“
“It has been suggested that patients who initiate highly active antiretroviral

therapy (HAART) late in their course of infection may have suboptimal CD4 T-cell gains, persistent alterations in T-cell subsets and residual inflammation. To address this issue, we carried out a comprehensive 48-week immunological study in HIV-infected patients who had experienced failures of prior therapies, had low CD4 cell counts, and were receiving enfuvirtide-based salvage therapy. Immunological monitoring of peripheral lymphocytes from enfuvirtide-responder patients was performed over a 48-week period. A detailed assessment of immune cell subsets, their activation state [CD38 and human leucocyte Z-VAD-FMK ic50 antigen (HLA)-DR expression] and homeostasis [activation-induced cell death (AICD) and Ki67 expression], and the expression of co-receptors was performed by flow cytometry. Cytokine and chemokine signatures were assessed using multianalyte profiling technology. Enfuvirtide-based salvage therapy induced a progressive restoration of naïve and central memory CD4 T cells, associated with a decrease in their activation state, suppression of premature priming for AICD and increased expression of Ki67. In addition, a significant decrease in C-C chemokine receptor GSK J4 5 (CCR5) expression was detected on CD4 T cells, which was strongly correlated with the suppression of immune activation. Changes in circulating proinflammatory molecules occurred; i.e. there were decreases in the

concentrations of interleukin (IL)-12, macrophage inflammatory protein

MIP-1α, MIP-1β, monokine induced by IFNγ (MIG) and interferon-γ-inducible protein-10 (IP-10). The decline in circulating IL-12 and IP-10 was correlated with both the reduction in the viral load and CD4 T-cell restoration. This study shows that suppression of HIV-1 replication with enfuvirtide-based salvage therapy in patients with low CD4 cell counts may result in an immunological benefit, characterized by the restoration of CD4 T-cell subsets associated with decreased immune activation and suppression of inflammation. The continuing development of effective antiretroviral therapies (ARTs) has allowed pharmacological until suppression of HIV-1 replication in many infected patients, resulting in an increase in the number of CD4 T cells and the functional reconstitution of the immune system [1]. However, virological failure can occur, allowing the selection of HIV-1 quasispecies resistant to antiretroviral drugs, which can limit future treatment options. Salvage therapy after viral rebound is more successful if an agent from a class of antiretroviral drugs to which the patient has not previously been exposed is included in the regimen, such as HIV entry inhibitors [2]. The fusion inhibitor enfuvirtide has demonstrated antiviral activity in treatment-experienced patients with HIV resistant to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).