Drug toxicity and viral resistance limit the long-term efficacy of antiviral drug treatment for human immunodeficiency virus (HIV) infection. Thus, alternative therapies need to be explored. We tested the infusion of T lymphocytes transduced with a retroviral vector (M87o) that expresses an HIV entry-inhibitory peptide (maC46). Gene-modified autologous T cells were infused into ten HIV-infected patients with advanced disease and multidrug-resistant virus during anti-retroviral combination therapy. T-cell infusions were tolerated well, with no severe side effects. A significant increase of CD4 counts was observed after infusion. At the end of the 1-year follow-up, the CD4 counts of all patients were still around or above baseline. Gene-modified cells could be detected in peripheral blood, lymph nodes, and bone marrow throughout the 1-year follow-up, and marking levels correlated with the cell dose. No significant changes of viral load were observed during the first 4 months. Four of the seven patients who changed their antiviral drug regimen thereafter responded with a significant decline in plasma viral load. In conclusion, the transfer of gene-modified cells was safe, led to sustained levels of gene marking, and may improve immune competence in HIV-infected patients with advanced disease and multidrug-resistant virus.

The immunological and virological impact of short-term treatment initiated during acute human immunodeficiency virus type 1 (HIV-1) infection was assessed prospectively in 20 subjects, 12 of whom initiated highly active antiretroviral therapy (HAART) for 24 weeks and then terminated treatment. Treatment resulted in suppression of viremia, an increase in the CD4+ T cell count, enhanced differentiation of HIV-1-specific CD8(+) T cells from effector memory to effector cells at week 24 of HAART, and significantly higher virus-specific interferon- gamma+ CD8+ T cell responses after viral rebound (at week 48). However, despite these immunological changes, no differences in viremia or in the CD4+ T cell count were found 6 months after HAART was stopped, when treated subjects were compared with untreated subjects.

The impact of antigenic stimulation on the dynamics of simian immunodeficiency virus (SIV) replication was studied following repeated intravenous BCG inoculation of a SIV infected macaque. At the site of a delayed type hypersensitivity reaction to purified protein derivative of M. tuberculosis, a distinctive SIV variant was noted, probably as a result of the infiltration of activated antigen-specific T cell clones as opposed to infection by blood borne virus in situ. The dynamics of SIV quasispecies in peripheral blood suggests sequential waves of viral replication, illustrating the role of antigenic stimulation as a driving force in viral dissemination and pathogenesis.

Immunohistological and electron microscopy studies of lymph nodes from patients infected with the human immunodeficiency virus 1 (HIV-1) demonstrated that follicular dendritic cells (FDC), the antigen-presenting cells of the B cell system, contain and may produce the virus. To elucidate the mode of infection of FDC with HIV-1 in vitro we developed an improved method for the preparation of single-cell suspensions of viable FDC with high purity (greater than 90% FDC). These isolated FDC were subjected to human T cell leukemia virus IIIB infection, which was monitored after 4 days in culture using the polymerase chain reaction. We were able to demonstrate that normal human FDC are highly susceptible to infection by HIV-1. Inhibition experiments with the monoclonal antibody OKT4a demonstrate that this infection is independent of the CD4 molecule.

Anti-HIV and -HCV therapy should be considered early in cases of concomitant acute HCV and HIV coinfection, because successful therapy of HCV viremia seems possible even during primary HIV infection. HCV-specific T cell immunity is generated during primary HIV infection and can be preserved by HCV treatment. However, the optimal treatment algorithm needs to be established in prospective, randomized trials.

The diversity of HIV-1 and human genetics complicates our ability to determine the impact of treatment during primary HIV-1 infection (PHI) on disease outcome. Here we show in a small group infected with virtually identical HIV-1 strains and treated during PHI that only subjects expressing protective HLA alleles had lower viral loads following treatment discontinuation. These data suggests that genetic factors play a pivotal role in the outcome of HIV-1 infection despite early therapy.

Background: Interleukin-12 (IL-12) is well characterized to induce cellular antitumoral immunity by activation of NK-cells and T-lymphocytes. However, systemic administration of recombinant human IL-12 resulted in severe toxicity without perceptible therapeutic benefit. Even though intratumoral expression of IL-12 leads to tumor regression and long-term survival in a variety of animal models, clinical trials have not yet shown a significant therapeutic benefit. One major obstacle in the treatment with IL-12 is to overcome the relatively low expression of the therapeutic gene without compromising the safety of such an approach. Our objective was to generate an adenoviral vector system enabling the regulated expression of very high levels of bioactive, human IL-12.

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