Holuigue, S.; (2005) The humoral immune response to HIV-1: Consequences for vaccine design. Doctoral thesis , University of London.

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Abstract

Some 42 million individuals worldwide are infected by the Human Immunodeficiency Virus (HIV) and no cure or vaccine is available. This thesis addresses approaches to humoral immunity to HIV-1. In primary infection, the cytotoxic T lymphocyte (CTL) response is detected early and is thought to play a role in the viral decline. Neutralising antibodies (NAbs) are detected much later. However, non-neutralising anti-HIV-1 Env glycoprotein Abs (non-NAbs) are present concomitantly with the CTL response. The possible role of non-NAbs with complement was investigated using sequential sera and viruses expressing gpl20 Env (gpl20) glycoproteins amplified from blood samples from a cohort of newly HIV-1 infected patients. Autologous gpl20 sequences were cloned and expressed into a replication-competent HIV-1 backbone. The autologous Ab pattern was studied. In the presence of complement, inactivation of autologous and heterologous HIV could be detected as early as day 9 post-onset of symptoms (POS). IgG were partly responsible for triggering the classical complement cascade. In parallel, a new approach was investigated to generate a recombinant vaccine to HIV-1. Camelids synthesise IgG devoid of light chains. These IgG fragments (Vhh) share the same characteristics as classical IgG but have unusually long CDR H3 regions that can adopt more flexible conformations. The possibility of generating Vhh fragments that mimic the neutralising CD4 binding site (CD4BS) of HIV-1 was investigated. A llama was immunised with IgGl bl2 (bl2), a potent cross-neutralising human NAb overlapping the CD4BS of HIV-1. The non-classical Vhh repertoire was cloned, the resulting libraries were panned against bl2 by phage display and five specific anti-bl2 Vhh fragments were isolated. Each of the five fragments was tested in animals for the induction of an anti-HIV-1 NAb response. These studies are discussed with reference to the control of HIV-1 infection by drugs and vaccines.

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