Examination of influenza specific T cell responses after influenza virus challenge in individuals vaccinated with MVA-NP+M1 vaccine.

Current influenza vaccines stimulate neutralising antibody to the haemagglutinin antigen but as there is antigenic drift in HA it is difficult to prepare a vaccine in advance against an emergent strain. A potential strategy is to induce CD8(+) and CD4(+) T cells that recognize epitopes within internal proteins that are less subject to antigenic drift. Augmenting humoral responses to HA with T cell responses to more conserved antigens may result in a more broadly protective vaccine.

Correlates of T-cell-mediated viral control and phenotype of CD8(+) T cells in HIV-2, a naturally contained human retroviral infection.

While a significant proportion of HIV-2-infected individuals are asymptomatic and maintain undetectable viral loads (controllers), 15% to 20% progress to AIDS and are predicted by detectable viremia. Identifying immune correlates that distinguish these 2 groups should provide insights into how a potentially pathogenic retrovirus can be naturally controlled. We performed a detailed study of HIV-2-specific cellular responses in a unique community cohort in Guinea-Bissau followed for over 2 decades.

High frequency of HIV mutations associated with HLA-C suggests enhanced HLA-C-restricted CTL selective pressure associated with an AIDS-protective polymorphism.

Delayed HIV-1 disease progression is associated with a single nucleotide polymorphism upstream of the HLA-C gene that correlates with differential expression of the HLA-C Ag. This polymorphism was recently shown to be a marker for a protective variant in the 3'UTR of HLA-C that disrupts a microRNA binding site, resulting in enhanced HLA-C expression at the cell surface. Whether individuals with "high" HLA-C expression show a stronger HLA-C-restricted immune response exerting better viral control than that of their counterparts has not been established.

Preliminary assessment of the efficacy of a T-cell-based influenza vaccine, MVA-NP+M1, in humans.

Background: The novel influenza vaccine MVA-NP+M1 is designed to boost cross-reactive T-cell responses to internal antigens of the influenza A virus that are conserved across all subtypes, providing protection against both influenza disease and virus shedding against all influenza A viruses. Following a phase 1 clinical study that demonstrated vaccine safety and immunogenicity, a phase 2a vaccination and influenza challenge study has been conducted in healthy adult volunteers.

Methods: Volunteers with no measurable serum antibodies to influenza A/Wisconsin/67/2005 received either a single vaccination with MVA-NP+M1 or no vaccination.

The antiviral efficacy of HIV-specific CD8⁺ T-cells to a conserved epitope is heavily dependent on the infecting HIV-1 isolate.

A major challenge to developing a successful HIV vaccine is the vast diversity of viral sequences, yet it is generally assumed that an epitope conserved between different strains will be recognised by responding T-cells. We examined whether an invariant HLA-B8 restricted Nef₉₀₋₉₇ epitope FL8 shared between five high titre viruses and eight recombinant vaccinia viruses expressing Nef from different viral isolates (clades A-H) could activate antiviral activity in FL8-specific cytotoxic T-lymphocytes (CTL). Surprisingly, despite epitope conservation, we found that CTL antiviral efficacy is dependent on the infecting viral isolate.

Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China.

Obstacles to developing an HIV-1 vaccine include extensive viral diversity and lack of correlates of protective immunity. High mutation rates allow HIV-1 to adapt rapidly to selective forces such as antiretroviral therapy and immune pressure, including HIV-1-specific CTLs that select viral variants which escape T-cell recognition. Multiple factors contribute to HIV-1 diversity, making it difficult to disentangle the contribution of CTL selection without using complex analytical approaches.

HLA-C as a mediator of natural killer and T-cell activation: spectator or key player?

The biochemical properties of the HLA-C antigen differ substantially from those of HLA-A and -B molecules. For this reason, HLA-C diversity and expression at the cell surface are much lower than its counterparts and in consequence HLA-C-restricted responses have been infrequently detected and described. In this review we summarise the key differences between HLA-C and other class I molecules and provide an update on natural killer and T-cell responses restricted by HLA-C.

Lessons from the failure of the adenovector HIV vaccine.

The much-publicised halting of the joint Merck/HIV Vaccine Trials Network phase IIB candidate HIV-1 vaccine trial in 2007 has led to an unprecedented degree of discussion and introspection amongst the HIV research community. In this commentary, we will summarise the lessons learned from the trial and examine the current state of HIV vaccine research.

Why T cells of thymic versus extrathymic origin are functionally different.

Age-related thymic involution severely impairs immune responsiveness. Strategies to generate T cells extrathymically are therefore being explored with intense interest. We have demonstrated that T cells produced extrathymically were functionally deficient relative to thymus-derived T cells.

T-cell development: an extrathymic perspective.

The lymph nodes (LNs) harbor a cryptic T-lymphopoietic pathway that is dramatically amplified by oncostatin M (OM). OM-transgenic mice generate massive amounts of T lymphocytes in the absence of Lin(-)c-Kit(hi)IL-7Ralpha- lymphoid progenitors and of reticular epithelial cells. Extrathymic T cells that develop along the OM-dependent LN pathway originate from Lin(-)c-Kit(lo)IL-7Ralpha+ lymphoid progenitors and are different from classic T cells in terms of turnover kinetics and function.

Do thymically and strictly extrathymically developing T cells generate similar immune responses?

If present in sufficient numbers, could extrathymic T cells substitute for thymus-derived T cells? To address this issue, we studied extrathymic T cells that develop in athymic mice under the influence of oncostatin M (OM). In this model, extensive T-cell development is probably due to amplification of a minor pathway of T-cell differentiation taking place only in the lymph nodes. Extrathymic CD4 T cells expanded poorly and were deficient in providing B-cell help after infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV).