HIV-1 Counteraction Mechanisms Versus APOBEC3-mediated Restriction

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HIV-1 Counteraction Mechanisms Versus APOBEC3-mediated Restriction

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2018-07

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Abstract

Human Immunodeficiency Virus type 1 (HIV-1) is responsible for the etiology of Acquired Immunodeficiency Syndrome (AIDS). Almost 40 years’ worth of intensive HIV-1 research have not yet led to a cure, nor is an efficacious vaccine available. The number of deaths caused by HIV-1/AIDs is declining due to effective, though non-curative, combinations of highly active antiretroviral therapy (HAART) regimens. Given that in 2016: 1.8 million newly infected people were infected with HIV-1 in 2016, 36.7 million people globally were living with HIV-, and 1 million people died from AIDS-related (UNAIDS Fact Sheet – 2018), every avenue to discovering a cure should be sought out. HIV-1’s life cycle is characterized by eight steps. Step 1 is known as attachment, where HIV-1 binds to the receptors of a CD4+ cells. Step 2 is fusion, where the viral envelope fuses with the cellular membrane, granting the virus entry to the host cell. Step 3 is reverse transcription, where the viral RNA that is now inside the host cells is converted into viral DNA. Step 4 is integration, where the HIV-1 DNA is shuttled into the nucleus, as part of a high molecular weight pre-integration complex, by co-opting host nuclear import machinery, followed by HIV-1 integrase catalyzes the insertion of the viral DNA into the host’s genome making a provirus. Step 5 is replication, where the integrated viral DNA hijacks host machinery to make viral RNA copies as well as viral structural proteins that are used as building blocks for HIV-1 particle formation. Step 6 is assembly, where newly synthesized HIV-1 proteins and viral RNA are trafficked and used to assemble an immature (noninfectious) particle at the cell membrane. Step 7 is known as budding, where the immature particle undergoes membrane scission with the host cell releasing the particle into extracellular space. Step 8 is maturation, where HIV-1 protease is activated in the newly released particle and it begins to cleave the structural proteins of the virus, releasing intra-virion proteins that are required to make the particle infectious (mature). APOBEC3 (A3) enzymes are packaged into budding virions from a cell already infected with HIV-1 (Steps 6-7). After a virion containing A3 enzymes enters a target cell (Steps 1-2), the A3s can restrict HIV-1 via deaminase-dependent and -independent mechanisms during reverse transcription (Step 3), which is described in more detail below. However, HIV-1 encodes virion infectivity factor (Vif), which allows the virus to retain high levels of infectivity via proteasomal degradation of cellular A3 restriction factors in cells producing virus. Restrictive A3 enzymes capacity to incapacitate HIV-1 is such that no appreciable infectivity is observed in Vif-null systems, thereby suggesting that modulation of the A3-Vif axis in the host’s favor could be a potentially curative antiretroviral approach. In this thesis, three separate projects combine to advance our understanding of the A3-mediated restriction mechanism and the Vif-mediated counteraction mechanism. Chapter 2 uses human APOBEC3F (A3F) to adapt HIV-1 and create a genetic and structural map of the Vif interaction surface. Chapter 3 compares the HIV-1 restriction activity of splice variants human APOBEC3H (A3H) and reports differential antiviral activities and a novel viral protease-dependent counteraction mechanism. Chapter 4 explores potential antiviral strategies using synthetic peptides derived from Vif. Collectively, these studies increase our overall understanding of how HIV-1 counteracts A3 restriction factors. Ultimately, this work informs the next generation of approaches directed at discovering ways to modulate these interactions in potentially curative ways.

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University of Minnesota Ph.D. dissertation.July 2018. Major: Pharmacology. Advisor: Reuben Harris. 1 computer file (PDF); xiv, 188 pages.

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Richards, Christopher. (2018). HIV-1 Counteraction Mechanisms Versus APOBEC3-mediated Restriction. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/200266.

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