Differential Expressions of Selected Activating and Inhibitory Receptors on K562-Stimulated Natural Killer (NK) Cells in HIV-1 and HIV-2 Infections


Context: The functional activity of NK cells depends on the balance between the engagement of activating and inhibitory receptors on the cell surface with their ligands, which enables them to kill infected cells. Objectives: The aim of this study was to evaluate and compare expressions of selected activating and inhibitory receptors on stimulated NK cells in HIV-1 and HIV-2 infections. Methods: PBMCs were analysed for activating (NKp30, NKp44, NKp46) and inhibitory (CD158a, CD158b, p70) receptor expressions in 30 HIV-1, 30 HIV-2 and 30 HIV uninfected healthy control (HC) subjects by flow cytometry after stimulating with K562 cells. Results: There was an expression of other receptors following an already in vitro engagement of NK cells with K562 cells. Higher expression of the activating receptors, NKp44 (p = 0.029) and NKp46 (p = 0.032) on NK cells from HIV-2 compared to HIV-1 infected individuals but similar NKp30 expression (p = 0.980). The levels of expression of inhibitory receptor CD158a were similar between HIV-1 and HIV-2 infected subjects (p = 0.309) but there was significant up-regulation of inhibitory receptors p70 (p = 0.010) and CD158b (p = 0.05) in HIV-1 compared to HIV-2 subjects. Conclusion: Despite the in vitro engagement of NK cells with stimulating K562 cells, our data showed differential expressions of other selected activating and inhibitory receptors in HIV-1 and HIV-2 infected subjects.

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V. Nuvor, S. , Rowland-Jones, S. , Whittle, H. and Jaye, A. (2015) Differential Expressions of Selected Activating and Inhibitory Receptors on K562-Stimulated Natural Killer (NK) Cells in HIV-1 and HIV-2 Infections. World Journal of AIDS, 5, 21-29. doi: 10.4236/wja.2015.51003.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Pantaleo, G. and Fauci, A.S. (1996) Immunopathogenesis of HIV Infection. Annual Review of Microbiology, 50, 825- 854. http://dx.doi.org/10.1146/annurev.micro.50.1.825
[2] Harrer, T., Harrer, E., Kalams, S.A., Elbeik, T., Staprans, S.I., Feinberg, M.B., et al. (1996) Strong Cytotoxic T Cell and Weak Neutralizing Antibody Responses in a Subset of Persons with Stable Nonprogressing HIV Type 1 Infection. AIDS Research and Human Retroviruses, 12, 585-592.
[3] Duvall, M.G., Jaye, A., Dong, T., Brenchley, J.M., Alabi, A.S., Jeffries, D.J., et al.(2006) Maintenance of HIV-Specific CD4+ T Cell Help Distinguishes HIV-2 from HIV-1 Infection. Journal of Immunology, 176, 6973-6981.http://dx.doi.org/10.4049/jimmunol.176.11.6973
[4] Gillespie, G.M., Stewart-Jones, G., Rengasamy, J., Beattie, T., Bwayo, J.J., Plummer, F.A., et al. (2006) Strong TCR Conservation and Altered T Cell Cross-Reactivity Characterize a B*57-Restricted Immune Response in HIV-1 Infection. Journal of Immunology, 177, 3893-3902.
[5] Nuvor, S.V., van der Sande, M., Rowland-Jones, S., Whittle, H. and Jaye, A. (2006) Natural Killer Cell Function Is Well Preserved in Asymptomatic Human Immunodeficiency Virus Type 2 (HIV-2) Infection but Similar to That of HIV-1 Infection When CD4 T-Cell Counts Fall. Journal of Virology, 80, 2529-2538.http://dx.doi.org/10.1128/JVI.80.5.2529-2538.2006
[6] Kottilil, S., Chun, T.W., Moir, S., Liu, S., McLaughlin, M., Hallahan, C.W., et al. (2003) Innate Immunity in Human Immunodeficiency Virus Infection: Effect of Viremia on Natural Killer Cell Function. Journal of Infectious Diseases, 187, 1038-1045. http://dx.doi.org/10.1086/368222
[7] Hultstrom, A.L., Bratt, G., Cosma, A., Erfle, V., Wahren, B. and Carbone, E. (2004) Autologous Cytotoxicity of Natural Killer Cells Derived from HIV-Infected Patients. Immunology Letters, 91, 155-158.http://dx.doi.org/10.1016/j.imlet.2003.11.012
[8] Lowin, B., Hahne, M., Mattmann, C. and Tschopp, J. (1994) Cytolytic T-Cell Cytotoxicity Is Mediated through Perforin and Fas Lytic Pathways. Nature, 370, 650-652. http://dx.doi.org/10.1038/370650a0
[9] Ahmad, R., Sindhu, S.T., Toma, E., Morisset, R., Vincelette, J., Menezes, J., et al. (2001) Evidence for a Correlation between Antibody-Dependent Cellular Cytotoxicity-Mediating Anti-HIV-1 Antibodies and Prognostic Predictors of HIV Infection. Journal of Clinical Immunology, 21, 227-233.
[10] Bonaparte, M.I. and Barker, E. (2003) Inability of Natural Killer Cells to Destroy Autologous HIV-Infected T Lymphocytes. AIDS, 17, 487-494. http://dx.doi.org/10.1097/00002030-200303070-00003
[11] Scott-Algara, D., Truong, L.X., Versmisse, P., David, A., Luong, T.T., Nguyen, N.V., et al. (2003) Cutting Edge: Increased NK Cell Activity in HIV-1-Exposed but Uninfected Vietnamese Intravascular Drug Users. The Journal of Immunology, 171, 5663-5667. http://dx.doi.org/10.4049/jimmunol.171.11.5663
[12] Fogli, M., Mavilio, D., Brunetta, E., Varchetta, S., Ata, K., Roby, G., et al. (2008) Lysis of Endogenously Infected CD4+ T Cell Blasts by rIL-2 Activated Autologous Natural Killer Cells from HIV-Infected Viremic Individuals. PLoS Pathogens, 4, e1000101. http://dx.doi.org/10.1371/journal.ppat.1000101
[13] Ward, J., Bonaparte, M., Sacks, J., Guterman, J., Fogli, M., Mavilio, D., et al. (2007) HIV Modulates the Expression of Ligands Important in Triggering Natural Killer Cell Cytotoxic Responses on Infected Primary T-Cell Blasts. Blood, 110, 1207-1214. http://dx.doi.org/10.1182/blood-2006-06-028175
[14] Moretta, A., Bottino, C., Vitale, M., Pende, D., Cantoni, C., Mingari, M.C., et al. (2001) Activating Receptors and Coreceptors Involved in Human Natural Killer Cell-Mediated Cytolysis. Annual Review of Immunology, 19, 197-223.http://dx.doi.org/10.1146/annurev.immunol.19.1.197
[15] Pende, D., Parolini, S., Pessino, A., Sivori, S., Augugliaro, R., Morelli, L., et al. (1999) Identification and Molecular Characterization of NKp30, a Novel Triggering Receptor Involved in Natural Cytotoxicity Mediated by Human Natural Killer Cells. The Journal of Experimental Medicine, 190, 1505-1516.
[16] Augugliaro, R., Parolini, S., Castriconi, R., Marcenaro, E., Cantoni, C., Nanni, M., et al. (2003) Selective Cross-Talk among Natural Cytotoxicity Receptors in Human Natural Killer Cells. European Journal of Immunology, 33, 1235- 1241. http://dx.doi.org/10.1002/eji.200323896
[17] Wiemann, K., Mittrucker, H.W., Feger, U., Welte, S.A., Yokoyama, W.M., Spies, T., et al. (2005) Systemic NKG2D Down-Regulation Impairs NK and CD8 T Cell Responses in Vivo. The Journal of Immunology, 175, 720-729.http://dx.doi.org/10.4049/jimmunol.175.2.720
[18] Ferlazzo, G., Tsang, M.L., Moretta, L., Melioli, G., Steinman, R.M. and Munz, C. (2002) Human Dendritic Cells Activate Resting Natural Killer (NK) Cells and Are Recognized via the NKp30 Receptor by Activated NK Cells. The Journal of Experimental Medicine, 195, 343-351.
[19] Mandelboim, O., Lieberman, N., Lev, M., Paul, L., Arnon, T.I., Bushkin, Y., et al. (2001) Recognition of Haemagglutinins on Virus-Infected Cells by NKp46 Activates Lysis by Human NK Cells. Nature, 409, 1055-1060.http://dx.doi.org/10.1038/35059110
[20] Vitale, M., Bottino, C., Sivori, S., Sanseverino, L., Castriconi, R., Marcenaro, E., et al. (1998) NKp44, a Novel Triggering Surface Molecule Specifically Expressed by Activated Natural Killer Cells, Is Involved in Non-Major Histocompatibility Complex-Restricted Tumor Cell Lysis. Journal of Experimental Medicine, 187, 2065-2072.http://dx.doi.org/10.1084/jem.187.12.2065
[21] Vieillard, V., Strominger, J.L. and Debre, P. (2005) NK Cytotoxicity against CD4+ T Cells during HIV-1 Infection: A gp41 Peptide Induces the Expression of an NKp44 Ligand. Proceedings of the National Academy of Sciences of the United States of America, 102, 10981-10986.
[22] Borrego, F., Kabat, J., Kim, D.K., Lieto, L., Maasho, K., Pena, J., et al. (2002) Structure and Function of Major Histocompatibility Complex (MHC) Class I Specific Receptors Expressed on Human Natural Killer (NK) Cells. Molecular Immunology, 38, 637-660. http://dx.doi.org/10.1016/S0161-5890(01)00107-9
[23] Schim van der Loeff, M.F., Jaffar, S., Aveika, A.A., Sabally, S., Corrah, T., Harding, E., et al. (2002) Mortality of HIV-1, HIV-2 and HIV-1/HIV-2 Dually Infected Patients in a Clinic-Based Cohort in The Gambia. AIDS, 16, 1775-1783. http://dx.doi.org/10.1097/00002030-200209060-00010
[24] Bonaparte, M.I. and Barker, E. (2004) Killing of Human Immunodeficiency Virus-Infected Primary T-Cell Blasts by Autologous Natural Killer Cells Is Dependent on the Ability of the Virus to Alter the Expression of Major Histocompatibility Complex Class I Molecules. Blood, 104, 2087-2094.
[25] Alter, G. and Altfeld, M. (2009) NK Cells in HIV-1 Infection: Evidence for Their Role in the Control of HIV-1 Infection. Journal of Internal Medicine, 265, 29-42.
[26] Cohen, G.B., Gandhi, R.T., Davis, D.M., Mandelboim, O., Chen, B.K., Strominger, J.L., et al. (1999) The Selective Downregulation of Class I Major Histocompatibility Complex Proteins by HIV-1 Protects HIV-Infected Cells from NK cells. Immunity, 10, 661-671.
[27] Moretta, L., Bottino, C., Pende, D., Castriconi, R., Mingari, M.C. and Moretta, A. (2006) Surface NK Receptors and Their Ligands on Tumor Cells. Seminars in Immunology, 18, 151-158.
[28] Mavilio, D., Benjamin, J., Daucher, M., Lombardo, G., Kottilil, S., Planta, M.A., et al. (2003) Natural Killer Cells in HIV-1 Infection: Dichotomous Effects of Viremia on Inhibitory and Activating Receptors and Their Functional Correlates. Proceedings of the National Academy of Sciences of the United States of America, 100, 15011-15016.http://dx.doi.org/10.1073/pnas.2336091100
[29] Valentin, A., Rosati, M., Patenaude, D.J., Hatzakis, A., Kostrikis, L.G., Lazanas, M., et al. (2002) Persistent HIV-1 Infection of Natural Killer Cells in Patients Receiving Highly Active Antiretroviral Therapy. Proceedings of the National Academy of Sciences of the United States of America, 99, 7015-7020. http://dx.doi.org/10.1073/pnas.102672999
[30] Kottilil, S., Shin, K., Planta, M., McLaughlin, M., Hallahan, C.W., Ghany, M., et al. (2004) Expression of Chemokine and Inhibitory Receptors on Natural Killer Cells: Effect of Immune Activation and HIV Viremia. The Journal of Infectious Diseases, 189, 1193-1198. http://dx.doi.org/10.1086/382090
[31] Yindom, L.M., Leligdowicz, A., Martin, M.P., Gao, X., Qi, Y., Zaman, S.M., et al. (2010) Influence of HLA Class I and HLA-KIR Compound Genotypes on HIV-2 Infection and Markers of Disease Progression in a Manjako Community in West Africa. Journal of Virology, 84, 8202-8208.

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