Overcoming macaque Tetherin to generate an improved animal model for HIV/AIDS

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HIV-1 is the causative agent of AIDS. So far no vaccine is available and due to the high mutability of the virus resistance to available antiretroviral therapies are emerging. For the development of an effective vaccine and new antiretroviral drugs an HIV-1 animal model is necessary. SIV infection in macaques has been studied intensively. However, due to high genetic divergence between HIV-1 and SIV this animal model cannot be used for preclinical studies. HIV-1 is not able to replicate in non-human primates mainly due to the presence of so called restriction factors. In contrast SIVMAC has developed ways to counteract these factors. By studying how these viruses antagonize restriction factors, attempts have been made to develop an HIV-1 variant that is able to replicate in pigtailed macaques. This virus variant called simian tropic HIV (stHIV) contains only the Vif protein of SIVMAC. It is able to replicate to high levels during the acute phase of infection but then does not lead to a sustained high viral load infection with AIDS like symptoms. Preliminary results in vitro indicate that stHIV replication in macaques is limited due to the presence of Interferon (IFN) inducible factors. Recently, an IFN inducible restriction factor called Tetherin that inhibits particle release has been discovered. HIV-1 is not able to counteract macaque Tetherin. Therefore, in this study, we will generate stHIV variants able to counteract macaque Tetherin by either manipulating the Nef or the Vpu protein of HIV-1. Subsequently, we will determine whether overcoming macaque Tetherin is necessary and sufficient to allow stHIV to replicate in vitro in macaque PBMCs in the absence or presence of IFN-¿ or whether additional restriction factors are present limiting stHIV replication. Finally, we will evaluate in vivo if this virus variant is able to induce a chronic infection in pigtailed macaques with persistent high viral loads, leading to an AIDS-like disease in these animals.