AIDS Dementia Is Associated with Massive, Activated HIV-1 Infection and Concomitant Expression of Several Cytokines (original) (raw)

Abstract

Background

We recently showed that acquired immunodeficiency syndrome (AIDS) dementia is associated with activated infection of microglia, neurons, and astrocytes by HIV-1. However, it is doubtful whether infection per se is responsible for the dramatic symptoms associated with AIDS dementia. The purpose of this study was to determine the histologic distribution of messenger RNAs (mRNAs) of several cytokines that have been implicated in AIDS pathogenesis and to correlate this expression pattern with the in situ localization of polymerase chain reaction (PCR)-amplified HIV-1 nucleic acids in the central nervous system (CNS).

Materials and Methods

HIV-1 DNA was detected by PCR in situ hybridization. HIV-1 RNA and cytokine expression, including tumor necrosis factor α (TNF), inducible nitric oxide synthetase (iNOS), and macrophage inflammatory protein α (MIP-1_α_) and MIP-1_β_ mRNA were detected by reverse transcriptase (RT) in situ PCR.

Results

Amplified viral DNA was detected in each of the seven HIV-1-positive cases and in none of the five negative controls. In people with AIDS dementia, many HIV-1 DNA-positive cells were detected in regions of the CNS that corresponded to clinical symptomatology. In AIDS patients with minimal CNS involvement, rare HIV-1-infected microglial cells were noted. Viral RNA was detected primarily in cases of AIDS dementia. TNF, iNOS, MIP-1_α_ and MIP-1_β_ expression localized to tissues from AIDS dementia cases where HIV-1 infected cells were plentiful. Colocalization experiments showed that these cytokines were transcribed mostly by viral-negative cells.

Conclusions

These results suggest that two key elements in AIDS dementia are massive productive viral infection, involving microglia, neurons, and astrocytes, and concomitant stimulation of cytokine transcription in the neighboring uninfected cells.

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References

  1. Price RW, Brew B, Sidti J, Rosenblum M, Scheck AC, Cleary P. (1988) The brain in AIDS: Central nervous system HIV-1 infection and AIDS dementia complex. Science 239:586–592.
    Article CAS PubMed Google Scholar
  2. Grant I, Atkinson JH, Hesselink JR. (1987) Evidence for early central nervous system involvement in acquired immunodeficiency syndrome and other human immunodeficiency virus infections. Ann. Intern. Med. 107: 828–836.
    Article CAS PubMed Google Scholar
  3. Weiser B, LaNeve D, Eilbott DJ, Seidman R, Burger H. (1990) Human immunodeficiency virus type 1 expression in the central nervous system correlates directly with extent of disease. Proc. Natl. Acad. Sci. U.S.A. 87: 3997–4001.
    Article CAS PubMed PubMed Central Google Scholar
  4. Wiley CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MBA. (1986) Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc. Natl. Acad. Sci. U.S.A. 83:7089–7093.
    Article CAS PubMed PubMed Central Google Scholar
  5. Tornatore C, Nath A, Amemiya K, Major EO. (1990) Persistent human immunodeficiency virus type 1 infection in human fetal glial cells reactivated by T-cell factor(s) or by the cytokines tumore necrosis factor alpha and interleukin-1 beta. J. Virol. 65:6094–6100.
    Google Scholar
  6. Watkins B, Dorn H, Kelley H, et al. (1990) Specific tropism of HIV-1 for microglial cells in primary human brain cultures. Science 249:549–553.
    Article CAS PubMed Google Scholar
  7. Cvetkovich TA, Lazar E, Blumberg BM, et al. (1992) Human immunodeficiency virus type 1 infection of neural xenografts. Proc. Natl. Acad. Sci. U.S.A. 89:5162–5166.
    Article CAS PubMed PubMed Central Google Scholar
  8. Harouse JM, Bhat S, Spitalnik SL, et al. (1991) Inhibition of entry of HIV-1 in neural cell lines by antibodies against galactosyl ceramide. Science 253:320–322.
    Article CAS PubMed Google Scholar
  9. Nuovo GJ, Gallery F, MacConnell P, Braun A. (1994) In situ detection of PCR-amplified HIV-1 nucleic acids and tumor necrosis factor RNA in the central nervous system. Am. J. Pathol. 144:659–666.
    PubMed PubMed Central CAS Google Scholar
  10. Lipton SA. (1991) HIV-1 related neurotoxicity. Brain Pathol. 1:193–199.
    Article CAS PubMed Google Scholar
  11. Yamada M, Zurbriggen A, Oldstone M, Fujinami R. (1991) Common immunologic determinant between human immunodeficiency virus type 1 gp41 and astrocytes. J. Virol. 65:1370–1376.
    PubMed PubMed Central CAS Google Scholar
  12. Dubrovsky L, Ulrich P, Nuovo GJ, Manogue KR, Cerami A, Burkinsky M. (1995) Nuclear localization signal of HIV-1 as a novel target for therapeutic intervention. Mol. Med. 1:217–230.
    Article PubMed PubMed Central CAS Google Scholar
  13. Schmidtmayerova H, Notte HS, Nuovo GJ, et al. (in press) HIV-1 infection alters chemokine β peptide expression in human monocytes: Implications for recruitment of leukocytes into brain and lymph nodes. Proc. Natl. Acad. Sci. U.S.A. (In press).
  14. Nuovo GJ. (1994) PCR in Situ Hybridization: Protocols and Applications. 2nd Ed., Raven Press, New York.
    Google Scholar
  15. Nuovo GJ, Becker J, Margiotta M, Burke M, Fuhrer J, Steigbigel R. (1994) In situ detection of PCR-amplified HIV-1 nucleic acids in lymph nodes and peripheral blood in asymptomatic infection and advanced stage AIDS. J. Acquir. Immune Defic. 7:916–923.
    CAS Google Scholar
  16. Bagasra O, Hauptman SP, Lischer HW, Sachs M, Pomerantz RJ. (1992) Detection of human immunodeficiency virus type 1 provirus in mononuclear cells by in situ polymerase chain reaction. N. Engl. J. Med. 326:1385–1391.
    Article CAS PubMed Google Scholar
  17. Nuovo GJ, Forde A. (1995) An improved system for reverse transcriptase in situ PCR. J. Histotech. 18:295–299.
    Article CAS Google Scholar
  18. Seshamma P, Bagasra O, Oakes J, Pomerantz RJ. (1992) Quantitative RT PCR for HIV-1 RNA specific species. J. Virol. Methods 40:331–346.
    Article CAS PubMed Google Scholar
  19. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH. (1991) Nitic oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl. Acad. Sci. U.S.A. 88:6368–6371.
    Article CAS PubMed PubMed Central Google Scholar
  20. Buttery LDK, Evans TJ, Cohen J, Polak JM. (1994) Immunohistochemical localization of inducible nitric oxide synthetase in endotoxin treated rats. Lab. Invest. 71:755–764.
    PubMed CAS Google Scholar
  21. Huang Z, Huang PL, Dalkara T, Fishman MC, Moskowitz MA. (1994) Effect of cerebral ischemia in mice deficient in neuronla nitic oxide synthetase. Science 265:1883–1885.
    Article CAS PubMed Google Scholar

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Acknowledgements

This work was supported by grants from the Lewis Foundation, the Perkin-Elmer Corporation, and the Center for Biotechnology of the State of New York (GJN).

I greatly appreciate the technical assistance of Ms. Angella Forde. I thank Dr. Micheal Bukrinsky for a critical review of the manuscript. I especially appreciate the strong interest of Mr. Salim B. Lewis in the in situ PCR technology and HIV-1 infection.

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Authors and Affiliations

  1. Department of Pathology, State University of New York at Stony Brook, Stony Brook, New York, 11794-8691, USA
    Gerard J. Nuovo & Maria Lynn Alfieri

Authors

  1. Gerard J. Nuovo
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  2. Maria Lynn Alfieri
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  3. A. Cerami
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Nuovo, G.J., Alfieri, M.L. & Cerami, A. AIDS Dementia Is Associated with Massive, Activated HIV-1 Infection and Concomitant Expression of Several Cytokines.Mol Med 2, 358–366 (1996). https://doi.org/10.1007/BF03401633

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