NK-associated regulatory receptors in a structured HAART interruption of HIV-1-positive individuals.

Since highly active antiretroviral therapy (HAART) was introduced a decade ago, it has been shown to be effective in keeping HIV-1 replication under control. Nevertheless, it is also known that HAART has certain limitations, such as its inability to completely inhibit the viral replication that maintains virus reservoirs, its high toxicity when the treatment is maintained for long periods of time, and the appearance of viral resistance to the therapy. These limitations have led to the introduction of structured treatment interruption (STI) of antiretroviral therapy, the principle of which is to reduce the clinical complications of HAART, and hypothetically to boost the cellular immune response of the patient host. The aim of this study was to analyze for the first time the impact of STI on the innate immune system. Specifically, we analyzed NK cells and their regulatory receptors (KIRs, NKG2, NCRs, and ILTs) and the cytokines that might control the NK response. Six months after the initiation of STI, the results revealed in most patients a significant increase in NK cells expressing ILT2 and NKp46 receptors. Slight or no changes were observed in other parameters studied, either during interruption or when HAART was reintroduced. Our data show that the STI strategy, irrespective of whether it improved the patients' clinical evolution, induced functional phenotype changes in NK cell subsets.

Impaired response of HIV type 1-specific CD8(+) cells from antiretroviral-treated patients.

Impairment of the response of HIV-specific CD8(+) T cells, in spite of the high frequency of occurrence of these cells even in the advanced phase of HIV-1 infection, has been demonstrated. It is also known that new antiretroviral treatments are able to reduce the viral load and partially repair the immunological damage caused by HIV-1, but it is not clear whether the extent of these changes affects the functional profile of HIV-specific CD8(+) T cells. We evaluated, in HIV-1(+) patients undergoing antiretroviral therapy, the HIV-specific CD8(+) subset distribution and their functional capacity as intracellular expression of IFN-gamma, TNF-alpha, and perforin after PMA stimulation. Our results indicate that HIV-1(+)-treated individuals show distributions of HIV-specific CD8 subsets similar to nontreated patients, while the frequency of HIV-specific CD8 cells expressing IFN-gamma and perforin after stimulation is lower in HAART-treated patients. This indicates that HAART, which controls viral replication, may impair the HIV-specific CD8(+) response.

Nucleoside reverse transcriptase inhibitors are able and protease inhibitors unable to induce the tolerogenic molecule HLA-G1 on monocytes from HIV-1 infected patients.

Our group has previously reported that a significantly larger proportion of peripheral monocytes from human immunodeficiency virus type 1 (HIV-1) seropositive individuals receiving highly active antiretroviral therapy (HAART) express HLA-G1 and also that one of the HAART components, the nucleoside reverse transcriptase inhibitors (NRTIs), may be involved in this effect. Because protease inhibitors (PIs) are another component of HAART that are administered with NRTIs, the aim of this work was to determine whether or not PIs are also involved in the HLA-G1 changes previously observed in treated HIV-1 positive patients. CD14(+) cells expressing HLA-G1 were therefore measured in 7 HIV-1 positive patients whose initial HAART was changed to a protease inhibitor-only regime due to drug toxicity and/or virologic resistance. Our results indicate that PIs do not appear to be implicated in the rise of HLA-G1 expression on CD14(+) cells from HIV-1 infected individuals receiving HAART, while we further confirm that NRTIs are involved in the surface induction of HLA-G1.

sHLA-G levels in the monitoring of immunosuppressive therapy and rejection following heart transplantation.

The aim of this study was to further determine the immediate influence, over a 12-h period, after the initiation of daily immunosuppressive treatment on the serum levels of sHLA-G in heart transplant patients during the post-transplant period (1 month). It was found that there are two patterns of patients in term of the changes observed in their levels of sHLA-G in response to the immunosuppressive treatment. One group (group A) showed no changes on sHLA-G while the other group (group B) a significant rise in sHLA-G levels was observed at 2 to 4 h post dose. Interestingly, it was observed that the patients in group B have better prognosis of acceptance of the heart graft than those of group A. On the other hand it was found that the patients with high levels of sHLA-G (77.3+/-34.8 ng/ml) in pre-transplant sera have a better prognosis of acceptance of the heart graft than those with low sHLA-G levels (9.7+/-7.1 ng/ml). In conclusion, both the intensity of changes of sHLA-G levels induced by immunosuppression and basal levels in pre-transplant could be used in the monitoring of the immunosuppression as well as the heart transplant evolution.

Soluble HLA-G in heart transplantation: their relationship to rejection episodes and immunosuppressive therapy.

The aims of this study were to quantify the level of soluble HLA-G in heart transplant patients, to determine the relationship between the sHLA-G levels and the appearance of acute rejection episodes, and to identify the influence of immunosuppressive therapy on sHLA-G levels. Analysis of sHLA-G, measured by enzyme-linked immunosorbent assay in the transplant patients, revealed the existence of two similarly sized groups of patients. One group displayed a significant increase (p < 0.001) in sHLA-G during the first month after transplantation while the other group maintained low levels of the molecule (0-30 ng/ml) throughout the study. The latter group displayed a high incidence of recurrent severe rejection. A significant increase (p < 0.01) in sHLA-G 2 hours after administration of immunosuppressive treatment (mycophenolate mofetil, cyclosporine A/FK506, corticoids) was found. These results suggest that sHLA-G participates in the induction of certain levels of immunological tolerance in these recipients.