Evolutionary Paradigms from Ancient and Ongoing Conflicts between the Lentiviral Vif Protein and Mammalian APOBEC3 Enzymes

Lentiviruses are a unique class of retroviruses that infect a subset of mammalian species, including humans. Human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2), simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), bovine immunodeficiency virus (BIV), maedi-visna virus (MVV), and caprine arthritis encephalitis virus (CAEV) infections result in immunodeficiency syndromes, neurological diseases, and other conditions. Disease is chronic, lifelong, and often fatal. Pathology is due in part to a capacity to immortalize by integrating into a host’s genomic DNA and a remarkable genetic plasticity that enables escape from potent adaptive immune responses without compromising vital viral functions. Lentiviruses encode three universal retroviral proteins (Gag, Pol, and Env), one lentivirus-specific protein called Vif (virus infectivity factor), and a handful of other less conserved accessory factors. Vif is required to protect lentiviruses from restriction by several members of the APOBEC3 family of DNA cytosine deaminases by forming a cellular polyubiquitin ligase complex to degrade these enzymes (Fig 1A). Viruses lacking Vif are inactivated because cytoplasmic APOBEC3 enzymes remain abundant, package into assembling virus particles, and prevent the production of a viable DNA copy of the viruses’ RNA genome by catalyzing the deamination of viral cDNA cytosines to uracils. Viral DNA genomes that make it through this gauntlet are rendered nonfunctional by the resulting guanine to adenine hypermutations (cDNA uracils template the insertion of genomic strand adenines that become immortalized as G-to-A mutations). In this Pearl, we review recent progress in understanding the Vif-APOBEC3 interaction and discuss a model that provides a molecular explanation for past zoonotic transmission events as well as present-day, likely ongoing optimizations that enable lentiviruses to thrive. Fig 1 Lentiviral Vif and APOBEC3 diversity and functionality in mammals. CBF-β is a specific co-factor for SIV and HIV Vif function Although HIV-1 was identified in 1983, Vif function evaded discovery for nearly 20 years, until APOBEC3G (A3G) emerged as a dominant cellular factor that strongly inhibited vif-deficient virus replication [1]. This advance led rapidly to elucidation of the proteasome-dependent APOBEC3 degradation mechanism, including the identification of cellular factors that Vif recruits to form the degradation complex (CUL5, ELOB, ELOC, and RBX2) (Fig 1A) [2, 3]. However, HIV-1 Vif still resisted biochemical and structural studies for nearly another decade, suggesting that the complex may be incomplete. This puzzle was solved in 2011, when the transcription cofactor CBF-β proved to be an essential part of the HIV-1 Vif ubiquitin ligase complex [4, 5]. CBF-β enabled the biochemical reconstitution of the Vif ubiquitin ligase complex [4] and, shortly thereafter, structural determination by X-ray crystallography [6]. Vif and CBF-β heterodimerize and form a scaffold for further assembly of an active ligase complex (Fig 1A and 1B). Surprisingly, CBF-β is only essential for HIV and SIV Vif function (Fig 1C) [7]. The APOBEC3 degradation activity of non-primate lentiviral Vif proteins is unaffected by cellular CBF-β [4, 5, 8–11]. These differing genetic and biochemical requirements were initially puzzling given that all known Vif proteins function to counteract host APOBEC3 enzymes (e.g., [12]). However, the HIV/SIV Vif requirement for CBF-βmay be reconciled by postulating that this adaptation occurred when an ancestral lentivirus transmitted from a non-primate mammal into a primate. Such an event likely took place millions of years ago, because an endogenous lentivirus with a putative Vif protein exists in the present-day genomes of at least two evolutionarily diverged lemur genera [13, 14]. Because exogenously spreading lentiviruses evolve too quickly to date based on cumulative genetic diversity, endogenization events such as this effectively fossilize a virus and provide rare opportunities for estimating the age of a particular viral species and making comparisons with present day descendants such as SIV and HIV.