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Title: Mechanisms underlying immunomodulation of HIV-1-specific T-cell responses
Author: Herasimtschuk, Anna Aracely
ISNI:       0000 0004 2732 614X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Highly active antiretroviral therapy (HAART) improves morbidity and mortality in HIV-1-infected patients yet reversal of immune dysfunction remains incomplete. The study objective was to determine the impact of immunomodulatory agents on T-cell function and phenotype in treated, chronic HIV-1 infection. Recombinant human growth hormone (rhGH) was administered daily to patients at a pharmacological dose for 12 weeks. Proliferative CD4 and IFN-γ-producing CD8 HIV- 1-specific T-cell responses were induced, however these responses declined with less frequent dosing. In a further study, patients that received a lower, physiological dose of rhGH for 40 weeks demonstrated increased IFN-γ ELISpot responses to pools of both MHC Class I and MHC Class II restricted HIV-1 Gag peptides at week 40. T-cell phenotypes showed a trend toward a reduction in the expression of activation markers. A randomised, open-label, phase I clinical trial investigated the effects of therapeutic immunisation, interleukin (IL)-2, granulocyte macrophage colony stimulating factor (GM-CSF) and rhGH in HIV-1+ subjects on HAART. Immunisation plus IL-2, GM-CSF and rhGH administration resulted in increased IFN-γ, IL-2 and perforin production in response to peptide pools of Gag, elevated CD4 T-cell counts and improved CD4/CD8 T-cell ratios at week 48. Subjects that received cytokine and hormone therapy (with or without immunisation) showed reduced immune activation and senescence, and for all patients, exhaustion markers were downregulated by week 48. Distinct Gag- and Nef- specific responses were not found to correlate with particular immunophenotypes. Further analysis of T-cell phenotypes from healthy controls showed immune defects to persist in HIV-1 infection despite HAART, and notwithstanding that, duration of HAART positively correlated with CD4 T-cell count. Together, the data presented here demonstrate the beneficial effects of immunotherapy in treated chronic HIV-1 infection and illustrate the potential to reverse T-cell dysfunction, furthermore highlighting the necessity for the induction and maintenance of HIV-1-specific immune responses.
Supervisor: Imami, Nesrina Sponsor: Medical Research Council ; TaMo Vac ; Chelsea and Westminster Hospital NHS Foundation Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral