Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection

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Early HIV-1 CNS replication likely provides a foundation for brain injury and a potentially important tissue reservoir. To explore the character and timing of emergence of early HIV-1 CNS replication, we examined paired cerebrospinal fluid (CSF) and blood samples from 72 ART-naïve adults, with one-half having longitudinal samples, during the first two years following HIV-1 subtype B infection. In a cross sectional analysis over the first two years of infection, 10–25% of subjects had evidence of either local viral replication in the CNS, defined by the presence of CSF compartmentalization, or a robust inflammatory response, and in approximately 16% of subjects this CNS involvement persisted over time. In some subjects, one of two transmitted viruses replicated predominantly within the CNS, providing insight into how HIV-1 can establish independently replicating populations early in different parts of the body. Based on their entry phenotype, all viruses were selected for replication in CD4+ T cells, although this phenotype was slightly altered in the compartmentalized virus. Overall, we suggest four states to model the nature of HIV-1 CNS infection, which imply distinct mechanisms of virus/host interaction within the CNS during early infection.

Vyšlo v časopise: Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004720
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004720

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Zdroje

1. Pilcher CD, Shugars DC, Fiscus SA, Miller WC, Menezes P, et al. (2001) HIV in body fluids during primary HIV infection: implications for pathogenesis, treatment and public health. AIDS 15 : 837–845. 11399956

2. Enting RH, Prins JM, Jurriaans S, Brinkman K, Portegies P, et al. (2001) Concentrations of human immunodeficiency virus type 1 (HIV-1) RNA in cerebrospinal fluid after antiretroviral treatment initiated during primary HIV-1 infection. Clin Infect Dis 32 : 1095–1099. 11264039

3. Tambussi G, Gori A, Capiluppi B, Balotta C, Papagno L, et al. (2000) Neurological symptoms during primary human immunodeficiency virus (HIV) infection correlate with high levels of HIV RNA in cerebrospinal fluid. Clin Infect Dis 30 : 962–965. 10880317

4. Schnell G, Price RW, Swanstrom R, Spudich S (2010) Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol 84 : 2395–2407. doi: 10.1128/JVI.01863-09 20015984

5. Spudich S, Gisslen M, Hagberg L, Lee E, Liegler T, et al. (2011) Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis 204 : 753–760. doi: 10.1093/infdis/jir387 21844301

6. Davis LE, Hjelle BL, Miller VE, Palmer DL, Llewellyn AL, et al. (1992) Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology 42 : 1736–1739. 1513462

7. Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, et al. (2012) Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis 206 : 275–282. doi: 10.1093/infdis/jis326 22551810

8. Ances BM, Ellis RJ (2007) Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol 27 : 86–92. 17226745

9. Fischer-Smith T, Rappaport J (2005) Evolving paradigms in the pathogenesis of HIV-1-associated dementia. Expert Rev Mol Med 7 : 1–26.

10. Harrington PR, Schnell G, Letendre SL, Ritola K, Robertson K, et al. (2009) Cross-sectional characterization of HIV-1 env compartmentalization in cerebrospinal fluid over the full disease course. Aids 23 : 907–915. doi: 10.1097/QAD.0b013e3283299129 19414991

11. Ohagen A, Devitt A, Kunstman KJ, Gorry PR, Rose PP, et al. (2003) Genetic and functional analysis of full-length human immunodeficiency virus type 1 env genes derived from brain and blood of patients with AIDS. J Virol 77 : 12336–12345. 14581570

12. Dunfee RL, Thomas ER, Gorry PR, Wang J, Taylor J, et al. (2006) The HIV Env variant N283 enhances macrophage tropism and is associated with brain infection and dementia. Proc Natl Acad Sci U S A 103 : 15160–15165. 17015824

13. Schnell G, Spudich S, Harrington P, Price RW, Swanstrom R (2009) Compartmentalized human immunodeficiency virus type 1 originates from long-lived cells in some subjects with HIV-1-associated dementia. PLoS Pathog 5: e1000395. doi: 10.1371/journal.ppat.1000395 19390619

14. Sturdevant CB, Dow A, Jabara CB, Joseph SB, Schnell G, et al. (2012) Central nervous system compartmentalization of HIV-1 subtype C variants early and late in infection in young children. PLoS Pathog 8: e1003094. doi: 10.1371/journal.ppat.1003094 23300446

15. Drummond AJ, Rambaut A (2007) BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evol Biol 7 : 214. 17996036

16. Ping LH, Joseph SB, Anderson JA, Abrahams MR, Salazar-Gonzalez JF, et al. (2013) Comparison of Viral Env Proteins From Acute and Chronic Infections of Subtype C Human Immunodeficiency Virus Type 1 Identifies Differences In Glycosylation and CCR5 Utilization and Suggests A New Strategy For Immunogen Design. J Virol.

17. Zarate S, Pond SLK, Shapshak P, Frost SDW (2007) Comparative study of methods for detecting sequence compartmentalization in human immunodeficiency virus type 1. Journal of Virology 81 : 6643–6651. 17428864

18. Slatkin M, Maddison WP (1989) A cladistic measure of gene flow inferred from the phylogenies of alleles. Genetics 123 : 603–613. 2599370

19. Hudson RR, Boos DD, Kaplan NL (1992) A Statistical Test for Detecting Geographic Subdivision. Molecular Biology and Evolution 9 : 138–151. 1552836

20. Hudson RR, Slatkin M, Maddison WP (1992) Estimation of levels of gene flow from DNA sequence data. Genetics 132 : 583–589. 1427045

21. Hudson RR (2000) A new statistic for detecting genetic differentiation. Genetics 155 : 2011–2014. 10924493

22. Fishman RA (1992) Cerebrospinal fluid in diseases of the nervous system, 2nd ed. Philadelphia, PA: W. B. Saunders Company.

23. Ho EL, Ronquillo R, Altmeppen H, Spudich SS, Price RW, et al. (2013) Cellular Composition of Cerebrospinal Fluid in HIV-1 Infected and Uninfected Subjects. PLoS One 8: e66188. 23822975

24. Rossi F, Querido B, Nimmagadda M, Cocklin S, Navas-Martin S, et al. (2008) The V1-V3 region of a brain-derived HIV-1 envelope glycoprotein determines macrophage tropism, low CD4 dependence, increased fusogenicity and altered sensitivity to entry inhibitors. Retrovirology 5 : 89. doi: 10.1186/1742-4690-5-89 18837996

25. Thomas ER, Dunfee RL, Stanton J, Bogdan D, Taylor J, et al. (2007) Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion. Virology 360 : 105–119. 17084877

26. Gorry PR, Taylor J, Holm GH, Mehle A, Morgan T, et al. (2002) Increased CCR5 affinity and reduced CCR5/CD4 dependence of a neurovirulent primary human immunodeficiency virus type 1 isolate. J Virol 76 : 6277–6292. 12021361

27. Alexander M, Lynch R, Mulenga J, Allen S, Derdeyn CA, et al. (2010) Donor and recipient envs from heterosexual human immunodeficiency virus subtype C transmission pairs require high receptor levels for entry. J Virol 84 : 4100–4104. doi: 10.1128/JVI.02068-09 20147398

28. Parrish NF, Wilen CB, Banks LB, Iyer SS, Pfaff JM, et al. (2012) Transmitted/founder and chronic subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin alpha4beta7. PLoS Pathog 8: e1002686. doi: 10.1371/journal.ppat.1002686 22693444

29. Dunfee R, Thomas ER, Gorry PR, Wang J, Ancuta P, et al. (2006) Mechanisms of HIV-1 neurotropism. Curr HIV Res 4 : 267–278. 16842080

30. Duenas-Decamp MJ, Peters PJ, Burton D, Clapham PR (2009) Determinants flanking the CD4 binding loop modulate macrophage tropism of human immunodeficiency virus type 1 R5 envelopes. J Virol 83 : 2575–2583. doi: 10.1128/JVI.02133-08 19129457

31. Martin-Garcia J, Cao W, Varela-Rohena A, Plassmeyer ML, Gonzalez-Scarano F (2006) HIV-1 tropism for the central nervous system: Brain-derived envelope glycoproteins with lower CD4 dependence and reduced sensitivity to a fusion inhibitor. Virology 346 : 169–179. 16309726

32. Johnston SH, Lobritz MA, Nguyen S, Lassen K, Delair S, et al. (2009) A quantitative affinity-profiling system that reveals distinct CD4/CCR5 usage patterns among human immunodeficiency virus type 1 and simian immunodeficiency virus strains. J Virol 83 : 11016–11026. doi: 10.1128/JVI.01242-09 19692480

33. Joseph SB, Arrildt KT, Swanstrom AE, Schnell G, Lee B, et al. (2013) Quantification of Entry Phenotypes of Macrophage-Tropic HIV-1 Across a Wide Range of CD4 Densities. J Virol.

34. Salazar-Gonzalez JF, Salazar MG, Keele BF, Learn GH, Giorgi EE, et al. (2009) Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J Exp Med 206 : 1273–1289. doi: 10.1084/jem.20090378 19487424

35. Isaacman-Beck J, Hermann EA, Yi Y, Ratcliffe SJ, Mulenga J, et al. (2009) Heterosexual transmission of human immunodeficiency virus type 1 subtype C: Macrophage tropism, alternative coreceptor use, and the molecular anatomy of CCR5 utilization. J Virol 83 : 8208–8220. doi: 10.1128/JVI.00296-09 19515785

36. Li H, Bar KJ, Wang S, Decker JM, Chen Y, et al. (2010) High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men. PLoS Pathog 6: e1000890. doi: 10.1371/journal.ppat.1000890 20485520

37. Ochsenbauer C, Edmonds TG, Ding H, Keele BF, Decker J, et al. (2012) Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages. J Virol 86 : 2715–2728. doi: 10.1128/JVI.06157-11 22190722

38. Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, et al. (2008) Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 105 : 7552–7557. doi: 10.1073/pnas.0802203105 18490657

39. Wilen CB, Parrish NF, Pfaff JM, Decker JM, Henning EA, et al. (2011) Phenotypic and immunologic comparison of clade B transmitted/founder and chronic HIV-1 envelope glycoproteins. J Virol 85 : 8514–8527. doi: 10.1128/JVI.00736-11 21715507

40. Ritola K, Robertson K, Fiscus SA, Hall C, Swanstrom R (2005) Increased human immunodeficiency virus type 1 (HIV-1) env compartmentalization in the presence of HIV-1-associated dementia. J Virol 79 : 10830–10834. 16051875

41. Schnell G, Joseph S, Spudich S, Price RW, Swanstrom R (2011) HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog 7: e1002286. doi: 10.1371/journal.ppat.1002286 22007152

42. Alexaki A, Liu Y, Wigdahl B (2008) Cellular reservoirs of HIV-1 and their role in viral persistence. Curr HIV Res 6 : 388–400. 18855649

43. Pomerantz RJ (2003) Reservoirs, sanctuaries, and residual disease: the hiding spots of HIV-1. HIV Clin Trials 4 : 137–143. 12671782

44. Spudich SS, Nilsson AC, Lollo ND, Liegler TJ, Petropoulos CJ, et al. (2005) Cerebrospinal fluid HIV infection and pleocytosis: relation to systemic infection and antiretroviral treatment. BMC Infect Dis 5 : 98. 16266436

45. Price RW, Peterson J, Fuchs D, Angel TE, Zetterberg H, et al. (2013) Approach to Cerebrospinal Fluid (CSF) Biomarker Discovery and Evaluation in HIV Infection. J Neuroimmune Pharmacol 8 : 1147–1158. doi: 10.1007/s11481-013-9491-3 23943280

46. Smith DM, Zarate S, Shao H, Pillai SK, Letendre SL, et al. (2009) Pleocytosis is associated with disruption of HIV compartmentalization between blood and cerebral spinal fluid viral populations. Virology 385 : 204–208. doi: 10.1016/j.virol.2008.11.010 19100592

47. Anderson JA, Ping LH, Dibben O, Jabara CB, Arney L, et al. (2010) HIV-1 Populations in Semen Arise through Multiple Mechanisms. PLoS Pathog 6: e1001053. doi: 10.1371/journal.ppat.1001053 20808902

48. Shaheen F, Sison AV, McIntosh L, Mukhtar M, Pomerantz RJ (1999) Analysis of HIV-1 in the cervicovaginal secretions and blood of pregnant and nonpregnant women. J Hum Virol 2 : 154–166. 10413367

49. Kemal KS, Foley B, Burger H, Anastos K, Minkoff H, et al. (2003) HIV-1 in genital tract and plasma of women: compartmentalization of viral sequences, coreceptor usage, and glycosylation. Proc Natl Acad Sci U S A 100 : 12972–12977. 14557540

50. Bull ME, Heath LM, McKernan-Mullin JL, Kraft KM, Acevedo L, et al. (2013) Human immunodeficiency viruses appear compartmentalized to the female genital tract in cross-sectional analyses but genital lineages do not persist over time. J Infect Dis 207 : 1206–1215. doi: 10.1093/infdis/jit016 23315326

51. Gisslen M, Hagberg L, Rosengren L, Brew BJ, Cinque P, et al. (2007) Defining and evaluating HIV-related neurodegenerative disease and its treatment targets: a combinatorial approach to use of cerebrospinal fluid molecular biomarkers. J Neuroimmune Pharmacol 2 : 112–119. 18040834

52. Eden A, Price RW, Spudich S, Fuchs D, Hagberg L, et al. (2007) Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy. J Infect Dis 196 : 1779–1783. doi: 10.1086/523648 18190258

53. Harrington PR, Connell MJ, Meeker RB, Johnson PR, Swanstrom R (2007) Dynamics of simian immunodeficiency virus populations in blood and cerebrospinal fluid over the full course of infection. J Infect Dis 196 : 1058–1067. 17763329

54. Edgar RC (2004) MUSCLE: a multiple sequence alignment method with reduced time and space complexity. Bmc Bioinformatics 5 : 1–19. 14706121

55. Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Research 32 : 1792–1797. 15034147

56. Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22 : 4673–4680. 7984417

57. McWilliam H, Li WZ, Uludag M, Squizzato S, Park YM, et al. (2013) Analysis Tool Web Services from the EMBL-EBI. Nucleic Acids Research 41: W597–W600. doi: 10.1093/nar/gkt376 23671338

58. Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 24 : 1596–1599. 17488738

59. O'Doherty U, Swiggard WJ, Malim MH (2000) Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding. Journal of Virology 74 : 10074–10080. 11024136

60. Gartner S, Markovits P, Markovitz DM, Kaplan MH, Gallo RC, et al. (1986) The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233 : 215–219. 3014648

61. Koyanagi Y, Miles S, Mitsuyasu RT, Merrill JE, Vinters HV, et al. (1987) Dual infection of the central-nervous-system by AIDS viruses with distinct cellular tropisms. Science 236 : 819–822. 3646751

62. Joseph SB, Arrildt KT, Swanstrom AE, Schnell G, Lee B, et al. (2014) Quantification of entry phenotypes of macrophage-tropic HIV-1 across a wide range of CD4 densities. Journal of Virology 88 : 1858–1869. doi: 10.1128/JVI.02477-13 24307580