[Truncated abstract] Failure to fully reconstitute the immune system is a common clinical problem in HIV patients who were severely immunodeficient before responding to combination antiretroviral therapy (CART). This can manifest as a deficiency in the number or function of CD4+ T-cells and occurs most often in patients who had a nadir CD4+ T-cell count below 100/μl when CART was commenced. Observational studies of large cohorts of HIV patients, such as the D:A:D study, have demonstrated that patients with low CD4+ T-cell counts have increased rates of death compared with patients who have normal CD4+ T-cell counts. Furthermore, individual case studies suggest that impaired recovery of pathogen-specific immune responses during CART is associated with opportunistic infections or disease progression. This thesis addresses possible causes of deficiencies in CD4+ T-cell number or function in HIV patients who were very immunodeficient prior to treatment and are responding (virologically) to CART. Firstly, the role of the thymus in producing naive CD4+ T-cells and the effects of persistent immune activation on the recovery of CD4+ T-cell numbers were assessed in patients with either low or high CD4+ T-cell counts after long-term CART. ... Proportions of antigen presenting cell (APC) subpopulations were examined in HIV patients with low or high CMV-specific CD4+ T-cell responses after long-term CART. HIV patients had significantly lower proportions of plasmacytoid dendritic cells (pDC) than HIV-negative controls. Furthermore, the proportions of pDC were positively correlated with CMV-specific CD4+ T-cell responses in HIV patients. Proportions of myeloid dendritic cells (mDC) were significantly higher in HIV patients than controls, and were also increased in patients with low CMV-specific CD4+ T-cell responses. Proportions of M-DC8+ dendritic cells or CD14+ monocytes did not differ between patients and controls, nor were they associated with CMV-specific CD4+ T-cell responses. Quantitation of cytokine (interferon-α, tumour necrosis factor-α, interleukin (IL) -12, IL-23, IL-15, IL-18 and IL-10) mRNA in unstimulated, purified populations of the APC described above revealed few significant differences between patients with low or high CD4+ T-cell IFN-γ responses to CMV. The only notable difference was the slight elevation of IL-15 mRNA levels in patients compared to controls. Since patients in the high responder group had the highest levels of IL-15 mRNA, this association may reflect the anti-apoptotic properties of IL-15. These studies provide valuable insights into the causes of persistent CD4+ T-cell deficiency and dysfunction in HIV patients on CART and may lead to better monitoring and treatments.
| Identifer | oai:union.ndltd.org:ADTP/221395 |
| Date | January 2007 |
| Creators | Fernandez, Sonia |
| Publisher | University of Western Australia. School of Surgery and Pathology |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Sonia Fernandez, http://www.itpo.uwa.edu.au/UWA-Computer-And-Software-Use-Regulations.html |
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