Progress and challenges in the use of latent HIV-1 reactivating agents

Acta Pharmacol Sin. 2015 Aug;36(8):908-16. doi: 10.1038/aps.2015.22. Epub 2015 Jun 1.

Abstract

Highly active antiretroviral therapy (HAART) can effectively suppress the replication of human immunodeficiency virus-1 (HIV-1) and block disease progression. However, chronic HIV-1 infection remains incurable due to the persistence of a viral reservoir, including the transcriptionally silent provirus in CD4(+) memory T cells and the sanctuary sites that are inaccessible to drugs. Reactivation and the subsequent elimination of latent virus through virus-specific cytotoxic effects or host immune responses are critical strategies for combating the disease. Indeed, a number of latency reactivating reagents have been identified through mechanism-directed approaches and large-scale screening, including: (1) histone deacetylase inhibitors (HDACi); (2) cytokines and chemokines; (3) DNA methyltransferase inhibitors (DNMTI); (4) histone methyltransferase inhibitors (HMTI); (5) protein kinase C (PKC) activators; (6) P-TEFb activators; and (7) unclassified agents, such as disulfram. They have proved to be efficacious in latent cell line models and CD4(+) T lymphocytes from HIV-1-infected patients. This review comprehensively summarizes the recent progress and relative challenges in this field.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-HIV Agents / pharmacology
  • Anti-HIV Agents / therapeutic use*
  • CD4-Positive T-Lymphocytes / virology
  • Cytokines / pharmacology
  • Cytokines / therapeutic use
  • DNA Modification Methylases / antagonists & inhibitors
  • HIV Infections / drug therapy*
  • HIV Infections / virology*
  • HIV-1 / drug effects*
  • HIV-1 / physiology*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / therapeutic use
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Humans
  • Virus Latency / drug effects*

Substances

  • Anti-HIV Agents
  • Cytokines
  • Histone Deacetylase Inhibitors
  • DNA Modification Methylases
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase