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


The mechanisms involved in resistance to HIV-1 infection, especially the role of innate immune response, have not been thoroughly explored in individuals who are repeatedly exposed to HIV-1, but do not get the infection, termed as Exposed sero-negative or ESN. Frequency and activation state of natural killer (NK) cells and plasmacytoid dendritic cells (pDC) in ESNs from North India were compared with those in recently infected HIV positives (RHIV), chronically infected HIV positives (HIV+) and healthy controls (HC). The activation state of NK cells in terms of cytokine response (IFNγ & TNFα) was significantly higher in ESNs compared to the healthy controls, recently infected HIV+ and chronically infected HIV+. Although the number of circulating pDC in different study groups was not significantly different, yet these cells seem to have significantly higher activation state in terms of IFNα production (ex-vivo in response to CpG ODN) in ESNs when compared with other groups. Increased activation status of NK cells and pDC in Exposed but Seronegative individuals indicates their continuous stimulation with HIV antigens due to regular exposure with infected partners and which might be imparting resistance to viral infection in these individuals.

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A. Singla, R. Jacobs, R. E. Schmidt, A. Wanchu and S. K. Arora, "Increased Activity of NK Cells and Plasmacytoid Dendritic Cells in HIV-Exposed Seronegative (ESN) Individuals," World Journal of AIDS, Vol. 2 No. 1, 2012, pp. 6-16. doi: 10.4236/wja.2012.21002.

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The authors declare no conflicts of interest.


[1] UNAIDS, WHO, “AIDS epidemic update December,” The Joint United Nations Programme on HIV and AIDS, Geneva 2010.
[2] B. L. Shacklett, “HIV-Exposed, Persistently Seronegative Individuals: An Unsolved Puzzle?” The HIV/AIDS Newsletter, Vol. 1, No. 2, 2008, pp. 1-3.
[3] M. Miyazawa, L. Lopalco, F. Mazzotta, Lo. S. Caputo, F. Veas and M. Clerici, “The Immunologic Advantage’ of HIV-Exposed Seronegative Individuals,” AIDS, Vol. 23, No. 12, 2009, pp. 161-175. doi:10.1097/QAD.0b013e3283196a80
[4] C. Tomescu, F. M. Duh, M. A. Lanier, A. Kapalko, K. C. Mounzer and M. P. Martin, “Increased Plasmacytoid Dendritic Cell Maturation and Natural Killer Cell Activation in HIV-1 Exposed, Uninfected Intra-Venous Drug Users,” AIDS, Vol. 24, No. 14, 2010, pp. 2151-2160. doi:10.1097/QAD.0b013e32833dfc20
[5] S. Ravet, D. Scott-Algara, E. Bonnet, H. K. Tran, T. Tran and N. Nguyen, “Distinctive NK-Cell Receptor Repertoires Sustain High-Level Constitutive NK-Cell Activation in HIV-Exposed Uninfected Individuals,” Blood, Vol. 109, No. 10, 2007, pp. 4296-4305. doi:10.1182/blood-2006-08-040238
[6] S. Pallikkuth, A. Wanchu, A. Bhatnagar, R. K. Sachdeva and M. Sharma, “Human Immunodeficiency Virus (HIV) Gag Antigen-Specific T-Helper and Granule-Dependent CD8 T-Cell Activities in Exposed but Uninfected Heterosexual Partners of HIV Type 1-Infected Individuals in North India,” Clinical Vaccine Immunology, Vol. 14, No. 9, 2007, pp. 1196-1202.
[7] P. Suresh, A. Wanchu, R. K. Sachdeva and A. Bhatnagar, “Gene Polymorphisms in CCR5, CCR2, CX3CR1, SDF-1 and RANTES in Exposed but Uninfected Partners of HIV-1 Infected Individuals in North India,” Journal of Clinical Immunology, Vol. 26, No. 5, 2006, pp. 476-484. doi:10.1007/s10875-006-9036-0
[8] A. Iannello, O. Debbeche, S. Samarani and A. Ahmad, “Antiviral NK Cell Responses in HIV Infection: II. Viral Strategies for Evasion and Lessons for Immunotherapy and Vaccination,” Journal of Leukocyte Biology, Vol. 84, No. 1, 2008, pp. 27-49. doi:10.1189/jlb.0907649
[9] R. Jacobs, K. Weber, K. Wendt, H. Heiken and R. E. Schmidt, “Altered Coexpression of Lectin-Like Receptors CD94 and CD161 on NK and T Cells in HIV Patients,” Journal of Clinical Immunology, Vol. 24, No. 3, 2004, pp. 281-286. doi:10.1023/B:JOCI.0000025449.16468.6f
[10] H. Bruunsgaard, C. Pedersen, P. Skinhoj and B. K. Pedersen, “Clinical Progression of HIV Infection: Role of NK Cells,” Scandinavian Journal of Immunology, Vol. 46, No. 1, 1997, pp. 91-95. doi:10.1046/j.1365-3083.1997.d01-98.x
[11] L. Azzoni, R. M. Rutstein, J. Chehimi, M. A. Farabaugh, A. Nowmos and L. A. Montaner, “Dendritic and Natural Killer Cell Subsets Associated with Stable or Declining CD4+ Cell Counts in Treated HIV-1—Infected Children,” Journal of Infectious Diseases, Vol. 191, No. 9, 2005, pp. 1451-1459. doi:10.1086/429300
[12] V. Soumelis, I. Scott, F. Gheyas, D. Bouhour, G. Cozon and L. Cotte, “Depletion of Circulating Natural Type 1 Interferon-Producing Cells in HIV-Infected AIDS Patients,” Blood, Vol. 98, 2001, pp. 906-912. doi:10.1182/blood.V98.4.906
[13] M. Muller-Trutwin and A. Hosmalin, “Role for Plasmacytoid Dendritic Cells in Anti-HIV Innate Immunity,” Immunology and Cell Biology, Vol. 83, No. 4, 2005, pp. 578-583. doi:10.1111/j.1440-1711.2005.01394.x
[14] V. Soumelis, I. Scott, Y. J. Liu and J. Levy, “Natural Type 1 Interferon Producing Cells in HIV Infection,” Human Immunology, Vol. 63, No. 12, 2002, PP. 1206-1212. doi:10.1016/S0198-8859(02)00760-7
[15] M. Colonna, G. Trinchieri and Y. J. Liu, “Plasmacytoid Dendritic Cells in Immunity,” Nature Immunology, Vol. 5, No. 12, 2004, pp. 1219-1226. doi:10.1038/ni1141
[16] W. A. Goh, J. Markee, R. E. Akridge, M. Meldorf, L. Musey and T. Karchmer “Protection against Human Immunodeficiency Virus Type 1 Infection in Persons with Repeated Exposure: Evidence for T Cell Immunity in the Absence of Inherited CCR5 Coreceptor Defects,” Journal of Infectious Diseases, Vol. 179, No. 3, 1999, pp. 548-557. doi:10.1086/314632
[17] N. Sachdeva, S. Sehgal and S. K. Arora, “Frequency of Drug-Resistant Variants of HIV-1 Coexistent with Wild-Type in Treatment-Naive Patients of India,” Medscap General Medicine, Vol. 7, No. 3, 2005, p. 68.
[18] E. Barker, C. E. Mackewicz, G. Reyes-Teran, A. Sato, S. A. Stranford and S. H. Fujimura, “Virological and Immunological Features of Long-Term Human Immunodeficiency Virus-Infected Individuals Who Have Remained Asymptomatic Compared with Those Who Have Progressed to Acquired Immunodeficiency Syndrome,” Blood, Vol. 92, No. 9, 1998, pp. 3105-3114.
[19] K. Honda, H. Yanai, H. Negishi, M. Asagiri, M. Sato and T. Mizutani, “IRF-7 is the Master Regulator of Type-I Interferon-Dependent Immune Responses,” Nature, Vol. 434, No. 7034, 2005, pp. 772-777. doi:10.1038/nature03464
[20] Y. Huang, W. A. Paxton, S. M. Wolinsky, A. U. Neumann, L. Zhang and T. He, “The Role of a Mutant CCR5 Allele in HIV-1 Transmission and Disease Progression,” Nature Medicine, Vol. 2, No. 11, 1996, pp. 1240-1243. doi:10.1038/nm1196-1240
[21] Beretta, S. H. Weiss, G. Rappocciolo, R. Mayur, C. D. Santis and J. Quirinale, “Human Immunodeficiency Virus Type 1 (HIV-1)-Seronegative Injection Drug Users at Risk for HIV Exposure Have Antibodies to HLA Class I Antigens and T Cells Specific for HIV Envelope,” Journal of Infectious Diseases, Vol. 173, No. 2, 1996, pp. 472-476. doi:10.1093/infdis/173.2.472
[22] S. Mazzoli, D. Trabattoni, S. L. Caputo, S. Piconi, C. Ble, F. Meacci, “HIV-Specific Mucosal and Cellular Immunity in HIV-Seronegative Partners of HIV-Seropositive Individuals,” Nature Medicine, Vol. 3, No. 11, 1997, pp. 1250-1257. doi:10.1038/nm1197-1250
[23] L. A. Pinto, J. Sullivan, J. A. Berzofsky, M. Clerici, H. A. Kessler and A. L. Landay, “ENV-Specific Cytotoxic T Lymphocyte Responses in HIV Seronegative Health Care Workers Occupationally Exposed to HIV-Contaminated Body Fluids,” Journal of Clinical Investigation, Vol. 96, No. 2, 1995, pp. 867-876. doi:10.1172/JCI118133
[24] L. X. Truong, T. T. Luong, D. Scott-Algara, P. Versmisse, A. David and D. Perez-Bercoff, “CD4 Cell and CD8 Cell-Mediated Resistance to HIV-1 Infection in Exposed Uninfected Intravascular Drug Users in Vietnam,” AIDS, Vol. 17, No. 10, 2003, pp. 1425-1434. doi:10.1097/00002030-200307040-00002
[25] C. J. Montoya, P. A. Velilla, C. Chougnet, A. L. Landay and M. T. Rugeles, “Increased IFN-Gamma Production by NK and CD3+/CD56+ Cells in Sexually HIV-1-Exposed but Uninfected Individuals,” Clinical Immunology, Vol. 120, No. 2, 2006, pp. 138-146. doi:10.1016/j.clim.2006.02.008
[26] G. Kaur, P. Singh, C. C. Rapthap, N. Kumar, M. Vajpayee and S. K. Sharma, “Polymorphism in the CCR5 Gene Promoter and HIV-1 Infection in North Indians,” Human Immunology, Vol. 68, No. 5, 2007, pp. 454-461. doi:10.1016/j.humimm.2007.01.016
[27] J. A. Levy, I. Scott and C. Mackewicz, “Protection from HIV/AIDS: The Importance of Innate Immunity,” Clinical Immunology, Vol. 108, No. 3, 2003, pp. 167-174. doi:10.1016/S1521-6616(03)00178-5
[28] D. Trabattoni, S. L. Caputo, G. Maffeis, F. Vichi, M. Biasin and P. Pierotti, “Human Alpha Defensin in HIV-Exposed but Uninfected Individuals,” Journal of Acquired Immune Deficiency Syndromes, Vol. 35, No. 5, 2004, pp. 455-463. doi:10.1097/00126334-200404150-00003
[29] D. Scott-Algara, L. X. Truong, P. Versmisse, A. David, T. T. Luong and N. V. Nguyen, “Cutting Edge: Increased Nk Cell Activity in HIV-1-Exposed but Uninfected Vietnamese Intravascular Drug Users,” Journal of Immunology, Vol. 171, No. 11, 2003, pp. 5663-5667.
[30] K. R. Fowke, R. Kaul, K. L. Rosenthal, J. Oyugi, J. Kimani and W. J. Rutherford, “HIV-1-Specific Cellular Immune Responses among HIV-1-Resistant Sex Workers,” Immunology and Cell Biology, Vol. 78, No. 6, 2000, pp. 586-595.
[31] G. Alter and M. Altfeld, “NK Cells in HIV-1 Infection: Evidence for Their Role in the Control of HIV-1 Infection,” Journal of Internal Medicine, Vol. 265, No. 1, 2009, pp. 29-42. doi:10.1111/j.1365-2796.2008.02045.x
[32] G. Alter, N. Teigen, B. T. Davis, M. M. Addo, T. J. Suscovich and M. T. Waring, “Sequential Deregulation of Nk Cell Subset Distribution and Function Starting in Acute HIV-1 Infection,” Blood, Vol. 106, No. 10, 2005, pp. 3366-3369. doi:10.1182/blood-2005-03-1100
[33] S. D. Douglas, S. J. Durako, N. B. Tustin, J. Houser, L. Muenz and S. E. Starr, “Natural Killer Cell Enumeration and Function in HIV-Infected and High-Risk Uninfected Adolescents,” AIDS Research and Human Retroviruses, Vol. 17, No. 6, 2001, pp. 543-552. doi:10.1089/08892220151126643
[34] R. Ahmad, S. T. Sindhu, P. Tran, E. Toma, R. Morisset and J. Menezes, “Modulation of Expression of the Mhc Class I-Binding Natural Killer Cell Receptors, and Nk Activity in Relation to Viral Load in HIV-Infected/AIDS Patients,” Journal of Medical Virology, Vol. 65, No. 3, 2001, pp. 431-40. doi:10.1002/jmv.2053
[35] Y. Koyanagi, W. A. O’Brien, J. Q. Zhao, D. W. Golde, J. C. Gasson and I. S. Chen, “Cytokines Alter Production of HIV-1 from Primary Mononuclear Phagocytes,” Science, Vol. 241, No. 4873, 1988, pp. 1673-1675. doi:10.1126/science.3047875
[36] D. Emilie, M. C. Maillot, J. F. Nicolas, R. Fior and P. Galanaud, “Antagonistic Effect of Interferon-Gamma on Tat-Induced Transactivation of HIV Long Terminal Repeat,” The Journal of Biological Chemistry, Vol. 267, No. 29, 1992, pp. 20565-20570.
[37] M. Clerici, A. Clivio and G. M. Shearer, “Resistance to HIV Infection: The Genes Are Only Part of the Solution,” Trends in Microbiology, Vol. 5, No. 1, 1997, pp. 2-4. doi:10.1016/S0966-842X(97)81762-3
[38] S. Kottilil, T. W. Chun, S. Moir, S. Liu, M. McLaughlin and C. W. Hallahan, “Innate Immunity in Human Immunodeficiency Virus Infection: Effect of Viremia on Natural Killer Cell Function,” Journal of Infectious Diseases, Vol. 187, No. 7, 2003, pp. 1038-1045. doi:10.1086/368222
[39] M. R. Goodier, N. Imami, G. Moyle, B. Gazzard and F. Gotch, “Loss of the CD56hiCD16 NK Cell Subset and Nk Cell Interferon-Gamma Production During Antiretroviral Therapy for HIV-1: Partial Recovery by Human Growth Hormone,” Clinical and Experimental Immunology, Vol. 134, No. 3, 2003, pp. 470-476. doi:10.1111/j.1365-2249.2003.02329.x
[40] C. Tomescu, J. Chehimi, V. C. Maino and L. J. Moontaner, “Retention of Viability, Cytotoxicity, And Response to IL-2, IL-15, or IFN-α by Human NK Cells after CD107a Degranulation,” Journal of Leukocyte Biology, Vol. 85, No. 5, 2009, pp. 871-876. doi:10.1189/jlb.1008635
[41] E. Martinelli, C. Cicala, R. D. Van, D. J. Goode, K. Macleod and J. Arthos, “HIV-1 gp120 Inhibits TLR9-Mediated activation and IFN-α Secretion in Plasmacytoid Dendritic Cells,” Proceedings of National Academy of Sciences USA, Vol. 104, No, 9, 2007, pp. 3396-3401. doi:10.1073/pnas.0611353104
[42] Y. J. Liu, “IPC: Professional Type 1 Interferon-Producing Cells and Plasmacytoid Dendritic Cell Precursors,” Annual Review of Immunology, Vol. 23, 2005, pp. 275-306. doi:10.1146/annurev.immunol.23.021704.115633
[43] A. Meier, J. J Chang, E. S. Chan, R. B. Pollard, H. K. Sidhu S. Kulkarni, et al., “Sex Differences in the Toll-Like Receptor-Mediated Response of Plasmacytoid Dendritic Cells to HIV-1,” Nature Medicine, Vol. 15, No. 8, 2009, pp. 955-959. doi:10.1038/nm.2004
[44] J. S. Finke, M. Shodell, K. Shah, F. P. Siegal and R. M. Steinma, “Dendritic Cell Numbers in the Blood of HIV-1 Infected Patients before and after Changes in Antiretroviral Therapy,” Journal of Clinical Immunology, Vol. 24, No. 6, 2004, pp. 647-52. doi:10.1007/s10875-004-6250-5
[45] J. C. Tilton, M. M. Manion, M. R. Luskin, A. J. Johnson, A. A. Patamawenu and C. W. Hallahan, “Human Immunodeficiency Virus Viremia Induces Plasmacytoid Dendritic Cell Activation in Vivo and Diminished Alpha Interferon Production in Vitro,” The Journal of Virology, Vol. 82, No. 8, 2008, pp, 3997-4006.

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