Whole_SULLIVAN_MD_THESIS_FINAL_NOVEMBER_2011.pdf (2.21 MB)
Immune reconstitution in HIV-1 infection : the effects of antiretroviral and immune therapy
thesisposted on 2023-05-28, 05:18 authored by Sullivan, AK
This thesis presents findings from two randomised, controlled pilot studies, with nested sub-studies, an observational study, a compassionate release programme and a mortality audit. It aims to examine the effects, at a clinical and cellular level, of antiretroviral and immunotherapy in HIV-1 infection. Combination antiretroviral therapy (cART) enables quantitative and a degree of qualitative immune recovery; however this is neither universal nor complete. The first part of the thesis explores the effects of cART on surrogate immune markers (SIM), treatment outcomes, disease progression and death. Significant variations are observed and further re-inforced by the mortality audit. I describe for the first time patterns of SIM decline and treatment response from which a model predicting treatment outcome could be developed. This section concludes with an observational study describing a differential effect on immune restoration of different classes of cART. Together this data suggests additional therapeutic interventions will be required to address the current inadequacies of cART to fully restore HIV-1 associated immune deficiencies. Therefore, the second part of the thesis examines the effect of interleukin-2 (IL-2) therapy in different settings; with and without cART, with therapeutic immunisation and in advanced disease. In the absence of cART, IL-2 increased CD4 T-cell counts without adversely affecting viral load or immune activation, potentially delaying the need for cART initiation. The compassionate release programme also demonstrated a 'delaying' effect which could be exploited in patients awaiting new therapies. The main therapeutic intervention study involved IL-2 and therapeutic immunisation in the context of cART, and reports novel findings of the acute effects of IL-2, including induction of HIV-1 specific responses. Overall increases were observed in CD4+, CD4+CD28+ and CD4+CD25+ T-cells, the latter being of particular interest as the precise function of these cells in HIV-1 infection and following IL-2 therapy is still to be fully defined. As a pilot study these findings are preliminary but there is a trend for several effects to be more marked and more sustained in the arm combing all three treatments; suggesting therapeutic potential for combination immunisation and cytokine therapy which is worth pursuing. Despite the fact that the final IL-2 study in this thesis was completed in 2003, the recent publication of two large clinical outcome studies of IL-2, with somewhat unexpected results, makes these findings all the more pertinent today, and may afford some insight into the negative results observed in these large phase three trials. In summary, cART results in incomplete immune reconstitution, which can be enhanced by IL-2 and therapeutic immunisation at a cellular level. The challenge is to determine how, if at all, this can be translated into clinical benefit. Using additional SIM may help in targeting and monitoring therapy; the timing, scheduling and combination of which will be key and warrants further investigation.
Rights statementCopyright Copyright 2011 the author Chapter 3 appears to be, in part, the equivalent of the pre-peer reviewed version of the following article: Sullivan, A. K., Burton, C. T., Nelson, M. R., Moyle, G., Mandalia, S., Gotch, F. M., Gazzard, B. G., Imami, N., 2003. Restoration of human immunodeficiency virus‚ÄövÑv™1‚ÄövÑv™specific responses in patients changing from protease to non‚ÄövÑv™nucleoside reverse transcriptase inhibitor‚ÄövÑv™based antiretroviral therapy, Scandinavian journal of immunology, 57(6), 600-607, which has been published in final form at https://doi.org/10.1046/j.1365-3083.2003.01276.x This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. The appendix contains what appears to be the equivalent of a post-print version of an article published as: Sullivan, A. K., Hardy, G. A. D., Nelson, M. R., Gotch, F., Gazzard, B. G., Imami, N., 2003. Interleukin-2 associated viral breakthroughs induce HIV-1-specific CD4 T-cell responses in patients on HAART, AIDS, 2003; 17(4), 628-629. It is not the final published version