets (NK vs ILC1 vs ILC3) within the cytokine-producing populations based on this more recent nomenclature is limited here, and future studies will be needed to incorporate these most recent definitions.

Despite these limitations, the observations that higher frequencies of IFNγ-producing ILCs, particularly in the NKp44+CD56 ILC population which typically does not produce IFNγ in the absence of HIV-1 infection, underscore the role these innate immune cells may play in HIV-1–associated mucosal inflammation and pathogenesis. Additional studies both in vivo and in vitro will be required to determine the extent to which the increased numbers are a result of a switch from IL-22 to IFNγ production versus expansion of the IFNγ-producing population versus an influx of inflammatory cells into the mucosal tissue. In summary, higher numbers of inflammatory colonic ILCs during untreated chronic HIV-1 infection associate with dysbiosis and gut mDC and T-cell activation suggesting a critical interplay between gut ILCs, the microbiome, and local immune responses that should be further explored.

Back to Top | Article Outline


The authors express their sincere gratitude to all the study participants as well as the physicians and staff at the University of Colorado Infectious Disease Group Practice Clinic. They thank the staff at the Clinical and Translational Research Center (CTRC) and the University Hospital endoscopy clinic for their assistance with their clinical study and Zachary Dong and Daniel Hecht for assistance with study participant recruitment.

Back to Top | Article Outline


1. Brenchley JM, Paiardini M, Knox KS, et al. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood. 2008;112:2826–2835.
2. Brenchley JM, Schacker TW, Ruff LE, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004;200:749–759.
3. Sankaran S, George MD, Reay E, et al. Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration. J Virol. 2008;82:538–545.
4. Tincati C, Douek DC, Marchetti G. Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection. AIDS Res Ther. 2016;13:19.
5. Ullrich R, Zeitz M, Riecken EO. Enteric immunologic abnormalities in human immunodeficiency virus infection. Semin Liver Dis. 1992;12:167–174.
6. Klase Z, Ortiz A, Deleage C, et al. Dysbiotic bacteria translocate in progressive SIV infection. Mucosal Immunol. 2015;8:1009–1020.
7. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365–1371.
8. Marchetti G, Cozzi-Lepri A, Merlini E, et al. Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count. AIDS. 2011;25:1385–1394.
9. Marchetti G, Tincati C, Silvestri G. Microbial translocation in the pathogenesis of HIV infection and AIDS. Clin Microbiol Rev. 2013;26:2–18.
10. Zevin AS, McKinnon L, Burgener A, et al. Microbial translocation and microbiome dysbiosis in HIV-associated immune activation. Curr Opin HIV AIDS. 2016;11:182–190.
11. Parks OB, Pociask DA, Hodzic Z, et al. Interleukin-22 signaling in the regulation of intestinal health and disease. Front Cell Dev Biol. 2015;3:85.
12. Schreiber F, Arasteh JM, Lawley TD. Pathogen resistance mediated by IL-22 signaling at the epithelial-microbiota interface. J Mol Biol. 2015;427:3676–3682.
13. Kim CJ, Nazli A, Rojas OL, et al. A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis. Mucosal Immunol. 2012;5:670–680.
14. Page EE, Greathead L, Metcalf R, et al. Loss of Th22 cells is associated with increased immune activation and IDO-1 activity in HIV-1 infection. J Acquir Immune Defic Syndr. 2014;67:227–235.
15. Kim CJ, McKinnon LR, Kovacs C, et al. Mucosal Th17 cell function is altered during HIV infection and is an independent predictor of systemic immune activation. J Immunol. 2013;191:2164–2173.
16. Cella M, Fuchs A, Vermi W, et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature. 2009;457:722–725.
17. Vitale M, Bottino C, Sivori S, et al. NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis. J Exp Med. 1998;187:2065–2072.
18. Almeida FF, Belz GT. Innate lymphoid cells: models of plasticity for immune homeostasis and rapid responsiveness in protection. Mucosal Immunol. 2016;9:1103–1112.
19. Artis D, Spits H. The biology of innate lymphoid cells. Nature. 2015;517:293–301.
20. Sonnenberg GF, Artis D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med. 2015;21:698–708.
21. Fernandes SM, Pires AR, Ferreira C, et al. Enteric mucosa integrity in the presence of a preserved innate interleukin 22 compartment in HIV type 1-treated individuals. J Infect Dis. 2014;210:630–640.
22. Bernink JH, Krabbendam L, Germar K, et al. Interleukin-12 and -23 control plasticity of CD127(+) group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity. 2015;43:146–160.
23. Bernink JH, Peters CP, Munneke M, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol. 2013;14:221–229.
24. Cella M, Otero K, Colonna M. Expansion of human NK-22 cells with IL-7, IL-2, and IL-1beta reveals intrinsic functional plasticity. Proc Natl Acad Sci U S A. 2010;107:10961–10966.
25. Glatzer T, Killig M, Meisig J, et al. RORgammat(+) innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44. Immunity. 2013;38:1223–1235.
26. Dillon SM, Lee EJ, Kotter CV, et al. Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T-cell activation in untreated HIV-1 infection. Mucosal Immunol. 2016;9:24–37.
27. Fausther-Bovendo H, Sol-Foulon N, Candotti D, et al. HIV escape from natural killer cytotoxicity: nef inhibits NKp44L expression on CD4+ T cells. AIDS. 2009;23:1077–1087.
28. Sennepin A, Baychelier F, Guihot A, et al. NKp44L expression on CD4+ T cells is associated with impaired immunological recovery in HIV-infected patients under highly active antiretroviral therapy. AIDS. 2013;27:1857–1866.
29. Ward J, Bonaparte M, Sacks J, et al. HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts. Blood. 2007;110:1207–1214.
30. Li H, Richert-Spuhler LE, Evans TI, et al. Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection. PLoS Pathog. 2014;10:e1004551.
31. Reeves RK, Rajakumar PA, Evans TI, et al. Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection. Blood. 2011;118:3321–3330.
32. Dillon SM, Kibbie J, Lee EJ, et al. Low abundance of colonic butyrate-producing bacteria in HIV infection is associated with microbial translocation and immune activation. AIDS. 2017;31:511–521.
33. Dillon SM, Lee EJ, Kotter CV, et al. An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol. 2014;7:983–994.
34. Dillon SM, Lee EJ, Bramante JM, et al. The natural killer cell interferon-gamma response to bacteria is diminished in untreated HIV-1 infection and defects persist despite viral suppression. J Acquir Immune Defic Syndr. 2014;65:259–267.
35. Dillon SM, Lee EJ, Donovan AM, et al. Enhancement of HIV-1 infection and intestinal CD4+ T cell depletion ex vivo by gut microbes altered during chronic HIV-1 infection. Retrovirology. 2016;13:5.
36. Dillon SM, Manuzak JA, Leone AK, et al. HIV-1 infection of human intestinal lamina propria CD4+ T cells in vitro is enhanced by exposure to commensal Escherichia coli. J Immunol. 2012;189:885–896.
37. Al-Sadi R, Boivin M, Ma T. Mechanism of cytokine modulation of epithelial tight junction barrier. Front Biosci (Landmark Ed). 2009;14:2765–2778.
38. Beaurepaire C, Smyth D, McKay DM. Interferon-gamma regulation of intestinal epithelial permeability. J Interferon Cytokine Res. 2009;29:133–144.
39. Clark E, Hoare C, Tanianis-Hughes J, et al. Interferon gamma induces translocation of commensal Escherichia coli across gut epithelial cells via a lipid raft-mediated process. Gastroenterology. 2005;128:1258–1267.
40. Dillon SM, Frank DN, Wilson CC. The gut microbiome and HIV-1 pathogenesis: a two-way street. AIDS. 2016;30:2737–2751.
41. Bates JM, Flanagan K, Mo L, et al. Dendritic cell CD83 homotypic interactions regulate inflammation and promote mucosal homeostasis. Mucosal Immunol. 2015;8:414–428.
42. Simoni Y, Fehlings M, Kloverpris HN, et al. Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity. 2016;46:148–161.
43. Kloverpris HN, Kazer SW, Mjosberg J, et al. Innate lymphoid cells are depleted irreversibly during acute HIV-1 infection in the absence of viral suppression. Immunity. 2016;44:391–405.
44. Kok A, Hocqueloux L, Hocini H, et al. Early initiation of combined antiretroviral therapy preserves immune function in the gut of HIV-infected patients. Mucosal Immunol. 2015;8:127–140.
45. Zhang Z, Cheng L, Zhao J, et al. Plasmacytoid dendritic cells promote HIV-1-induced group 3 innate lymphoid cell depletion. J Clin Invest. 2015;125:3692–3703.
46. Klatt NR, Estes JD, Sun X, et al. Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection. Mucosal Immunol. 2012;5:646–657.
47. Xu H, Wang X, Lackner AA, et al. Type 3 innate lymphoid cell depletion is mediated by TLRs in lymphoid tissues of simian immunodeficiency virus-infected macaques. FASEB J. 2015;29:5072–5080.
48. Xu H, Wang X, Liu DX, et al. IL-17-producing innate lymphoid cells are restricted to mucosal tissues and are depleted in SIV-infected macaques. Mucosal Immunol. 2012;5:658–669.
49. Noguera-Julian M, Rocafort M, Guillén Y, et al. Gut microbiota linked to sexual Preference and HIV infection. EBioMedicine. 2016;5:135–146.
50. Kelley CF, Kraft CS, de Man TJ, et al. The rectal mucosa and condomless receptive anal intercourse in HIV-negative MSM: implications for HIV transmission and prevention. Mucosal Immunol. 2017;10:996–1007.
51. Bjorklund AK, Forkel M, Picelli S, et al. The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing. Nat Immunol. 2016;17:451–460.
52. Spits H, Artis D, Colonna M, et al. Innate lymphoid cells–a proposal for uniform nomenclature. Nat Rev Immunol. 2013;13:145–149.

HIV-1; innate lymphoid cells; dysbiosis; microbial translocation; inflammation

Supplemental Digital Content

Back to Top | Article Outline
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.