Identification of immunological targets for HIV-1 vaccine and cure strategies

HIV-1 chronically infected individuals represent a large disease burden, making the development of a therapeutic vaccine for use in chronic infection a priority. However, therapeutic vaccination has not been successful to date. Most approaches have employed viral vectored vaccines encoding full length viral proteins, which aimed to boost pre-existing CD8+ T cell responses by mimicking natural HIV-1 infection. Simply boosting these pre-existing CD8+ T cell responses which have previously failed to control the virus may be insufficient. Although HIV-1 has a huge capacity to diversify, certain regions are less tolerant of mutations due to structural and functional constraints. We therefore hypothesised that it would be necessary to redirect the immune response to more vulnerable regions of the proteome, such as conserved regions. HIVconsv is a rationally designed conserved region vaccine. Vaccination of 19 chronically HIV-1 infected HAART treated patients with MVA.HIVconsv was safe and well tolerated. There was a significant increase in the magnitude of HIVconsv-specific T cell response following vaccination (p = 0.001), as measured by IFN-γ Elispot assay, but changes observed in vaccinees did not reach statistical significance when compared with placebo recipients (p = 0.48). The capacity of CD8+ T cells to inhibit HIV-1 replication in vitro is highly predictive of virus control in vivo and is thus a possible surrogate of vaccine efficacy. There was a trend towards increased CD8+ T cell mediated inhibition following vaccination with 2x108pfu MVA.HIVconsv (17% inhibition pre- vs 54% inhibition post-vaccination, p = 0.06). However, measurement of the latent HIV-1 reservoir by quantification of total HIV-1 DNA in circulating CD4+ T cells by droplet digital PCR showed no reduction in size upon vaccination, indicating CD8+ T cells induced by vaccination with MVA.HIVconsv were not of sufficient potency to impact the reservoir. In a second cohort of HIV-1 infected individuals, antiviral inhibitory activity was measured in 36 HIV-1-infected STEP and Phambili trial participants. Sustained potent CD8+ T cell antiviral inhibitory responses were rare but were strongly correlated with IFN-γ responses to so-called ‘beneficial’ low entropy regions in HIV-1 Gag and Pol, that had been reported previously to be associated with HIV-1 control, (r = 0.69, p = 0.0001). This correlation was still significant after controlling for protective HLA alleles, whereas responses to conserved elements were only weakly correlated with viral inhibition (r = 0.41, p = 0.04). These data indicate that immunogens that are based on the selection of regions within the viral proteome by conservation score alone may not induce the most effective HIV-1-specific T cell responses and they highlight the importance of systematically selecting specific regions associated with HIV-1 control, together with exclusion of immunodominant decoy epitopes.This thesis is not currently available via ORA