Examination of the APOBEC3 Barrier to Cross Species Transmission of Primate Lentiviruses

Abstract

The transmission of viruses from animal hosts into humans have led to the emergence of several diseases. Usually these cross-species transmissions are blocked by host restriction factors, which are proteins that can block virus replication at a specific step. In the natural virus host, the restriction factor activity is usually suppressed by a viral antagonist protein, but this is not the case for restriction factors from an unnatural host. However, due to ongoing viral evolution, sometimes the viral antagonist can evolve to suppress restriction factors in a new host, enabling cross-species transmission. Here we examine the classical case of this paradigm by reviewing research on APOBEC3 restriction factors and how they can suppress human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). APOBEC3 enzymes are single-stranded DNA cytidine deaminases that can induce mutagenesis of proviral DNA by catalyzing the conversion of cytidine to promutagenic uridine on single-stranded viral (−)DNA if they escape the HIV/SIV antagonist protein, Vif. APOBEC3 degradation is induced by Vif through the proteasome pathway. SIV has been transmitted between Old World Monkeys and to hominids. Here we examine the adaptations that enabled such events and the ongoing impact of the APOBEC3-Vif interface on HIV in humans.

Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers

“…The evolutionary pressure that restriction factors and antagonists have exerted on each other resulted in further adaptations at the virus-host interface. Thus, restriction factors are often less effective against viral infections of their natural host but constitute potent barriers to cross-species infections [ 3 ].…”

Special Issue “APOBECs and Virus Restriction”

“…The apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) enzyme family in humans has 11 members with diverse functions in metabolism and immunity [ 1 , 2 , 3 , 4 ]. The enzymes deaminate cytosine in RNA or single-stranded (ss) DNA, which forms uracil.…”

“…To inhibit HIV, the APOBEC3 enzymes must become encapsidated into the budding virion [ 2 , 3 , 12 ]. This enables access to the viral genome and newly synthesized (-) DNA during reverse transcription.…”

“…This results in uracil templating the addition of adenine upon synthesis of the (+)DNA, resulting in a hypermutated and likely inactivated virus. APOBEC3s can also physically block reverse transcriptase, which prevents full proviral DNA synthesis [ 2 ]. HIV produces a protein called Vif which tries to prevent APOBEC3 encapsidation by multiple mechanisms.…”

“…Although these polymorphisms have a role in battling present day HIV infection, the origins date back to the transmission of HIV into humans from simian immunodeficiency viruses (SIV) in other primates. Uriu et al and Gaba et al describe how HIV was transmitted into humans [ 2 , 4 ]. HIV-1 is a transmission from chimpanzee or gorilla [ 2 , 4 ].…”