Effect of multi-epitope derived from HIV-1 on REM sleep deprivation-induced spatial memory impairment with respect to the level of immune factors in mice

Document Type : Original Article


1 Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

2 Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran

3 Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran

4 Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran


Objective(s): Sleep deprivation (SD) has a negative impact on cognitive functions including learning and memory. Many studies have shown that rapid-eye-movement (REM) SD also disrupts memory performance. In this study, we aimed to investigate the effect of multi-epitope Gag-Pol-Env-Tat derived from Human immunodeficiency virus 1 (HIV-1) on REM SD-induced spatial memory impairment with respect to the levels of interleukin-4 (IL-4), interleukin-17 (IL-17), interferon-gamma (IFN-γ), immunoglobulin G1 (IgG1), immunoglobulin G2a (IgG2a), and lymphocyte proliferation in NMRI mice. We used multi-epitope Gag-Pol-Env-Tat derived from HIV-1 because Gag-Pol-Env-Tat immunogen sequence is one of the most sensitive immunogen sequences of HIV-1 that can significantly augment cellular and humoral immune systems, leading to the improvement of cognitive functions. 
Materials and Methods: Morris water maze apparatus was used to assess spatial memory, and multi-platform apparatus was used to induce RSD for 24 hr. Multi-epitope derived from HIV-1 was subcutaneously injected at the dose of 20 µgr/ml, once and fourteen days before RSD. 
Results: RSD impaired spatial memory and injection of multi-epitope derived from HIV-1 reversed this effect. RSD decreased IL-4, IgG1, and IgG2a levels, while multi-epitope derived from HIV-1 reversed these effects. Multi-epitope derived from HIV-1 also increased lymphocyte proliferation and decreased IL-17 levels in both control and RSD mice. 
Conclusion: Multi-epitope derived from HIV-1 may improve memory performance via induction of anti-inflammatory immune response. 


1. Kordestani-Moghadam P, Nasehi M, Vaseghi S, Khodagholi F, Zarrindast MR. The role of sleep disturbances in depressive-like behavior with emphasis on alpha-ketoglutarate dehydrogenase activity in rats. Physiol Behav 2020; 224:113023.
2. Eydipour Z, Nasehi M, Vaseghi S, Jamaldini SH, Zarrindast MR. The role of 5-HT4 serotonin receptors in the CA1 hippocampal region on memory acquisition impairment induced by total (TSD) and REM sleep deprivation (RSD). Physiol Behav 2020; 215:112788.
3. Kordestani-Moghadam P, Nasehi M, Khodagholi F, Vaseghi S, Zarrindast MR, Khani M. The fluctuations of metabotropic glutamate receptor subtype 5 (mGluR5) in the amygdala in fear conditioning model of male Wistar rats following sleep deprivation, reverse circadian and napping. Brain Res 2020; 1734:146739.
4. Rezaie M, Nasehi M, Vaseghi S, Mohammadi-Mahdiabadi-Hasani MH, Zarrindast MR, Nasiri Khalili MA. The protective effect of alpha lipoic acid (ALA) on social interaction memory, but not passive avoidance in sleep-deprived rats. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:2081-2091.
5. Javad-Moosavi BZ, Nasehi M, Vaseghi S, Jamaldini SH, Zarrindast MR. Activation and inactivation of nicotinic receptnors in the dorsal hippocampal region restored negative effects of total (tsd) and rem sleep deprivation (RSD) on memory acquisition, locomotor activity and pain perception. Neuroscience 2020; 433:200-211.
6. Rezaie M, Nasehi M, Vaseghi S, Alimohammadzadeh K, Vaghar MI, Mohammadi-Mahdiabadi-Hasani MH, et al. The interaction effect of sleep deprivation and cannabinoid type 1 receptor in the CA1 hippocampal region on passive avoidance memory, depressive-like behavior and locomotor activity in rats. Behav Brain Res 2020:112901.
7. Ibarra-Coronado EG, Perez-Torres A, Pantaleon-Martinez AM, Velazquez-Moctezuma J, Rodriguez-Mata V, Morales-Montor J. Innate immunity modulation in the duodenal mucosa induced by REM sleep deprivation during infection with Trichinella spirallis. Sci Rep 2017; 7:45528.
8.Savard J, Laroche L, Simard S, Ivers H, Morin CM. Chronic insomnia and immune functioning. Psychosom Med 2003; 65:211-221.
9. Yehuda S, Sredni B, Carasso RL, Kenigsbuch-Sredni D. REM sleep deprivation in rats results in inflammation and interleukin-17 elevation. J Interferon Cytokine Res 2009; 29:393-398.
10. Liu P, Zhao B, Wei M, Li Y, Liu J, Ma L, et al. Activation of inflammation is associated with amyloid-beta accumulation induced by chronic sleep restriction in rats. J Alzheimers Dis 2020; 74:759-773.
11. Kumari K, Usmani S, Siddiqui SJ, Husain J. The effects of sleep deprivation on the job performance of working mothers. IBT journal of business studies (jbs) 2016; 12:95-120.
12. Shochat T. Impact of lifestyle and technology developments on sleep. Nat Sci Sleep 2012; 4: 19-31. 
13. Alikhani M, Ebrahimi A, Farnia V, Khazaie H, Radmehr F, Mohamadi E, et al. Effects of treatment of sleep disorders on sleep, psychological and cognitive functioning and biomarkers in individuals with HIV/AIDS and under methadone maintenance therapy. J Psychiatr Res 2020; 130:260-272.
14. Patil SP, Brown TT, Jacobson LP, Margolick JB, Laffan A, Johnson-Hill L, et al. Sleep disordered breathing, fatigue, and sleepiness in HIV-infected and-uninfected men. PLoS One 2014; 9:e99258.
15. Mahmood Z, Hammond A, Nunez RA, Irwin MR, Thames AD. Effects of sleep health on cognitive function in HIV+ and HIV- adults. J Int Neuropsychol Soc 2018; 24:1038-1046.
16. Becker BW, Thames AD, Woo E, Castellon SA, Hinkin CH. Longitudinal change in cognitive function and medication adherence in HIV-infected adults. AIDS Behav 2011; 15:1888-1894.
17. Byun E, Gay CL, Lee KA. Sleep, fatigue, and problems with cognitive function in adults living with HIV. J Assoc Nurses AIDS Care 2016; 27:5-16.
18. d’Ettorre G, Borrazzo C, Pinacchio C, Santinelli L, Cavallari EN, Statzu M, et al. Increased IL-17 and/or IFN-gamma producing T-cell subsets in gut mucosa of long-term-treated HIV-1-infected women. AIDS 2019; 33:627-636.
19. Calza L, Colangeli V, Borderi M, Beci G, Esposito F, Bon I, et al. Rosuvastatin decreases serum inflammatory markers and slows atherosclerosis progression rate in treated HIV-infected patients with metabolic syndrome. Infect Dis (Lond) 2020:1-8.
20. Kashi VP, Jacob RA, Shamanna RA, Menon M, Balasiddaiah A, Varghese RK, et al. The grafting of universal T-helper epitopes enhances immunogenicity of HIV-1 Tat concurrently improving its safety profile. PLoS One 2014; 9:e114155.
21. Roodbari F, Sabahi F, Sarbolouki MN, Barkhordari F, Adeli A, Jamedar A, et al. Immune responses against a new HIV-1 p24-gp41/pCAGGS-IL-12 DNA vaccine in BAlB/c mice. Iran J Immunol 2012; 9:86-97.
22. Rastgou R, Rouhollah F. The role of levamisole and HIV-1 Nef-p24 fusion protein in IL-4 gene expression for evaluating humoral immune response. Archives of Advances in Biosciences 2020; 11:29-37.
23. Arabi S, Aghasadeghi MR, Memarnejadian A, Kohram F, Aghababa H, Khoramabadi N, et al. Cloning, expression and purification of a novel multi-epitopic HIV-1 vaccine candidate: A preliminary study on immunoreactivity. Vaccine Res 2014; 1:10-15.
24. Villafuerte G, Miguel-Puga A, Murillo Rodríguez E, Machado S, Manjarrez E, Arias-Carrión O. Sleep deprivation and oxidative stress in animal models: A systematic review. Oxidative medicine and cellular longevity 2015; 2015:1-15.
25. Vaseghi S, Babapour V, Nasehi M, Zarrindast MR. Synergistic but not additive effect between ACPA and lithium in the dorsal hippocampal region on spatial learning and memory in rats: Isobolographic analyses. Chem Biol Interact 2019; 315:108895.
26. Vaseghi S, Babapour V, Nasehi M, Zarrindast MR. The role of CA1 CB1 receptors on lithium-induced spatial memory impairment in rats. EXCLI J 2018; 17:916-934.
27. Aleisa AM, Helal G, Alhaider IA, Alzoubi KH, Srivareerat M, Tran TT, et al. Acute nicotine treatment prevents REM sleep deprivation-induced learning and memory impairment in rat. Hippocampus 2011; 21:899-909.
28. McDermott CM, LaHoste GJ, Chen C, Musto A, Bazan NG, Magee JC. Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons. J Neurosci 2003; 23:9687-9695.
29. Vecsey CG, Baillie GS, Jaganath D, Havekes R, Daniels A, Wimmer M, et al. Sleep deprivation impairs cAMP signalling in the hippocampus. Nature 2009; 461:1122-1125.
30. Alhaider IA, Aleisa AM, Tran TT, Alkadhi KA. Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine. Mol Cell Neurosci 2011; 46:742-751.
31. Postnikova TY, Trofimova AM, Ergina JL, Zubareva OE, Kalemenev SV, Zaitsev AV. Transient switching of NMDA-dependent long-term synaptic potentiation in CA3-CA1 hippocampal synapses to mGluR1-Dependent potentiation after pentylenetetrazole-induced acute seizures in young rats. Cell Mol Neurobiol 2019; 39:287-300.
32. Meerlo P, Mistlberger RE, Jacobs BL, Heller HC, McGinty D. New neurons in the adult brain: the role of sleep and consequences of sleep loss. Sleep Med Rev 2009; 13:187-194.
33. Vaseghi S, Arjmandi-Rad S, Kholghi G, Nasehi M. Inconsistent effects of sleep deprivation on memory function. EXCLI J 2021; 20:1011-1027.
34. Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, Wood CA, et al. Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep. Neuroimmunomodulation 2006; 13:357-374.
35. Mullington J, Korth C, Hermann DM, Orth A, Galanos C, Holsboer F, et al. Dose-dependent effects of endotoxin on human sleep. Am J Physiol Regul Integr Comp Physiol 2000; 278:R947-955.
36. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6:1123-1132.
37. Wadhwa M, Chauhan G, Roy K, Sahu S, Deep S, Jain V, et al. Caffeine and modafinil ameliorate the neuroinflammation and anxious behavior in rats during sleep deprivation by inhibiting the microglia activation. Front Cell Neurosci 2018; 12:1-16.
38. Esumi LA, Palma BD, Gomes VL, Tufik S, Hipolide DC. Inflammatory markers are associated with inhibitory avoidance memory deficit induced by sleep deprivation in rats. Behav Brain Res 2011; 221:7-12.
39. Zhao Q, Xie X, Fan Y, Zhang J, Jiang W, Wu X, et al. Phenotypic dysregulation of microglial activation in young offspring rats with maternal sleep deprivation-induced cognitive impairment. Sci Rep 2015; 5:9513.
40. Harty JT, Badovinac VP. Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol 2008; 8:107-119.
41. Kabba JA, Xu Y, Christian H, Ruan W, Chenai K, Xiang Y, et al. Microglia: Housekeeper of the central nervous system. Cell Mol Neurobiol 2018; 38:53-71.
42. Camara ML, Corrigan F, Jaehne EJ, Jawahar MC, Anscomb H, Baune BT. Effects of centrally administered etanercept on behavior, microglia, and astrocytes in mice following a peripheral immune challenge. Neuropsychopharmacology 2015; 40:502-512.
43. Hirotsu C, Pedroni MN, Berro LF, Tufik S, Andersen ML. Nicotine and sleep deprivation: impact on pain sensitivity and immune modulation in rats. Sci Rep 2018; 8:13837.
44. Han Y, Wang J, Zhao Q, Xie X, Song R, Xiao Y, et al. Pioglitazone alleviates maternal sleep deprivation-induced cognitive deficits in male rat offspring by enhancing microglia-mediated neurogenesis. Brain Behav Immun 2020; 87:568-578.
45. Wang G, Zhang X, Lu X, Liu J, Zhang Z, Wei Z, et al. Fish oil supplementation attenuates cognitive impairment by inhibiting neuroinflammation in STZ-induced diabetic rats. Aging (Albany NY) 2020; 12:15281-15289.
46. Rizk NI, Rizk MS, Mohamed AS, Naguib YM. Attenuation of sleep deprivation dependent deterioration in male fertility parameters by vitamin C. Reprod Biol Endocrinol 2020; 18:1-13.
47. Ibarra-Coronado EG, Velazquez-Moctezuma J, Diaz D, Becerril-Villanueva LE, Pavon L, Morales-Montor J. Sleep deprivation induces changes in immunity in Trichinella spiralis-infected rats. Int J Biol Sci 2015; 11:901-912.
48. Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003; 52:65-70.
49. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol 2014; 5:1-17.
50. Ferrante A, Beard LJ, Feldman RG. IgG subclass distribution of antibodies to bacterial and viral antigens. Pediatr Infect Dis J 1990; 9:S16-24.
51. Schauer U, Stemberg F, Rieger CH, Buttner W, Borte M, Schubert S, et al. Levels of antibodies specific to tetanus toxoid, haemophilus influenzae type b, and pneumococcal capsular polysaccharide in healthy children and adults. Clin Diagn Lab Immunol 2003; 10:202-207.
52. Hammarstrom L, Carbonara AO, DeMarchi M, Lefranc G, Moller G, Smith CI, et al. Subclass restriction pattern of antigen-specific antibodies in donors with defective expression of IgG or IgA subclass heavy chain constant region genes. Clin Immunol Immunopathol 1987; 45:461-470.
53. Ryazantsev S, Tischenko V, Nguyen C, Abramov V, Zav’yalov V. Three-dimensional structure of the human myeloma IgG2. PLoS One 2013; 8:e64076.
54. Azeredo da Silveira S, Kikuchi S, Fossati-Jimack L, Moll T, Saito T, Verbeek JS, et al. Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high affinity anti-erythrocyte autoantibody. J Exp Med 2002; 195:665-672.
55. Cetre C, Pierrot C, Cocude C, Lafitte S, Capron A, Capron M, et al. Profiles of Th1 and Th2 cytokines after primary and secondary infection by Schistosoma mansoni in the semipermissive rat host. Infect Immun 1999; 67:2713-2719.
56. Gracie JA, Bradley JA. Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody subclass. Eur J Immunol 1996; 26:1217-1221.
57. Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev 2003; 8:223-246.
58. Liu S, Shi D, Wang HC, Yu YZ, Xu Q, Sun ZW. Co-immunization with DNA and protein mixture: a safe and efficacious immunotherapeutic strategy for Alzheimer’s disease in PDAPP mice. Sci Rep 2015; 5:7771.
59. Chang EH, Volpe BT, Mackay M, Aranow C, Watson P, Kowal C, et al. Selective impairment of spatial cognition caused by autoantibodies to the N-methyl-D-aspartate receptor. EBioMedicine 2015; 2:755-764.
60. Chalmers SA, Wen J, Shum J, Doerner J, Herlitz L, Putterman C. CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus. Clin Immunol 2017; 185:100-108.