New insights into evaluating effective T-cell responses to HIV.

HIV-1 establishes a lifelong infection in the human body, but host factors that influence viral persistence remain poorly understood. Cell-intrinsic characteristics of CD4 T cells, the main target cells for HIV-1, may affect the composition of the latent viral reservoir by altering the susceptibility to CD8 T-cell-mediated killing. We observed that susceptibilities of CD4 T cells to CD8 T-cell-mediated killing, as determined in direct ex vivo assays, were significantly higher in persons with natural control of HIV-1 (elite controllers) than in individuals effectively treated with antiretroviral therapy. These differences were most pronounced in naive and in terminally differentiated CD4 T cells and corresponded to a reduced viral reservoir size in elite controllers. Interestingly, the highest susceptibility to CD8 T-cell-mediated killing and lowest reservoirs of cell-associated HIV-1 DNA was consistently observed in elite controllers expressing the protective HLA class I allele B57. These data suggest that the functional responsiveness of host CD4 T cells to cytotoxic effects of HIV-1-specific CD8 T cells can contribute to shaping the structure and composition of the latently infected CD4 T-cell pool.

The role of human leukocyte antigen E and G in HIV infection

Adenovirus 5 serotype vector-specific immunity and HIV-1 infection: a tale of T cells and antibodies

Early and late cytotoxic T lymphocyte responses in HIV infection

Regulatory T cells in HIV infection: pathogenic or protective participants in the immune response?

Cytokines as adjuvants for improving anti-HIV responses

Immunization With a Bivalent Adenovirus-vectored Tuberculosis Vaccine Provides Markedly Improved Protection Over Its Monovalent Counterpart Against Pulmonary Tuberculosis

Vaccine-induced T cells Provide Partial Protection Against High-dose Rectal SIVmac239 Challenge of Rhesus Macaques

The history of successful vaccination against severe viral diseases such as smallpox poliomyelitis or measles led to the initial hope that a vaccine against AIDS would be developed quickly. However an effective vaccine against HIV needs to overcome substantial obstacles that emerged as research progressed. Due to life cycle HIV can effectively hide from the host immune response integrating itself as proviral DNA in the host cell genome. A strategy pursued to deal with this difficulty is to include early viral regulatory proteins such as Tat Rev or Nef as vaccine antigens for induction of immune responses that can recognize and destroy HIV-infected cells as soon as the virus life cycle is activated [12]. The virus preferentially targets and destroys host immune cells such as T-helper lymphocytes macrophages and dendritic cells that are probably essential to maintain an effective antiviral immune response. This would imply that vaccine-elicited immunity unlikely to be able to prevent infection itself must be able to quickly control virus replication to prevent harm to the immune system. The high antigenic variability of HIV can be considered as an extremely effective immune-evasion strategy. Because of the low fidelity of the viral RNA polymerase virus progeny always represents a collection of RNA genomes (quasi-species) with random mutations. In vivo selection of immunodeficiency virus variants that can evade the recognition of neutralizing antibodies is common and strong virus-specific cytotoxic T-cell responses can select for escape variants already during resolution of primary viremia [3]. Most HIV infections are acquired sexually via the genital or rectal mucosae; however at these entry sites it appears difficult to induce strong antiviral immunity by vaccination. Finally HIV infection is a poverty-related disease that is particularly threatening health in societies of the developing world. Therefore vaccine candidates must be safe and feasible in production and administration to be eligible for use where most needed. (excerpt)

New perspectives for T-cell-based HCV vaccines

BackgroundT-cell mediated immunity likely plays an important role in controlling HIV-1 infection and progression to AIDS. Several candidate vaccines against HIV-1 aim at stimulating cellular immune responses, either alone or together with the induction of neutralizing antibodies, and assays able to measure CD8 and CD4 T-cell responses need to be implemented. At present, the IFN-γ-based ELISPOT assay is considered the gold standard and it is broadly preferred as primary assay for detection of antigen-specific T-cell responses in vaccine trials. However, in spite of its high sensitivity, the measurement of the sole IFN-γ production provides limited information on the quality of the immune response. On the other hand, the introduction of polychromatic flow-cytometry-based assays such as the intracellular cytokine staining (ICS) strongly improved the capacity to detect several markers on a single cell level.ResultsThe cumulative analysis of 275 samples from 31 different HIV-1 infected individuals using an ICS staining procedure optimized by our laboratories revealed that, following antigenic stimulation, IFN-γ producing T-cells were also producing MIP-1β whereas T-cells characterized by the sole production of IFN-γ were rare. Since the analysis of the combination of two functions decreases the background and the measurement of the IFN-γ+ MIP-1β+ T-cells was equivalent to the measurement of the total IFN-γ+ T-cells, we adopted the IFN-γ+ MIP-1β+ data analysis system to evaluate IFN-γ-based, antigen-specific T-cell responses. Comparison of our ICS assay with ELISPOT assays performed in two different experienced laboratories demonstrated that the IFN-γ+ MIP-1β+ data analysis system increased the sensitivity of the ICS up to levels comparable to the sensitivity of the ELISPOT assay.ConclusionThe IFN-γ+ MIP-1β+ data evaluation system provides a clear advantage for the detection of low magnitude HIV-1-specific responses. These results are important to guide the choice for suitable highly sensitive immune assays and to build reagent panels able to accurately characterize the phenotype and function of responding T-cells. More importantly, the ICS assay can be used as primary assay to evaluate HIV-1-specific responses without losing sensitivity in comparison to the ELISPOT assay.

DNA Vaccines Encoding Ii-PADRE Generates Potent PADRE-specific CD4+ T-Cell Immune Responses and Enhances Vaccine Potency

HCV-Specific T-Cell Response in Relation to Viral Kinetics and Treatment Outcome (DITTO-HCV Project)

Baculovirus-based Vaccination Vectors Allow for Efficient Induction of Immune Responses Against Plasmodium falciparum Circumsporozoite Protein

HIV/host interactions: new lessons from the Red Queen's country.