Human immunodeficiency virus type-1 (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), has caused one of the most widespread and devastating pandemics in human history, and continues to persist as a substantial burden on global healthcare, social and economic systems, despite significant advances in modern anti-retroviral therapies. HIV-1 primarily infects CD4+ T lymphocytes, and to a lesser degree, macrophages, monocytes and dendritic cells. In the absence of therapeutic intervention, HIV-1 infection results in the gradual depletion of CD4+ T cells, leading to a severely compromised immune response and increased susceptibility to a wide range of opportunistic infections and malignancies. The innate immune response to HIV-1 infection in CD4+ T cells is mediated in part by members of the APOBEC3 family of DNA cytosine deaminases. In the absence of the viral Vif protein, multiple APOBEC3 enzymes can package into virions budding from an infected cell. Following virus entry into a new target cell, the APOBEC3 enzymes catalyze the deamination of cytosines to uracils in viral reverse transcription intermediates, resulting in mutations that can render viral gene products non-functional. The HIV-1 Vif protein counteracts the antiviral activity of the APOBEC3 enzymes by commandeering a cellular ubiquitin ligase comprised of CBF-β, ELOB, ELOC, CUL5 and RBX2, to polyubiquitylate the APOBEC3 enzymes and target them for proteasomal degradation. Thus, viral progeny are mostly protected from APOBEC3 mutagenesis. Despite significant advances in understanding the mechanisms that govern APOBEC3-dependent HIV-1 restriction, as well as Vif-dependent counteraction of this iii host defense, little is known about how these innate antiviral enzymes are regulated at the transcriptional level. The first part of this thesis identifies the CBF-β/RUNX transcription complex as a critical regulator of APOBEC3 gene expression in CD4+ T cells (APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H, but not APOBEC3A or APOBEC3B). This unexpected discovery suggests that HIV-1 Vif may employ a secondary mechanism in counteracting the host APOBEC3 defense by hijacking CBF-β from RUNX-associated transcription complexes to downregulate transcription of the APOBEC3 genes themselves. Thus, Vif may disarm the host APOBEC3 response by targeting these enzymes for proteasomal degradation, while simultaneously interfering with their ongoing expression at the transcriptional level. The seven membered APOBEC3 gene family is highly polymorphic within the human population, and several common genetic variations manifest as clear biochemical phenotypes. The second part of this thesis focuses on a rare variant of APOBEC3C (S188I), which confers enhanced HIV-1 restriction activity in comparison to the predominant S188 variant, which has been largely disregarded as playing a role in innate immunity to HIV-1 in T cells. The studies within characterize the antiviral activity of this APOBEC3C variant in multiple CD4+ T cell lines, and ultimately demonstrate that the S188I polymorphism renders APOBEC3C capable of protecting cells against Vif- deficient virus replication. These findings provide an additional example of meaningful variation within the human APOBEC3 repertoire that may impact virus replication and transmission in vivo, and will likely be the subject of follow up in several large ongoing HIV-1 infected patient cohort studies.