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.
Highlights
Human immunodeficiency virus type 1 (HIV-1) was first discovered in 1983 as the agent that causes acquired immune deficiency syndrome (AIDS) (Barre-Sinoussi et al, 1983)
HIV1 disrupts the immune system by infecting immune cells, such as CD4+ T cells, macrophages, and dendritic cells, which leads to AIDS and related opportunistic infections
Efforts have been made to quantify the size of the latent reservoirs [reviewed by Wang et al (2018); Lambrechts et al (2020)]; studies have demonstrated that the majority of proviral DNA in the latent reservoirs is replication-defective and does not contribute to viral rebound when combination antiretroviral therapy (cART) ceases
Summary
Human immunodeficiency virus type 1 (HIV-1) was first discovered in 1983 as the agent that causes acquired immune deficiency syndrome (AIDS) (Barre-Sinoussi et al, 1983). HIV-1 viral infectivity factor (Vif) recruits an E3 ubiquitin ligase complex to promote the degradation of A3 proteins through a proteasome-mediated pathway and counteracts their antiviral activity [reviewed by Harris and Dudley (2015); Salamango and Harris (2020); Figure 1B]. This possibility is supported by previous studies showing that HIV-1-infected patients (including long-term non-progressors) with at least one allele of stable A3H haplotypes have slower disease progression to AIDS (Ooms et al, 2013; Sakurai et al, 2015).
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