Non-immune Modulators of Cellular Immune Surveillance to HIV-1 and Other Retroviruses: Future Artificial Intelligence-Driven Goals and Directions

  • Francesco ChiappelliEmail author
  • Allen Khakshooy
  • Nicole Balenton


Immune surveillance to viruses and other foreign pathogens involves a specific process, which is well-characterized in terms of the immune and non-immune cells and factors involved, and their specific timeline. For example, first exposure to a viral antigen involves major histocompatibility complex type I molecules to present the ‘self’ and ‘nonself’ antigen to CD3 + CD8 + CD45RA+ T cells. This presentation initiates the event of T cell activation, which results in the production of T cell growth factor (interleukin 2, IL-2), interferon-gamma (IFN-g) and other immune soluble products, which together act to promote the clonal proliferative expansion of the responding cell population. Soluble immune factors produced during this initial phase of the immune response also initiate the maturation of the responding T cells into CD3 + CD8 + CD45R0+ memory cells against that specific viral antigen, and of related cell populations that act to control and dampen cellular immune reactivity. Contemporaneously, these soluble immune factors trigger non-immune cells to release of non-immune soluble factors, including pituitary and adrenocortical hormones (e.g., glucocorticoids), which finely modulate immune cell responses. Together, immune and non-immune cells and soluble factors act in concert to engender and sustain a finely tuned immune surveillance process, whose ultimate end (Y) is to regain homeostatic balance of the organism – a healthy state, that is eradication of the immune-pathological signs and symptoms that derived from the viral infection, referring here to homeostatic balance Y.

In brief, immune and non-immune cells and soluble factors are concerted predicting factors for regaining Y, to the same extent as the initial viral challenge, and other factors related to the state of heterostasis of the organism. These states, which include unhealthy eating habits, sleep deprivation, stress, and the like, act in concert to delay, hamper and counter Y.

Therefore, from a biostatistical viewpoint, the problem becomes a relatively basic multiple regression, in which the outcome Y, the homeostatic state of health regained following a viral infection, is simply the sum of positive and negative factors and/or events. Positive factors and events (Π) inherently push allostasis forward (i.e., the orderly process of immune activation and maturation), but the negative (Ν) factors and events, allostatically speaking, interfere with attaining Y. Simplistically, Y is the product of the fine, coordinated and time-regulated interaction between all the interacting Π’s and Ν’s during the immune surveillance process (Y = ΣΠ + ΣΝ).

The question then becomes, knowing what we know today about the constituents of ΣΠ and of ΣΝ, can we not design, by means of bioinformatics, artificial Π’s and Ν’s, that may push the organism’s response more securely through all the allostatic phases to Y, the homeostatic state of health regained following a viral infection? Physiology has been able to a related feat by producing bioinformatics particles, which when injected in patients help regulate cholesterol levels. Future artificial intelligence (AI) advances will produce the artificial Π’s and Ν’s, which will aid regaining Y. In the meanwhile, as science continues to complete our knowledge of all the Π’s and of all the Ν’s involved, “tweening”, the computerized process by which, knowing the end-product of a sequence, the steps in-between can be programmed, will be applied to our conceptualization of immune surveillance events.

In conclusion, the novel science of immune-tweening will helps us understand and complete a set of immune and non-immune events that lead to Y, the homeostatic state of health regained following a viral infection. AI, on the other hand, holds strong promise to help us generate and produce bioinformatics or ‘micro-adjuvants’, as it were, of immune surveillance. We envisage that these giant steps in the future of viral immunity will first be achieved in the context of infection with the human immunodeficiency virus (HIV) because it has become the model for our understanding of anti-viral immune surveillance.


Viral immune surveillance Neuroendocrine modulators of cellular immunity Allostasis Bayesian prediction model Artifial intelligence Immune-tweening 


  1. 1.
    Chiappelli F. Immunophysiological role and clinical implications of non-immunoglobulin soluble products of immune effector cells. Adv Neuroimmunol. 1991;1:234–40.CrossRefGoogle Scholar
  2. 2.
    Barkhodarian A, Thames AD, Du AM, Jan AL, Nahcivan M, Nguyen MT, Sama N, Chiappelli F. Viral immune surveillance: toward a TH17/TH9 gate to the central nervous system. Bioinformation. 2015;11:47–54.CrossRefGoogle Scholar
  3. 3.
    Murphy K, Weaver C. Janeway Immunobiology. 9th ed. New York, NY: Garland Science/Taylor & Francis Group; 2017.Google Scholar
  4. 4.
    Chiappelli F, Manfrini E, Gwirtsman H, Garcia C, Pham L, Lee P, Frost P. Steroid receptor-mediated modulation of CD4+CD62L+ cell homing. Implications for drug abusers. Ann N Y Acad Sci. 1994;746:421–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Chiappelli F, Kung MA. Immune surveillance of the oral cavity and lymphocyte migration: relevance for alcohol abusers. Lymphology. 1995;28(4):196–207.PubMedGoogle Scholar
  6. 6.
    Angeli V, Randolph GJ. Inflammation, lymphatic function, and dendritic cell migration. Lymphat Res Biol. 2006;4(4):217–28.PubMedCrossRefGoogle Scholar
  7. 7.
    Liao S, von der Weid PY. Lymphatic system: an active pathway for immune protection. Semin Cell Dev Biol. 2015;38:83–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Randolph GJ, Ivanov S, Zinselmeyer BH, Scallan JP. The lymphatic system: integral roles in immunity. Annu Rev Immunol. 2017;35:31–52.PubMedCrossRefGoogle Scholar
  9. 9.
    Ryter A. Relationship between ultrastructure and specific functions of macrophages. Comp Immunol Microbiol Infect Dis. 1985;8(2):119–33.PubMedCrossRefGoogle Scholar
  10. 10.
    Langermans JA, Hazenbos WL, van Furth R. Antimicrobial functions of mononuclear phagocytes. J Immunol Methods. 1994;174(1–2):185–94.PubMedCrossRefGoogle Scholar
  11. 11.
    Withers DR. Innate lymphoid cell regulation of adaptive immunity. Immunology. 2016;149:123–30.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Burnet FM. Cellular immunology: self and notself. Cambridge: Cambridge University Press; 1969.Google Scholar
  13. 13.
    Bretscher P, Cohn M. A theory of self-nonself discrimination. Science. 1970;169(3950):1042–9.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Chiappelli F, Gormley GJ, Gwirstman HE, Lowy MT, Nguyen LD, Nguyen L, Esmail I, Strober M, Weiner H. Effects of intravenous and oral dexamethasone on selected lymphocyte subpopulations in normal subjects. Psychoneuroendocrinology. 1992;17(2–3):145–52.PubMedCrossRefGoogle Scholar
  15. 15.
    Chiappelli F, Kung M, Lee P, Pham L, Manfrini E, Villanueva P. Alcohol modulation of human normal T-cell activation, maturation, and migration. Alcohol Clin Exp Res. 1995;19(3):539–44.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383(6603):787–93.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol. 1998;16(1):111–35.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Langman RE, Cohn M. A minimal model for the self-nonself discrimination: a return to the basics. Semin Immunol. 2000;12(3):189–95.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Guermonprez P, Valladeau J, Zitvogel L, Théry C, Amigorena S. Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol. 2002;20(1):621–67.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Holtmeier W, Kabelitz D. gammadelta T cells link innate and adaptive immune responses. Chem Immunol Allergy. 2005;86:151–83.PubMedCrossRefGoogle Scholar
  21. 21.
    Girardi M. Immunosurveillance and immunoregulation by gammadelta T cells. J Invest Dermatol. 2006;126(1):25–31.PubMedCrossRefGoogle Scholar
  22. 22.
    Andersen MH, Schrama D, Thor Straten P, Becker JC. Cytotoxic T cells. J Invest Dermatol. 2006;126(1):32–41.PubMedCrossRefGoogle Scholar
  23. 23.
    Copeland KF, Heeney JL. T helper cell activation and human retroviral pathogenesis. Microbiol Rev. 1996;60(4):722–42.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7(2):131–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Restifo NP, Gattinoni L. Lineage relationship of effector and memory T cells. Curr Opin Immunol. 2013;25(5):556–63.PubMedCrossRefGoogle Scholar
  26. 26.
    Sall FB, Germini D, Kovina AP, Ribrag V, Wiels J, Toure AO, Iarovaia OV, Lipinski M, Vassetzky Y. Effect of environmental factors on nuclear organization and transformation of human B lymphocytes. Biochemistry (Mosc). 2018;83(4):402–10.CrossRefGoogle Scholar
  27. 27.
    Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol. 2015;15(3):149–59.PubMedCrossRefGoogle Scholar
  28. 28.
    Seliger B, Ritz U, Ferrone S. Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation. Int J Cancer. 2006;118(1):129–38.PubMedCrossRefGoogle Scholar
  29. 29.
    Walker B, McMichael A. The T-cell response to HIV. Cold Spring Harb Perspect Med. 2012;2(11):a007054.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Braciale TJ, Hahn YS. Immunity to viruses. Immunol Rev. 2013;255(1):10.1111–12109.CrossRefGoogle Scholar
  31. 31.
    Wortzman ME, Clouthier DL, McPherson AJ, Lin GH, Watts TH. The contextual role of TNFR family members in CD8(+) T-cell control of viral infections. Immunol Rev. 2013;255(1):125–48.CrossRefGoogle Scholar
  32. 32.
    Harris JF, Micheva-Viteva S, Li N, Hong-Geller E. Small RNA-mediated regulation of host-pathogen interactions. Virulence. 2013;4(8):785–95.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Tacchetti C, Favre A, Moresco L, Meszaros P, Luzzi P, Truini M, Rizzo F, Grossi CE, Ciccone E. HIV is trapped and masked in the cytoplasm of lymph node follicular dendritic cells. Am J Pathol. 1997;150(2):533–42.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Price RW, Brew B, Sidtis J, Rosenblum M, Scheck AC, Cleary P. The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science. 1988;239(4840):586–92.PubMedCrossRefGoogle Scholar
  35. 35.
    Chiappelli F, Kung MA, Villanueva P. Neuropsychoimmunology of drugs of abuse and AIDS. J Neuroimmunol. 1996;69:48–9.Google Scholar
  36. 36.
    Minagar A, Commins D, Alexander JS, Hoque R, Chiappelli F, Singer EJ, Nikbin B, Shapshak P. NeuroAIDS: characteristics and diagnosis of the neurological complications of AIDS. Mol Diagn Ther. 2008;12(1):25–43.PubMedCrossRefGoogle Scholar
  37. 37.
    Shapshak P, Chiappelli F, Commins D, Singer E, Levine AJ, Somboonwit C, Minagar A, Pellionisz AJ. Molecular epigenetics, chromatin, and NeuroAIDS/HIV: translational implications. Bioinformation. 2008;3(1):53–7.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Chiappelli F, Shapshak P, Commins D, Singer E, Minagar A, Oluwadara O, Prolo P, Pellionisz AJ. Molecular epigenetics, chromatin, and NeuroAIDS/HIV: immunopathological implications. Bioinformation. 2008;3(1):47–52.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Chiappelli F. Psychoneuroimmunology of immune reconstitution inflammatory syndrome (IRIS): the new frontier in translational biomedicine. Transl Biomed. 2015;6:11–4.Google Scholar
  40. 40.
    Chiappelli F, Bakhordarian A, Thames AD, Du AM, Jan AL, Nahcivan M, Nguyen MT, Sama N, Manfrini E, Piva F, Rocha RM, Maida CA. Ebola: translational science considerations. J Transl Med. 2015;13:11.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Chiappelli F, Franceschi C, Ottaviani E, Solomon GF, Taylor AN. Neuroendocrine modulation of the immune system. In: Greger R, Koepchen HP, Mommaerts W, Winhorst U, editors. Human physiology: from cellular mechanisms to integration. New York: Springer; 1996. p. 1707–29, Section L Chapter 86.CrossRefGoogle Scholar
  42. 42.
    Chiappelli F, Abanomy A, Hodgson D, Mazey KA, Messadi DV, Mito RS, Nishimura I, Spigleman I. Clinical, experimental and translational psychoneuroimmunology research models in oral biology and medicine. In: Ader R, et al., editors. Psychoneuroimmunology, vol. III: Academic Press; 2001. p. 645–70, Chapter 64.Google Scholar
  43. 43.
    Prolo P, Chiappelli F, Fiorucci A, Dovio A, Sartori ML, Angeli A. Psychoneuroimmunology: new avenues of research for the 21st century. Ann N Y Acad Sci. 2002;966:400–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Chiappelli F, Prolo P, Fiala M, Cajulis O, Iribarren J, Panerai A, Neagos N, Younai F, Bernard G. Allostasis in HIV infection and AIDS. In: Minagar PA, Shapshak P, editors. Neuro-AIDS: Nova Science Publisher, Inc.; 2006. p. 121–65, Chapter VI.Google Scholar
  45. 45.
    Barkhordarian A, Ajaj R, Ramchandani MH, Demerjian G, Cayabyab R, Danaie S, Ghodousi N, Iyer N, Mahanian N, Phi L, Giroux A, Manfrini E, Neagos N, Siddiqui M, Cajulis OS, Brant X, Shapshak P, Chiappelli F. Osteoimmunopathology in HIV/AIDS: a translational evidence-based perspective. Pathol Res Int. 2011, Article ID 359242 epub 21 May 2011.Google Scholar
  46. 46.
    Chiappelli F, Kutschman MM. Current and Future Directions in Psychobiology. In: Chiappelli F, editor. Advances in Psychobiology. Hauppauge, NY: NovaScience Publisher, Inc.; 2018, Chapter 1.Google Scholar
  47. 47.
    Chiappelli F, Cajulis OS. Psychobiological views on “stress-related oral ulcers”. Quintessence Int. 2004;35:223–7.PubMedGoogle Scholar
  48. 48.
    Turner-Cobb JM. Psychological and stress hormone correlates in early life: a key to HPA-axis dysregulation and normalization. Stress. 2005;8(1):47–57.PubMedCrossRefGoogle Scholar
  49. 49.
    Chiappelli F, Trignani S. Neuroendocrine-immune interactions: implications for clinical research. Adv Biosci. 1993;90:185–98.Google Scholar
  50. 50.
    Chiappelli F, Manfrini E, Franceschi C, Cossarizza A, Black K. Steroid regulation of cytokines: relevance for TH1→TH2 shift? Ann N Y Acad Sci. 1994;746:204–16.PubMedCrossRefGoogle Scholar
  51. 51.
    Chiappelli F, Liu NQ. Non-mammalian models of neuroendocrine-immune modulation: relevance for research in oral biology and medicine. Int J Oral Biol. 1999;24:47–61.Google Scholar
  52. 52.
    Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52(4):595–638.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Romeo HE, Tio DL, Rahman SU, Chiappelli F, Taylor AN. The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: relevance to neuroimmune surveillance of the oral cavity. J Neuroimmunol. 2001;115:91–100.PubMedCrossRefGoogle Scholar
  54. 54.
    Yun AJ, Lee PY, Bazar KA. Modulation of host immunity by HIV may be partly achieved through usurping host autonomic functions. Med Hypotheses. 2004;63:362–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Chiappelli F, Alwan J, Prolo P, Christensen R, Fiala M, Cajulis OS, Bernard G. Neuro-immunity in stress-related oral ulcerations: a fractal analysis. Front Biosci. 2005;10:3034–41.PubMedCrossRefGoogle Scholar
  56. 56.
    Angeli A, Dovio A, Sartori ML, Masera RG, Ceoloni B, Prolo P, Racca S, Chiappelli F. Interactions between glucocorticoids and cytokines in the bone microenvironment. Ann N Y Acad Sci. 2002;966:97–107.PubMedCrossRefGoogle Scholar
  57. 57.
    Kenney MJ, Ganta CK. Autonomic nervous system and immune system interactions. Compr Physiol. 2014;4:1177–200.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Chiappelli F, Bakhordarian A, Bach Q, Demerjian GG. Translational psychoneuroimmunology in oral biology & medicine. For Immunopathol Dis Therap. 2016;6:119–32.Google Scholar
  59. 59.
    Khakshooy A, Chiappelli F. Hypothalamus-pituitary-adrenal - cell-mediated immunity regulation in the immune restoration inflammatory syndrome. Bioinformation. 2016;12:28–30.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Diazzi C, Brigante G, Ferrannini G, Ansaloni A, Zirilli L, De Santis MC, Zona S, Guaraldi G, Rochira V. Pituitary growth hormone (GH) secretion is partially rescued in HIV-infected patients with GH deficiency (GHD) compared to hypopituitary patients. Endocrine. 2017;55:885–98.PubMedCrossRefGoogle Scholar
  61. 61.
    Chiappelli F. Fundamentals of evidence-based health care and translational science. Heidelberg: Springer; 2014.CrossRefGoogle Scholar
  62. 62.
    Khakshooy A, Chiappelli F, editors. Practical biostatistics in translational healthcare. New York, NY: Springer; 2018.Google Scholar
  63. 63.
    Draper NR, Smith H. Applied regression analysis. 3rd ed. Hoboken, NJ: John Wiley; 1998.CrossRefGoogle Scholar
  64. 64.
    Bingham NH, Fry JM. Regression: linear models in statistics. Heidelberg: Springer; 2010.CrossRefGoogle Scholar
  65. 65.
    Donald BR. Algorithms in structural molecular biology. Cambridge, MA: The MIT Press; 2011.Google Scholar
  66. 66.
    Russell SJ, Norvig P. Artificial intelligence: a modern approach. Englewood Cliffs, N.J: Prentice Hall; 2003.Google Scholar
  67. 67.
    Hogeweg P, Searls DB. The roots of bioinformatics in theoretical biology. PLoS Comput Biol. 2011;7(3):e1002021.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Sim AYL, Minary P, Levitt M. Modeling nucleic acids. Curr Opin Struct Biol. 2012;22(3):273–8.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Simonyan V, Goecks J, Mazumder R. Biocompute objects—a step towards evaluation and validation of biomedical scientific computations. PDA J Pharm Sci Technol. 2017;7(2):136–46.CrossRefGoogle Scholar
  70. 70.
    Saha S, Bhasin M, Raghava GP. Bcipep: a database of B-cell epitopes. BMC Genomics. 2005;6:79.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Lund O, Nielsen M, Lundegaard C, Kesmir C, Brunak S. Immunological bioinformatics. Cambridge, MA: The MIT Press; 2005.CrossRefGoogle Scholar
  72. 72.
    Chiappelli F. Osteoimmunopathology: evidence-based perspectives from molecular biology to systems biology. New York: Springer; 2011.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Francesco Chiappelli
    • 1
    Email author
  • Allen Khakshooy
    • 1
  • Nicole Balenton
    • 1
  1. 1.UCLA School of DentistryLos AngelesUSA

Personalised recommendations