Borthwick, Nicola Joy; (1995) T cell functional defects in HIV-1 infection. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The activation response of T lymphocytes was investigated and compared in HIV-1 infected and uninfected individuals and patients with acute viral infections (AVI). A spontaneous cell death was seen in unstimulated T cells from AVI patients and to a lesser extent in HIV-1 infection. This spontaneous death occurred by apoptosis, associated with a decrease in CD3+ T cells expressing Bcl-2, a protein that blocks apoptosis. Bcl-2 negative lymphocytes expressed CD45RO, a marker of primed T cells that is greatly increased during viral infections. After activation, CD45RA+ T cells from HIV-1- individuals lost Bcl-2 expression as the T cells acquired CD45RO, indicting that the loss of Bcl-2 may occur as a normal consequence of acute stimulation, providing a mechanism for the removal of effector T cells. The presence of IL-2 greatly reduced spontaneous cell death, indicating the absolute requirement for IL-2 of this vulnerable population. Cell death in HIV-1 infection was greatly increased after mitogenic stimulation. Activation associated death did not correlate with Bcl-2 expression and could not be prevented by IL-2. In addition, it did not appear to occur by apoptosis. This proliferative defect was due to the absence of the co-stimulatory molecule, CD28, on CD3+, CD8+ T cells. This increased CD3+, CD8+, CD28- population expressed the activation markers CD45RO, HLA-DR and CD38 and was responsible for the CD8+ lymphocytosis observed throughout the course of HIV-1 disease. The CD28- T cells did not lack expression of Bcl-2 but did contain the cytotoxic granule proteins TIA-1 and perforin. Indeed, CD8+ T cells from HIV-1+ individuals were highly cytolytic in a redirected killing assay, indicating that this population may be terminally differentiated cytotoxic effector cells. Cell death after stimulation may be an abortive response that occurs because of the absence of a second signal normally provided through CD28.

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