HIV-1 immune responses induced by natural infection or immunisation

Sammanfattning: The development of an effective HIV-1 vaccine must be considered as one of today s greatest biomedical goals and challenges. The nature of the HIV-1 virus, characterised by its tropism for the CD4+ T cells of the immune system and its integration into the host genome, together with the vast viral variability, allows the HIV-1 virus to establish a latent infection and evade the host defence mechanisms. In our endeavour to develop a genetic HIV-vaccine that elicits broad and robust immune responses to several virus variants, we have demonstrated major cross-clade Gag responses in patients infected with different subtypes of HIV-1. This indicates that genetic vaccines encoding Gag from a few strains may act to induce immunity to broad ranges of HIV-1 clades. We also found that HIV-1 infection results in release of intracellular perforin into the serum of HIV infected individuals and in SIV/SHIV infected monkeys. As perforin secretion/production has been shown to be associated with control of HIV-1 infection, the aberrant perforin release may be a result of a yet unknown viral immune escape mechanism. Individuals enrolled in two therapeutic and one prophylactic HIV-1 vaccine trial were analysed for their vaccine-specific immune responses. Analyses of the therapeutic vaccine samples revealed that: 1) Multiple injections with recombinant HIV-1 glycoprotein 160 induces an increased central memory T cell population, which can be associated with increased antigenspecific cellular immune responses in treatment naïve HIV-1 infected individuals. 2) Topical DNA immunisation, combined with repeated treatment interruptions in patients on successful antiretroviral therapy, induced novel HIV-1 specific cellular immune responses. Such treatment did permit extended drug-free periods for all participants. Moreover, the viral load set points were significantly lower after the treatment protocol than before initial onset of any antiretroviral treatment. However, the decreased viral load set points were not related to the HIV-1 immunisation. In the prophylactic study, HIV-1 DNA followed by a recombinant vaccinia virus vector boost induced strong and broad HIV-1 specific cellular immune responses. In healthy individuals, we found that previous immunity to vaccinia only moderately reduced the HIV-specific immune responses when vaccinia was used as a vector for HIV genes. This finding suggests that vaccinia-based immunogens can be used despite the presence of pre-existing immunity to this vector. Immunisation of HIV-1 infected individuals is difficult, as HIV-1 infection leads to a dysfunctional immune system. Despite efforts to induce new and improve existing immune responses by therapeutic vaccination, no clinical trial has yet been able to show long-term sustained clinical effects of immunisation. The modest and transient effects observed by us with currently available DNA vaccines highlight the need to develop immunisation strategies which combine immunisation with novel antiviral therapies.