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Slow progression in HIV-1 infection : clinical, virological and immunological study
The aim of the present thesis was to study factors that could possibly influence the course of HIV-1 infection with special emphasis on slow progression of the disease. Clinical, virological and immunological parameters were evaluated. One important clinical factor for the outcome of HIV-1 infection was identified. In a seven year follow-up study symptomatic primary HIV-1 infection was found to strongly predict an accelerated progression to AIDS and death of AIDS, when compared to patients who had had asymptomatic seroconversion (53% vs 7%; p<0.0001).
In order to determine the kinetics of the viral load and its potential relationship to different patterns of clinical progression, twenty HIV-1 infected long-term asymptomatic patients were included in a prospective study. Four years later twelve patients had progressed (slow progressors), while eight patients were classified as long-term non-progressors (LTNP). The twelve slow progressors displayed higher plasma HIV-1 RNA levels already at inclusion in the study when compared to the eight LTNP (p<0.05). The slow progressors thereafter showed continuously increasing HIV-1 RNA levels (p<0.01). A difference in the HIV-1 DNA level over time was also noted in that the slow progressors also showed increasing HIV-1 DNA levels with time. This pattern differed from the one found in the LTNP who exhibited low or very low RNA values and stable or decreasing HIV-1 DNA levels.
In slow progressors, including LTNP, no alteration of programmed cell death (apoptosis) of CD4+ cells was found. However, all HIV-1 infected individuals showed increased B-cell apoptosis, as compared to HIV-1 negative controls. Higher rates of B-cell apoptosis were observed in individuals with poor neutralising activity. Slow progressors displayed a lesser degree of B-cell apoptosis than progressors. In this study LTNP were not analysed separately.
In a group of four slow progressors maintained antibody responses, both with respect to the levels and the avidity, to autologous HIV-1 V3 peptides were noted. This differed from patients with a fast disease progression and may suggest an efficient humoral control of the infection. Slow progressors also displayed close to normal serological responses both to other and HIV-1 specific viral antigens after 8 - 9 years of HIV-1 infection. In a cross-sectional study of cellular immunophenotypes, the LTNPs displayed lower frequency of expression of the activation-marker CD8+ CD38+, not only as compared to progressors (p<0.001), but also to recently infected sub jects (p<0.05). The LTNP also showed lower levels of CD4+ CD26+, a marker reactive to recall antigens, as compared to recently infected (p<0.05). Prospective studies will be needed, to evaluate if these patterns of expression are present in LTNP already after seroconversion.
In conclusion, various clinical, virological and immunological factors were identified as being of potential importance for the course of the infection. Acute clinical illness during seroconversion correlated to a poor prognosis. Among the LTNP the viral replication kinetics were characterized by low or extremely low plasma virus levels and decreasing or stable HIV-1 DNA levels over time. This finding suggests that the viral replication is under strict control in the LTNP. Among LTNP the HIV-1 specific humoral responses were well maintained indicating a functional T-cell support which is consistent with the observed lack of CD4+ cell apoptosis. Collectively, in a small number of HIV-1 infected individuals many factors may help to control their HIV-1 infection efficiently whereby no signs of progression is seen even after 17 years of infection.
History
Defence date
1998-06-03Department
- Department of Medicine, Solna
Publication year
1998Thesis type
- Doctoral thesis
ISBN-10
91-628-3025-2Language
- eng