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.

Genomic instability genes in lung and colon adenocarcinoma indicate organ specificity of transcriptomic impact on Copy Number Alterations

“…Other genes/pathways of interest include APOBEC3 (HR4.6), due to the strong HR, and B3GNT4 (HR2.4), due to its relation to mucin function. APOBEC3D encodes double-domain deaminase and is a member of the APOBEC3 family genes 51 . APOBEC3 proteins form Apolipoprotein B Editing Complex and mediate intrinsic responses to infection by retroviruses [e.g., HIV 52 ,], but also can act as a strong mutagenic factor 53 .…”

Host Restriction Factors Modulating HIV Latency and Replication in Macrophages

“…Although an in-depth discussion of this topic is beyond the scope of the present articles, some key information is summarized in Table 3. Vif APOBEC family members [125] Vpr Several (see Table 1) [126,127] Vpx SAMHD1 [128] Several inhibitors are being studied in the perspective of potentiating antigen presentation to CD8 + cytotoxic T lymphocytes by reverting Nef-induced downregulation of MHC class I, as discussed [123]. Vif inhibition of the cytidine deaminase activity of APOBEC family members has been selected as a target of pharmacological screening by mutagenizing these restriction factors [125].…”

“…Vif APOBEC family members [125] Vpr Several (see Table 1) [126,127] Vpx SAMHD1 [128] Several inhibitors are being studied in the perspective of potentiating antigen presentation to CD8 + cytotoxic T lymphocytes by reverting Nef-induced downregulation of MHC class I, as discussed [123]. Vif inhibition of the cytidine deaminase activity of APOBEC family members has been selected as a target of pharmacological screening by mutagenizing these restriction factors [125]. In consideration of the multiple levels of Vpr interference with cell function, including metabolism and cell cycle regulation, there has been an active search of inhibitors without thus far succeeding in the identification of specific candidates that could be tested in a clinical setting, as discussed [126,127].…”

Design of Vif-Derived Peptide Inhibitors with Anti-HIV-1 Activity by Interrupting Vif-CBFβ Interaction

“…Targeting the protein–protein interactions (PPIs) between Vif and the proteins in the E3 ubiquitin ligase complex to restore the mutagenic activity of A3 enzymes is an important direction for the development of anti-HIV-1 drugs [ 22 ]. Extensive studies have been conducted to develop inhibitors to disrupt the interactions, and most of them target the Vif-A3G and Vif-EloC interfaces [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ].…”