title: Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs.
abstract: BACKGROUND
  Treatments combining T-cell activating agents and potent antiretroviral drugs have been proposed as a possible means of reducing the reservoir of long-lived HIV-1 infected quiescent CD4 T-cells.
  
  
  OBJECTIVE
  To analyse the effect of such therapies on HIV-1 dynamics and T-cell homeostasis.
  
  
  METHODS
  A mathematical framework describing HIV-1 dynamics and T-cell homeostasis was developed. Three patients who were kept on a particularly potent course of highly active antiretroviral therapy (HAART) were treated with the anti-CD3 monoclonal antibody OKT3 and interleukin (IL)-2. Plasma HIV-RNA, and HIV-RNA and DNA in peripheral blood mononuclear cells and lymph node mononuclear cells were measured. These results and other published studies on the use of IL-2 alone were assessed using our mathematical framework.
  
  
  RESULTS
  We show that outcome of treatment is determined by the relative rates of depletion of the infected quiescent T-cell population by activation and of its replenishment through new infection. Which of these two processes dominates is critically dependent on both the potency of HAART and also the degree of T-cell activation induced. We demonstrate that high-level T-cell stimulation is likely to produce negative outcomes, both by failing to reduce viral reservoirs and by depleting the CD4 T-cell pool and disrupting CD4/CD8 T-cell homeostasis. In contrast, repeated low-level stimulation may both aid CD4 T-cell pool expansion and achieve a substantial reduction in the long-lived HIV-1 reservoir.
  
  
  CONCLUSIONS
  Our analysis suggests that although treatment that activates T-cells can reduce the long-lived HIV-1 reservoir, caution should be used as high-level stimulation may result in a negative outcome.
authors.affiliation: Wellcome Trust Centre for the Epidemiology of Infectious Disease, University of Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Fraser
authors.forename: N M
authors.initials: NM
authors.lastname: Ferguson
authors.forename: A C
authors.initials: AC
authors.lastname: Ghani
authors.forename: J M
authors.initials: JM
authors.lastname: Prins
authors.forename: J M
authors.initials: JM
authors.lastname: Lange
authors.forename: J
authors.initials: J
authors.lastname: Goudsmit
authors.forename: R M
authors.initials: RM
authors.lastname: Anderson
authors.forename: F
authors.initials: F
authors.lastname: de Wolf
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D004279:DNA, Viral / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008954:Models, Biological; D016853:Muromonab-CD3 / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000627:therapeutic use; D019562:Viral Load; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016853:Muromonab-CD3; D012367:RNA, Viral; D011994:Recombinant Proteins