Abstract
Numerous challenges have impeded HIV-1 vaccine development. Among these is the lack of a convenient small animal model in which to study antibody elicitation and efficacy. We describe a chimeric Rhabdo-Immunodeficiency virus (RhIV) murine model that recapitulates key features of HIV-1 entry, tropism and antibody sensitivity. RhIVs are based on vesicular stomatitis viruses (VSV), but viral entry is mediated by HIV-1 Env proteins from diverse HIV-1 strains. RhIV infection of transgenic mice expressing human CD4 and CCR5, exclusively on mouse CD4+ cells, at levels mimicking those on human CD4+ T-cells, resulted in acute, resolving viremia and CD4+ T-cell depletion. RhIV infection elicited protective immunity, and antibodies to HIV-1 Env that were primarily non-neutralizing and had modest protective efficacy following passive transfer. The RhIV model enables the convenient in vivo study of HIV-1 Env-receptor interactions, antiviral activity of antibodies and humoral responses against HIV-1 Env, in a genetically manipulatable host.
Highlights
Numerous challenges have impeded the development of a vaccine that protects against HIV-1 infection
We generated a panel of chimeric Rhabdo-Immunodeficiency viruses (RhIVs) encoding Env proteins from diverse HIV-1 strains including those representative of strains circulating in human populations
We generated a larger panel of RhIV constructs expressing a variety of physiologically relevant envelope proteins from HIV-1 clades A, B, and C, including transmitted founder (T/F) viruses
Summary
Numerous challenges have impeded the development of a vaccine that protects against HIV-1 infection. The ability to genetically engineer both the virus and the mouse host – for example by making mice that produce human antibodies – allows further studies into the development of antibodies that recognize the HIV-1 envelope. What distinguishes the rare individuals who generate bNAbs, and whether it is possible to generate bNAbs in a significant fraction of humans through vaccination, are key issues confronting the HIV-1 vaccine research field (Landais and Moore, 2018) Another significant impediment to HIV-1 vaccine development is the availability of a convenient animal model system in which to study antibody elicitation and efficacy (Hatziioannou and Evans, 2012). We generated recombinant derivatives of the rhabdovirus, vesicular stomatitis virus (VSV), in which the native envelope glycoprotein (G) is replaced by HIV-1 Env from various subtypes, including transmitted founder strains In these Rhabdo-Immunodeficiency viruses (RhIV), replication is entirely dependent on HIV-1 Env, as well as human CD4 and coreceptors on target cells. The RhIV model enables the convenient in vivo study of HIV-1 Envreceptor interactions, and their inhibition by antibodies in a genetically manipulatable host
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