The antiretroviral potency of APOBEC1 deaminase from small animal species

Abstract

Although the role of the APOBEC3-dependent retroelement restriction system as an intrinsic immune defense against human immunodeficiency virus type1 (HIV-1) infection is becoming clear, only the rat ortholog of mammalian APOBEC1s (A1) thus far has been shown to possess antiviral activity. Here, we cloned A1 cDNAs from small animal species, and showed that similar to rat A1, both wild-type and Δvif HIV-1 infection was inhibited by mouse and hamster A1 (4- to 10-fold), whereas human A1 had negligible effects. Moreover, rabbit A1 significantly reduced the infectivity of both HIV-1 virions (>300-fold), as well as that of SIVmac, SIVagm, FIV and murine leukemia virus. Immunoblot analysis showed that A1s were efficiently incorporated into the HIV-1 virion, and their packaging is mediated through an interaction with the nucleocapsid Gag domain. Interestingly, there was a clear accumulation of particular C-T changes in the genomic RNAs of HIV-1 produced in their presence, with few G-A changes in the proviral DNA. Together, these data reveal that A1 may function as a defense mechanism, regulating retroelements in a wide range of mammalian species.

APOBEC1-Mediated Editing and Attenuation of Herpes Simplex Virus 1 DNA Indicate That Neurons Have an Antiviral Role during Herpes Simplex Encephalitis

“…6H, we found the preferred context to be 5ЈGpC on both viral DNA and RNA (Fig. 6H), although previous studies indicated a tendency of rodent A1 to prefer 5ЈTpC (11,29,49). Altogether, these results indicate that rat A1 acts directly on DNA for editing.…”

“…A1 homologues are putative inducers of mutations in retrovirus DNA and also in DNA of A1-expressing bacteria (8,24,29,44,49). Thus, to investigate the mechanism of the A1-dependent inhibition of HSV-1 gene expression, we looked at the potential editing of HSV-1 viral DNA.…”

The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas

“…On the other hand, APOBEC1 can also target DNA in bacteria and in vitro [15][16][17]. Based on this activity, other roles have been suggested, from controlling DNA methylation [18,19], to being part of a restriction pathway against retroviruses and mobile elements, similar to the APOBEC3s [20][21][22][23][24][25].…”

Intrinsic restriction activity by AID/APOBEC family of enzymes against the mobility of retroelements

“…[12][13][14] In addition, several reports indicated that A1s from several mammalian species inhibit a wide range of exogenous retroviruses such as HIV-1. [15][16][17][18] These results raise the possibility that not only A3 proteins but also AID and A1 cytidine deaminases are likely to participate in the intrinsic immunity in various mammalian species against the retrotransposition of endogenous and exogenous retroviruses. The catalytic activity of A1s appeared to be critical for these repressive potentials.…”

“…The catalytic activity of A1s appeared to be critical for these repressive potentials. 14,17 In addition, although the expression of A1 in human has only been formally documented in gastrointestinal tissue, the distribution for mouse, rat and rabbit A1s is much wider, including tissues such as hepatocytes and spleen which are assumed to have little apoB mRNA. Furthermore, A1 mRNA is expressed in ovarian and testis tissue, at least in mouse and rabbit, placing A1 in a compartment where endogenous retrovirus may have the greatest impact in vivo.…”