Chemistry:AV-HALT

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AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs) are an investigational class of antiretroviral drugs used to treat Human Immunodeficiency Virus (HIV) infection. Unlike other antiretroviral agents given to reduce viral replication, AV-HALTs are single or combination drugs designed to reduce the rate of viral replication while, at the same time, also directly reducing the state of immune system hyperactivation now believed to drive the loss of CD4+ T helper cells leading to disease progression and Acquired Immunodeficiency Syndrome (AIDS).

Mechanism

Chronic immune stimulation due to persistent HIV replication and microbial translocation across impaired gut-associated lymphoid tissues (GALT) induces continuous T-cell activation and proliferation of both HIV-infected and bystander cells, ultimately resulting in the exhaustion of the immune system.[1][2][3][4][5][6]

There is a growing recognition that successful long-term therapy for the treatment of HIV infection should not only reduce viral replication, but also limit the hyper-activation of the immune system now proposed as the cause of the eventual progression to AIDS.[7][8][9][10] AV-HALTs are designed to accomplish two goals – the reduction of viral load (decreased viral load) and the reduction of immune system hyperactivation (decreased markers of cellular activation and proliferation). First generation AV-HALTs accomplish this by combining an antiviral drug (e.g. didanosine) with a cytostatic agent (e.g. hydroxyurea).[11]

Examples

  • VS411, investigational first generation combination AV-HALT (low-dose hydroxyurea + didanosine) (Phase II) - ViroStatics, srl[12]
  • VS1-002, investigational second generation single-drug AV-HALT (Pre-clinical) - ViroStatics, srl[12]

Synonyms

  • virostatics (antiVIRal + cytOSTATICS)

References

  1. ↑ Ameisen, J. C.; Capron, A (1991). "Cell dysfunction and depletion in AIDS: The programmed cell death hypothesis". Immunology Today 12 (4): 102–5. doi:10.1016/0167-5699(91)90092-8. PMID 1676268. 
  2. ↑ McCune, J. M. (2001). "The dynamics of CD4+ T-cell depletion in HIV disease". Nature 410 (6831): 974–9. doi:10.1038/35073648. PMID 11309627. Bibcode: 2001Natur.410..974M. 
  3. ↑ Meyaard, L.; Otto, S. A.; Keet, I. P.; Roos, M. T.; Miedema, F. (1994). "Programmed death of T cells in human immunodeficiency virus infection. No correlation with progression to disease". Journal of Clinical Investigation 93 (3): 982–988. doi:10.1172/JCI117105. PMID 8132784. 
  4. ↑ Grossman, Z; Paul, W. E. (2000). "The impact of HIV on naïve T-cell homeostasis". Nature Medicine 6 (9): 976–7. doi:10.1038/79667. PMID 10973313. 
  5. ↑ Hellerstein, M. K.; Hoh, R. A.; Hanley, M. B.; Cesar, D; Lee, D; Neese, R. A.; McCune, J. M. (2003). "Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection". Journal of Clinical Investigation 112 (6): 956–66. doi:10.1172/JCI17533. PMID 12975480. 
  6. ↑ Finkel, T. H.; Tudor-Williams, G; Banda, N. K.; Cotton, M. F.; Curiel, T; Monks, C; Baba, T. W.; Ruprecht, R. M. et al. (1995). "Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes". Nature Medicine 1 (2): 129–34. doi:10.1038/nm0295-129. PMID 7585008. 
  7. ↑ Brenchley, J. M.; Price, D. A.; Schacker, T. W.; Asher, T. E.; Silvestri, G; Rao, S; Kazzaz, Z; Bornstein, E et al. (2006). "Microbial translocation is a cause of systemic immune activation in chronic HIV infection". Nature Medicine 12 (12): 1365–71. doi:10.1038/nm1511. PMID 17115046. 
  8. ↑ Douek, D. C. (2003). "Disrupting T-cell homeostasis: How HIV-1 infection causes disease". AIDS Reviews 5 (3): 172–7. PMID 14598566. 
  9. ↑ Hunt, P. W.; Martin, J. N.; Sinclair, E; Bredt, B; Hagos, E; Lampiris, H; Deeks, S. G. (2003). "T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy". The Journal of Infectious Diseases 187 (10): 1534–43. doi:10.1086/374786. PMID 12721933. 
  10. ↑ Kaufmann, G. R.; Perrin, L; Pantaleo, G; Opravil, M; Furrer, H; Telenti, A; Hirschel, B; Ledergerber, B et al. (2003). "CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: The Swiss HIV Cohort Study". Archives of Internal Medicine 163 (18): 2187–95. doi:10.1001/archinte.163.18.2187. PMID 14557216. 
  11. ↑ Lori, F.; Foli, A.; Groff, A.; Lova, L.; Whitman, L.; Bakare, N.; Pollard, R.; Lisziewicz, J. (2005). "Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ('virostatic') mechanisms". AIDS 19 (11): 1173–1181. doi:10.1097/01.aids.0000176217.02743.d1. PMID 15990570. 
  12. ↑ 12.0 12.1 "Research and Development". ViroStatics. Archived from the original on 2011-07-17. https://web.archive.org/web/20110717215100/http://www.virostatics.com/research.htm. Retrieved 2011-09-22. 



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