APOBEC3-Related Editing and Non-Editing Determinants of HIV-1 and HTLV-1 Restriction

Abstract

The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3/A3) family of cytosine deaminases serves as a key innate immune barrier against invading retroviruses and endogenous retroelements. The A3 family's restriction activity against these parasites primarily arises from their ability to catalyze cytosine-to-uracil conversions, resulting in genome editing and the accumulation of lethal mutations in viral genomes. Additionally, non-editing mechanisms, including deaminase-independent pathways, such as blocking viral reverse transcription, have been proposed as antiviral strategies employed by A3 family proteins. Although viral factors can influence infection progression, the determinants that govern A3-mediated restriction are critical in shaping retroviral infection outcomes. This review examines the interactions between retroviruses, specifically human immunodeficiency virus type 1 and human T-cell leukemia virus type 1, and A3 proteins to better understand how editing and non-editing activities contribute to the trajectory of these retroviral infections.

Keywords: APOBEC3 family proteins; HIV-1; HTLV-1; deaminase-dependent mechanisms; deaminase-independent mechanisms; retrovirus restriction.

Figure 1

Mechanisms underlying A3-mediated restriction of HIV-1 infection. The A3-mediated restriction of Vif-deficient HIV-1 infection involves the binding of A3 proteins to viral RNA (red), which is then packaged into nascent virions during viral assembly in the producer cells. In target cells, A3 proteins perform deamination-dependent editing on the viral single-stranded cDNA intermediates (brown), introducing potentially lethal G-to-A mutations (highlighted in orange). Additionally, A3 proteins exert a deaminase-independent, non-editing restriction by physically hindering viral reverse transcription and altering the selection of proviral DNA integration sites, favoring transcriptionally silent regions of host DNA. To counteract A3-meditated restriction, HIV-1 employs its accessory protein Vif, which ubiquitinates A3 proteins, targeting them for proteasomal degradation. Consequently, A3 proteins are poorly incorporated into nascent virions, and the cDNA intermediates experience few or no sublethal G-to-A mutations, resulting in a reduced restriction of HIV-1 replication. Each A3 Z domains are colored, respectively, light green: Z2 domains, dark green: Z1 domain, and blue: Z3 domain. A3: apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3/APOBEC3, ARIH2: Ariadne homolog 2, CBF-β: Core-binding factor β, Cul-5: Cullin 5, ELOB: Elongin B, ELOC: Elongin C, Env: Envelope, Gag: Group-specific antigen, RBX2: RING-box protein 2, RT: Reverse transcriptase, Ub: Ubiquitin, Vif: Viral infectivity factor.

Figure 2

Structural, cellular, and substrate-based regulation of A3 family protein activity. The activity of A3 family proteins is influenced by various factors, including their protein properties, domain organization, amino acid composition, and conserved secondary structural features near the catalytic site, which affect substrate selection and regulate deamination enzymatic activity. Genetic variants of individual A3 proteins can lead to variable deamination activity. The presence of preferred nucleotides in the substrates enhances the deamination activity of specific A3 proteins. Cellular factors, such as protein localization, phosphorylation status, and the influence of cellular cofactors (e.g., HSP90) or upstream regulators (e.g., IFNs), further modulate the activity of A3 proteins, influencing both their editing and non-editing functions.

Figure 3

Controversial outcome of the A3–HTLV-1 interaction. During HTLV-1 reverse transcription, A3 proteins can induce editing activity (left) via A3-mediated deamination. A3G, for instance, induces G-to-A mutations in the proviruses of HTLV-1 carriers and patients with ATL. Overexpression studies also suggest that A3A, A3B, and A3H stable haplotypes can restrict HTLV-1 infection. However, HTLV-1 appears to be relatively resistant to A3 protein activity due to its distinct replicative strategy and transmission methods (right). The integrated HTLV-1 genome drives the clonal expansion of infected CD4⁺ T cells (top right), promoting viral dissemination without the production of large numbers of viral particles. HTLV-1 uses cell-based transmission mechanisms (middle right), including viral synapses, tunneling nanotubes, and cellular protrusions, minimizing exposure to A3 proteins. Finally, the HTLV-1 NC protein (bottom right) impairs A3G packaging into HTLV-1 virions, further contributing to the virus’ resistance to A3-mediated restriction.