Early psychomotor slowing predicts the development of HIV dementia and autopsy-verified HIV encephalitis.

OBJECTIVES- To ask if slowed motor speed predicts later human immunodeficiency virus (HIV) dementia and HIV encephalitis. METHODS- In 100 deceased acquired immunodeficiency syndrome (AIDS) patients prior results from repeated testing of the movement reaction time test were correlated with later clinical signs of HIV dementia and with neuropathological signs of HIV encephalitis. Autopsy was performed in 72 patients. RESULTS- Movement reaction time 1-2 years prior to death, or at the time of clinical AIDS diagnosis predicted both development of HIV dementia (P<0.05) and HIV encephalitis at autopsy (P<0.01). CONCLUSION- Testing for early psychomotor slowing may be used to identify patients at risk of HIV dementia and HIV encephalitis.

In vivo expansion coincident with excessive in vitro cell death within the memory subset of CD8+ T cells in HIV type 1 infection.

In HIV-1-infected individuals the CD8+ T cell subset is considerably expanded. This has been shown to be caused predominantly by an increase in the number of CD8+CD28- T cells. To characterize further the subsets of CD8+ T cells, we have performed analyses of cell surface phenotype, T cell receptor Vbeta usage, and ability to survive in unstimulated cultures. CD8+CD28- T cells frequently expressed CD45RA. Nonetheless, coincident expression of CD95 (Fas) and high levels of integrins suggested that these cells were immunologically experienced. Contrary to what has been observed in CD8+CD28- T cells from uninfected individuals, a common hierarchy of Vbeta usage was found in CD8+CD28- T cells from HIV-1-infected individuals, which was adhered to by all the study participants, and which was shown to be similar to that observed within CD8+CD28+ T cells. Cells from the memory subsets of CD8+ T cells showed a high incidence of spontaneous death in unstimulated cultures, indicating that these cells have received signals for death by apoptosis in vivo. In contrast, most naive CD8+CD28+CD45RA+ cells survived. The CD8+CD28- memory subset is expanded in vivo despite evidence for coincident excessive cell death in vitro. Our results are consistent with the notion that frequent transitions occur from the memory CD8+CD28+CD45RA- T cell subset to the end-stage CD8+CD28- subset during HIV-1 infection.

Normal CD4 T-cell receptor repertoire in tonsillar tissue despite perturbed repertoire in peripheral blood in HIV-1 infected individuals.

OBJECTIVE: To compare the T-cell receptor (TCR) repertoire of T-cell subsets in peripheral blood and lymphoid tissue from HIV-1 infected individuals. DESIGN: Biopsies of tonsillar tissue and samples of peripheral blood were obtained from 10, mostly treatment-naive, HIV-1-infected individuals. CD4 and CD8 T-cell subsets were quantified, the TCR repertoire was analysed within 'naive' and 'memory' subsets, and results compared between identical subsets in tonsillar tissue and blood. METHODS: Cell subsets were quantified by flow cytometry. CD4 T cells and CD8 T cells were isolated by immunomagnetic beads. Populations were in most cases further subdivided by immunomagnetic selection on the basis of CD45RO expression. TCR repertoire was studied by spectratyping of the TCR beta variable (BV) complementarity determining region 3 (CDR3) transcripts. RESULTS: Amongst CD4 T cells, an abnormal TCR repertoire was found in median 25% (range, 0-88%) of BV families in peripheral blood, but in 0% (0-7%) in tonsillar tissue (P<0.05). Large peaks suggestive of expanded clones were common within CD8 T-cells, both in peripheral blood and tonsillar tissue. However, the expanded clones were rarely identical in the two compartments. Expanded CDR3 peaks, suggesting the presence of clonally expanded cells, were observed within both CD45RO+ and CD45RO- cells from all T-cell subsets, but, again they were mainly of different lengths. CONCLUSION: CD4 T cells were preserved in number and TCR repertoire in tonsillar tissue compared with blood in HIV-1 infected individuals. T-cells collected from the peripheral blood may not be representative of those residing in lymphoid tissue.

Demonstration of identical expanded clones within both CD8+CD28+ and CD8+CD28- T cell subsets in HIV type 1-infected individuals.

In HIV-1-infected individuals, the CD8+CD28- T cell subset is considerably expanded and is frequently the largest subset of T cells found in peripheral blood. It has been assumed, but not proven, that CD8+CD28- T cells derive from CD8+CD28+ T cells in vivo. To further study the ontogeny of CD8+CD28- T cells, we have performed analyses of the complementarity determining region 3 (CDR3) of the TCRB of CD8+CD28+ and CD8+CD28- T cells from the peripheral blood of HIV-1-infected individuals. When cells from the same individual were compared, expanded peaks in CDR3 length analysis within a given BV family were frequently observed at the same location in both CD8+ subsets (p < 0.001). Sequencing of cDNA corresponding to dominant peaks revealed the presence of identical expanded CD8+ T cell clones within both the CD28+ and CD28- subsets on eight of nine attempts. Our results show that CD8+CD28+ and CD8+CD28- T cells are phenotypic variants of the same lineage, most likely evolving from CD8+CD28+ to end-stage CD8+CD28- T cells.

Risk of toxoplasmic encephalitis in AIDS patients: indications for prophylaxis.

To establish the indications for primary prophylaxis against toxoplasmic encephalitis in the Norwegian HIV-positive population, we estimated the incidence of toxoplasmic encephalitis, and related the degree of immunodeficiency and the presence of IgG antibodies against Toxoplasma gondii (T. gondii) to the development of toxoplasmic encephalitis. This retrospective study includes all HIV-positive patients at our hospital from April 1983 to October 1994 (n = 705). A total of 238 patients had AIDS, which represents almost 90% of all AIDS patients in Oslo. Autopsy was done in over 70% of the patients who died during this period; 19 patients developed toxoplasmic encephalitis (8.0%). The median CD4 cell count was 75 x 10(6) cell/I (range 0-280) at the time of diagnosis of toxoplasmic encephalitis. T. gondii serology was studied in 698 (99.0%) of the patients, and was found positive for 17.8%. Of the patients with toxoplasmic encephalitis 18/19 had IgG antibodies against T. gondii and of the 40 AIDS patients who had anti-T. gondii IgG, 18 (45%) developed toxoplasmic encephalitis. We conclude that there is indication for prophylactic treatment of HIV positive patients who have IgG antibodies against T. gondii and who have fewer than 200 x 10(6) CD4 cells/I.

Expression of costimulatory molecule CD28 on T cells in human immunodeficiency virus type 1 infection: functional and clinical correlations.

To study the functional integrity of T cells from human immunodeficiency virus type 1 (HIV-1)-infected persons, CD4+ and CD8+ cells were examined for proliferation and secretion of interleukin-2 (IL-2) in response to staphylococcal superantigens and antibodies to CD3 and the alpha beta T cell receptor. A functional defect within CD8+ but not within CD4+ cells from HIV-1-infected persons was observed. Within CD8+ cells, proliferation and secretion of IL-2 was restricted to cells expressing the costimulatory molecule CD28. Such cells were proportionally reduced in HIV-1-infected persons. In patients with advanced immunodeficiency, however, evidence of functional derangement was found also within the CD28+ CD8+ cells. In a cross-sectional study of 73 HIV-infected persons and 15 controls, a significant correlation was observed between the number of CD28+ CD8+ cells and the presence of HIV-related disease. Our results suggest that regulation of expression of CD28 may play an important role in the immunopathogenesis of AIDS.