Early effects of antiretroviral combination therapy on activation, apoptosis and regeneration of T cells in HIV-1-infected children and adolescents

Böhler, Thomas; Walcher, Judith; Hölzl-Wenig, Gabi; Geiss, Magdalena; Buchholz, B.; Linde, R.; Debatin, Klaus‐Michael

doi:10.1097/00002030-199905070-00006

Cited by 80 publications

(52 citation statements)

References 28 publications

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“…One possibility is HIV-1 protease that is well known to cleave host cell proteins and transfected HIV-1 protease kill host cells (67). HIV-1 protease inhibitor-based therapy to treat AIDS inhibits apoptosis (68). HIV-1 protease inhibitors have had little impact on HAD because they have limited penetration across the blood-brain FIGURE 11.…”

Section: Discussionmentioning

confidence: 99%

Induction of Apoptosis by HIV-1-Infected Monocytic Cells

Sperber

Beuria

Singha³

et al. 2003

The Journal of Immunology

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We have previously described a soluble 6000-Da peptide produced by an HIV-1-infected human macrophage cell line, clone 43HIV, which induces apoptosis in T and B cells. We have identified this factor as the novel cDNA clone FL14676485 that encodes for the human hypothetical protein, FLJ21908. The FL14676485 cDNA clone was isolated from a 43HIV λ ZAP Escherichia coli expression library and screened with a panel of rabbit and mouse anti-apoptotic Abs. We transfected the FL14676485 clone into Bosc cells and non-HIV-1-infected 43 cells. Western blot analysis of lysates from the FL14676485-transfected 43 cells and Bosc cells using anti-proapoptotic factor Abs revealed a protein with a molecular mass of 66 kDa corresponding to the size of the full-length gene product of the FL14676485 clone, while Western blot of the supernatant demonstrated a doublet of 46-kDa and 6000-Da peptide that corresponds to our previously described proapoptotic factor. Primary HIV-1BaL-infected monocytes also produce the FLJ21908 protein. Supernatants from these transfected cells induced apoptosis in PBMC, CD4+, and CD8+ T and B cells similar to the activity of our previously described proapoptotic factor. PCR analysis of 43 cells and 43HIV cells revealed a base pair fragment of 420 bp corresponding to the FL14676485 gene product in 43HIV cells, but not in 43 cells. The FLJ21908 protein induces apoptosis through activation of caspase-9 and caspase-3. We have further demonstrated that the FLJ21908 protein has apoptotic activity in the SH-SY5Y neuronal cell line and can be detected in brain and lymph tissue from HIV-1-infected patients who have AIDS dementia. The FLJ21908 protein may contribute to the apoptosis and dementia observed in AIDS patients.

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Section: Discussionmentioning

confidence: 99%

Induction of Apoptosis by HIV-1-Infected Monocytic Cells

Sperber

Beuria

Singha³

et al. 2003

The Journal of Immunology

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“…Recent studies have reported that the susceptibility of peripheral blood T cells to apoptosis decreased in HIV-1 infected adults and children under HAART [41,42]. However, whether such a phenomenon reflects the direct down-regulation of Tlymphocyte apoptosis by PIs or is merely the consequence of normalized T-lymphocyte function (such as increased proliferation to recall antigens, decreased plasma cytokines, declined serum b2-microglobulin and other soluble activation markers) [2,4,28] remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Highly active antiretroviral therapy restores in vitro mitogen and antigen-specific T-lymphocyte responses in HIV-1 perinatally infected children despite virological failure

Peruzzi

Azzari

Galli

et al. 2002

Clinical and Experimental Immunology

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SUMMARY To analyse the effect of highly active antiretroviral therapy (HAART) on T-lymphocyte functions we selected seven HIV-1 perinatally infected children (CDC immunological category 1 or 2) who had neither a fall in their plasma HIV-1 RNA levels nor a significant rise in CD4+ lymphocyte counts while receiving HAART. Clinical signs and symptoms were monitored monthly. Plasma viral load, CD4+, CD8+, CD19+ lymphocyte counts and in vitro T-lymphocyte proliferative responses to mitogens (anti-CD3, phytohaemoagglutinin, concanavalin A and pokeweed mitogen) and recall antigens (Candida albicans and tetanus toxoid) were tested at baseline and after 1, 3, 6 and 12 months of HAART. Twenty-two healthy age-matched children were studied as controls. A gain in body weight, no worsening of the disease and no recurrence of opportunistic infections were observed. At baseline, the majority of the children had low responses to mitogens, and all of them had a defective in vitro antigen-specific T-lymphocyte response (<2 standard deviations below the mean result for controls). During HAART, a significant increase in the response to mitogens and antigens was observed in all the patients. The T-lymphocyte response was restored more consistently against antigens to which the immune system is constantly exposed (Candida albicans, baseline versus 12 months: P < 0·001) compared with a low-exposure antigen (tetanus toxoid, baseline versus 12 months: P < 0·01). HAART restores in vitro T-lymphocyte responses even in the absence of a significant viral load decrease and despite any significant increase in CD4+ lymphocyte counts. It implies that a direct mechanism might be involved in the overall immune recovery under HAART.

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“…55 Importantly, the magnitude of CD4 þ T-cell apoptosis observed in HIV-infected individuals correlates well with the stage of HIV disease. [56][57][58][59][60][61] In addition, changes in the levels of T-cell apoptosis after highly active antiretroviral therapy (HAART) predict the immunological response (i.e., increase in CD4 T-cell count), thus confirming the link between disease progression and apoptosis. [62][63][64] Taken together, these observations indicate that the increased susceptibility to apoptosis of T lymphocytes from HIV-infected individuals is a marker of HIV disease progression and support the hypothesis that the chronic immune system activation that Figure 2 Overview of apoptosis pathway.…”

Section: T-cell Apoptosis and Aidsmentioning

confidence: 92%