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Die antiretrovirale Therapie basierte bislang auf der Kombination von drei Wirksstoffen aus zwei unterschiedlichen Substanzklassen. Mittlerweile wurden neue Daten aus großen Zulassungsstudien zur Therapie mit nur noch zwei Wirkstoffen präsentiert. Welches Potenzial haben Zweifachtherapien für den Einsatz in der Praxis?

Several cytokines and chemokines including chemokine (C-C motif) ligand-2 (CCL2) are induced in HIV-1 infection. However, the impact of HIV-1 viremia on CCL2 regulation is largely unknown. We utilized a DNA oligonucleotide microarray covering 110 inflammatory genes. Five genes were induced by at least 2-fold in PBMCs of HIV-1 viremic (>100.000 RNA copies ml−1) as compared with aviremic (<50 RNA copies ml−1) individuals. These genes were CCL2, CXC chemokine ligand-10, IFN-γ, GTP-cyclohydrolase-1 and C-C chemokine receptor-1. In addition to microarray data verification by real-time PCR, analysis of independent patient samples revealed a similar expression pattern. CCL2 was the most strongly regulated gene at mRNA level and its serum concentration was significantly elevated in viremic compared with aviremic and HIV-1 seronegative controls, indicating a positive correlation between viremia and CCL2. Flow cytometric studies demonstrated a higher percentage of CCL2-expressing CD14+ monocytes in viremic compared with aviremic individuals. These results suggest a highly restricted modulation of host inflammatory gene response by HIV. Genes up-regulated in the viremic state, in particular CCL2, presumably serve as potential enhancing factors in HIV-1 replication, represented by high viral load in HIV-1 viremic patients. Inhibition of increased CCL2 production could provide a new therapeutic intervention in HIV-1 infection.

HIV patients either on highly active antiviral therapy (HAART) or therapy naive were analyzed for their CD56 phenotype and cytokine production in comparison to healthy controls (HC). Both NK cell populations (CD56dimand CD56bright) are found to be present in all groups with selectively decreased CD56dimNK cells in HAART naive patients. Patients on HAART exhibited significantly diminished numbers of CD161+CD56dimNK cells. CD56dimwere equally potent in producing IFNγ in all three groups. The number of TNFα+CD56brightNK cells from patients on HAART and TNFα+CD56dimNK cells from HAART naive patients was significantly reduced as compared to healthy controls. In summary our data revealed that functional capacities and coexpression patterns of lectin-like receptors on lymphocytes are differentially affected in HIV patients depending on the state of therapy (under HAART or HAART naive) or the cell type (NK or T cells), respectively.

Visualization of antigen-specific T cells has become an important tool in studying immune responses. The aim of this study was to analyze CMV-specific CD4+T cells in healthy and HIV-infected individuals. Peripheral blood mononuclear cells (PBMC) were examined for antigen-induced intracellular cytokine responses. We found significant numbers of CMV-specific CD4+T cells detectable in most CMV-IgG+HIV-1 infected individuals, whereas CMV-specific CD4+T cells could not be demonstrated in CMV-IgG-patients. Median frequency of CMV-specific CD4+T cells were lower in HIVinfected subjects who had been treated with highly active antiretroviral therapy (HAART) for more than 1 year than in untreated HIV-infected individuals. In patients under therapy for less than 1 year median CMV-specific CD4+T cell responder frequency was higher than in subjects treated for more than 1 year but lower than in untreated subjects. HIV suppression with HAART might lead to a progressive reduction of CMV-specific CD4+T cells indicating an efficient elimination of an opportunistic pathogen.

We studied natural immunity mediated by natural killer (NK) cells in 62 HIV-1 infected individuals, 54 HIV-1 infected individuals receiving highly active antiretroviral therapy (HAART) for more than one year and 8 HIV-1 infected individuals without antiretroviral therapy. 22 individuals had a complete suppression of viral replication characterized by viral load values <50 copies/ml, whereas 32 individuals presented with persistent viral replication. The 8 untreated patients had an indication to start antiretroviral treatment. Lytic activity of NK cells was measured in a 51 chromium release assay. In patients with persistent viral replication under HAART NK cell activity was significantly decreased compared to patients with effective control of HIV viremia. Patients with complete suppression of HIV replication displayed a similar NK activity to healthy control persons. Differences in antibody-dependent cellular cytotoxicity (ADCC) were not observed. Further studies will investigate whether decreased NK cell activity is a reason for or the consequence of persistent viral replication.