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Human Immunodeficiency Virus (HIV) is the etiological agent of AIDS and is responsible for the AIDS pandemic worldwide. According to UNAIDS, as of 2016, there were approximately 36.7 million people living with HIV globally, and 1.8 million new infections that year. While antiretroviral therapies and education continue to reduce these numbers, a preventative vaccine is still required to curb this epidemic. The envelope glycoprotein trimer of HIV, which is the sole protein on the surface of the virus and facilitates entry of the virus into host cells, is of keen interest to the HIV vaccine and drug-development field. Recently, the structure of this trimer was solved which has opened the door for the design of new immunogens and drugs. These solved envelope protein trimer structures demonstrate that the major variable loops of the env protein are positioned at the apex of the trimer where they play a role in trimer stability. Data from our lab has shown previously that both the V2 and V3 loop contain elements that are critical for envelope trimer stability.
The work presented in this dissertation expands on these initial studies and confirms that the V2 and V3 loops contribute to envelope trimer stability and functionality in HIV-1, HIV-2 and in Simian Immunodeficiency Virus (SIV) species. We have demonstrated that the hydrophobic patch near the tip of the V3 loop, which is present in all primate lentiviruses, is critical for trimer stability in subtype C HIV-1, HIV-2 and in SIV species. Additionally, we further explored the role of the twin-cysteine motif found in the V2 loop of HIV-2 and SIV species, but not in HIV-1. We have shown that this motif is critical for the stability of the envelope protein of these viruses. Both observations are supported by our experimental data and by molecular modeling. This work supports the released trimer structures and provides a further understanding of the forces that stabilize the envelope trimer of primate lentiviruses, and will aid in the development of stabilized envelope trimer based immunogens in the effort to develop an effective HIV vaccine.
Advisor: Shi-Hua Xiang