Control of human herpes virus type 8-associated diseases by NK cells.

The "natural killer" (NK) cells preferentially kill targets lacking surface major histocompatibility complex class I (MHC-I) molecule expression. NK cells recognize these targets through membrane receptors, which can trigger activating or inhibitory signals for killing. Several tumors or virus-infected cells downregulate MHC-I expression as a mechanism to evade recognition and killing by cytotoxic T lymphocytes (CTL). They, however, become targets for NK cells cytotoxic activity. NK cell activity is reduced during disease progression in human immunodeficiency virus (HIV) infection, and in individuals with AIDS-associated tumors linked with infection by the oncogenic human herpes virus type-8 (HHV8), including Kaposi's sarcoma (KS) and primary effusion lymphomas (PEL). We have demonstrated that AIDS-related KS (AIDS-KS) is characterized by an increased expression of inhibitory receptors by T lymphocytes, and that HIV-non-infected patients with KS (classic KS, C-KS) have a substantial number of NK cells bearing these same receptors. NK cells from patients with C-KS are normally equipped with cytolytic molecules including granzyme A and perforin. However, the cytotoxic activity of NK cells is reduced in patients with C-KS, AIDS-KS, or PEL patients, who are all infected by the HHV8, and this correlates with disease severity. Moreover, we have found that HHV8-infected cell lines established from PELs have a reduced surface expression of MHC-I molecules and are sensitive to the lysis mediated by NK cells. Since PEL cells express the same HHV8 latency program as KS cells, these data point to MHC-I downregulation by HHV8 as a primary immune evasion mechanism against CTL responses, further reinforced by upregulation of inhibitory receptors on T and NK cells in the setting of HIV and/or HHV8 infection. Thus, studies on killing receptor regulation and signaling in T and NK cells may shed light on the pathogenesis of HHV8-associated tumors both in HIV-infected or -noninfected patients.

Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART.

UNLABELLED: Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+) T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+) and CD8(+) cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+) T cells and B cells with reduction of CD8(+) T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+) and CD8(+) T cells were accompanied by increases of CD4(+) and CD8(+) T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00751595.

NK cell activity controls human herpesvirus 8 latent infection and is restored upon highly active antiretroviral therapy in AIDS patients with regressing Kaposi's sarcoma.

Kaposi's sarcoma (KS) develops upon reactivation of human herpesvirus 8 (HHV8) infection and virus dissemination to blood and tissue cells, including endothelial and KS spindle cells where the virus is mostly present in a latent form. However, this may likely require the presence of compromised host immune responses and/or the evasion of infected cells from the host immune response. In this regard, mechanisms of evasion of productively infected cells from both CTL and NK cell responses, and resistance of latently infected cells from specific CTL, have already been shown. Here we show that cells which are latently infected by HHV8 are indeed efficiently lysed by NK cells from individuals with a normal immune response. Notably, NK cell-mediated immunity was found to be significantly reduced in AIDS patients with progressing KS as compared to both HIV-negative patients with indolent classic KS or normal blood donors. However, it was restored after treatment with the highly active antiretroviral therapy (HAART) in AIDS-KS patients, that showed regression and clearance of HHV8 from PBMC. By contrast, AIDS-KS patients with a more aggressive disease and no clinical response had persistent HHV8 viremia associated with reduced NK cell cytotoxicity. These results suggest a key role for NK cells in the control of HHV8 latent infection, KS development, and in disease remission upon HAART.