Potential Utilization of APOBEC3-Mediated Mutagenesis for an HIV-1 Functional Cure

Abstract

The introduction of combination antiretroviral therapy (cART) has managed to control the replication of human immunodeficiency virus type 1 (HIV-1) in infected patients. However, a complete HIV-1 cure, including a functional cure for or eradication of HIV-1, has yet to be achieved because of the persistence of latent HIV-1 reservoirs in adherent patients. The primary source of these viral reservoirs is integrated proviral DNA in CD4⁺ T cells and other non-T cells. Although a small fraction of this proviral DNA is replication-competent and contributes to viral rebound after the cessation of cART, >90% of latent viral reservoirs are replication-defective and some contain high rates of G-to-A mutations in proviral DNA. At least in part, these high rates of G-to-A mutations arise from the APOBEC3 (A3) family proteins of cytosine deaminases. A general model has shown that the HIV-1 virus infectivity factor (Vif) degrades A3 family proteins by proteasome-mediated pathways and inactivates their antiviral activities. However, Vif does not fully counteract the HIV-1 restriction activity of A3 family proteins in vivo, as indicated by observations of A3-mediated G-to-A hypermutation in the proviral DNA of HIV-1-infected patients. The frequency of A3-mediated hypermutation potentially contributes to slower HIV-1/AIDS disease progression and virus evolution including the emergence of cytotoxic T lymphocyte escape mutants. Therefore, combined with other strategies, the manipulation of A3-mediated mutagenesis may contribute to an HIV-1 functional cure aimed at cART-free remission. In this mini-review, we discuss the possibility of an HIV-1 functional cure arising from manipulation of A3 mutagenic activity.

Keywords: A3 expression; A3-interacting proteins; APOBEC3-mediated mutagenesis; Vif inhibitors; adaptive immunity; genetic factors.

FIGURE 1

A model of HIV-1 restriction by A3 family proteins and counteraction by HIV-1 Vif. (A) Illustration of human A3 family genes. Human A3 family genes are composed of seven members with one or two zinc-coordinating domains (single of double-domain deaminases); these belong to three phylogenetically different groups, which are shown in green, yellow, and blue. (B) A schematic of HIV-1 restriction by five A3 family proteins and neutralization by HIV-1 Vif. A3C, A3D, A3F, A3G, and A3H are packaged into HIV-1 virions in producer cells and inactivate the virus through cytosine-to-uracil (C-to-U)/guanine-to-adenine (G-to-A) mutations (top). HIV-1 Vif neutralizes the restriction activities of these A3 proteins through proteasome-mediated degradation (bottom). Vif, virus infectivity factor; A3, APOBEC3.

FIGURE 2

Potential effects of A3-mediated mutagenesis on CTL responses. A3F- and A3G-mediated mutagenesis alters CTL responses through the accumulation of G-to-A mutations on the viral genome, which leads to the modification of epitope sequences and their flanking regions involved in antigen processing/presentation, HLA binding, and TCR recognition. The two examples show that A3-mediated hypermutation on epitope sequences potentially alters HLA binding of the epitopes and TCR recognition. Sublethal A3-mediated mutagenesis is involved in the emergence of CTL escape variants (top), whereas lethal A3-mediated hypermutation likely increases the number of HIV-derived epitopes and consequently enhances HIV-1-specific CTL responses (bottom). A3, APOBEC3; CTL, cytotoxic T lymphocyte; HLA, human leukocyte antigen; TCR, T cell receptor.