Mechanisms Underlying Immunomodulation of HIV-1-Specific T-cell Responses
Author(s)
Herasimtschuk, Anna Aracely
Type
Thesis
Abstract
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.
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.
Date Issued
2012-05
Date Awarded
2012-12
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Imami, Nesrina
Sponsor
Medical Research Council (Great Britain) ; TaMo Vac ; Chelsea and Westminster Hospital NHS Foundation Trust
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)