Decreased T cell apoptosis and T cell recovery during highly active antiretroviral therapy (HAART).

T cell apoptosis represents a common mechanism of T cell depletion in HIV-1-infected individuals reflecting maturational and functional T cell abnormalities either directly or indirectly induced by the virus. In the present study, the effects of highly active antiretroviral therapy (HAART) on the spontaneous apoptosis of distinct T cell subsets were investigated during a 6-month follow-up in a cohort of HIV-1-infected individuals with CD4(+) cell counts between 100 and 500 cells/microliter and plasma HIV-1 RNA levels >/=10, 000 copies/ml. We determined that the rapid and sustained increase of both naive (CD45RA(+)CD62L(+)) and memory (CD45R0(+) and CD45RA(+)/CD62L(-)) CD4(+) and, to as lesser extent, CD8(+) T cells in peripheral blood was associated with a significant decrease of apoptotic CD4(+) and CD8(+) as well as CD3(+)CD4(-)CD8(-) T cells. Among CD4(+) lymphocytes, at enrollment, the highest frequency of apoptotic cells was observed within the memory compartment, as defined by CD45R0 expression. During HAART, however, the frequency of CD4(+)CD45R0(+) apoptotic T cells progressively decreased in association with a significant downregulation of surface activation markers that indicated decreased levels of systemic immune stimulation. These results indicate that effective viral suppression can contribute to progressive normalization of maturational and functional T cell abnormalities responsible for the high levels of T cell apoptosis in HIV-1-infected individuals. This, in turn, may contribute to a reduced rate of T cell loss and immune reconstitution during HAART.

Apoptosis in asymptomatic HIV-1 seropositives immunized with HIV-1 env glycoprotein (gp160): effects of administration of Zidovudine in vivo and interleukin-2 in vitro.

In this paper we report the effects of VaxSyn (Protein Sciences Corp.) immunization on spontaneous apoptosis occurring in vitro after culture of PBMC in medium alone in 30 HIV-seropositive patients enrolled in a double-blind clinical trial that included three groups: treatment with VaxSyn, AZT and VaxSyn, and AZT. Our data show no significant modifications in the levels of apoptosis observed in the three groups over the long-term follow-up (up to 720 days). This was not associated with any significant modifications in other clinical or immunological features. However, analysis of apoptosis performed shortly after the first immunization (at days 3 and 7) showed a significant reduction in the rate of apoptosis in patients receiving AZT and AZT and VaxSyn, as compared with patients receiving VaxSyn alone (30.42 +/- 2.52 SE at day 0 and 23.74 +/- 1.84 at day 3; p = 0.039). Our data also indicate that addition of IL-2 in vitro had a significant inhibitory effect on mortality in all the randomization groups, especially in those receiving AZT (alone or in combination with VaxSyn).

Apoptosis-related mortality in vitro of mononuclear cells from patients with HIV infection correlates with disease severity and progression.

Peripheral blood mononuclear cells (PBMC) from 103 HIV-infected patients were tested for their mortality rate (MR) when incubated in vitro for 3 days in a culture medium. MR was related to apoptosis as shown by DNA analysis and morphological evaluation of ethidium bromide-stained PBMC by flow cytometry. MR was significantly higher in patients in CDC stage IV as compared to patients in stage II or III (p = 0.017). MR was also higher in patients with low CD4 cells/mm3 (p = 0.014 for patients with < 400 cells; p = 0.001 for patients with < 200 CD4 cells/mm3) and with low percentage of CD4 cells (p = 0.001 for patients with < 10% of CD4 cells). A significant negative correlation was observed between MR and both absolute numbers or percentages of CD4 cells (p < 0.001). The addition of interleukin-2 (IL-2) and fibro-blast-conditioned medium (FCM) to the cultures significantly reduced MR. However, the ability of both IL-2 and FCM to preserve viability was significantly associated with p24 negativity. Clinical and immunological follow-up was available for 60 patients for a mean period of 26 months. MR at the beginning of the study was significantly higher in the group of patients who clinically progressed (according to the CDC classification) or died during the follow-up (p < 0.0001). Our data suggest that MR correlates with both disease severity and progression and that MR is directly related to the depletion of CD4 cells in cultures.(ABSTRACT TRUNCATED AT 250 WORDS)