The Host Restriction Factor APOBEC3G and Retroviral Vif Protein Coevolve due to Ongoing Genetic Conflict

Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA.
Cell host & microbe (Impact Factor: 12.19). 01/2012; 11(1):91-8. DOI: 10.1016/j.chom.2011.11.010
Source: PubMed

ABSTRACT APOBEC3G (A3G) is a host cytidine deaminase that inhibits retroviruses. HIV and related primate lentiviruses encode Vif, which counteracts A3G by inducing its degradation. This Vif-mediated A3G inhibition is species specific, suggesting that the A3G-Vif interaction has evolved as primate lentiviruses have adapted to their hosts. We examined the evolutionary dynamics of the A3G-Vif interaction within four African green monkey (AGM) subspecies, which are each naturally infected with a distinct simian immunodeficiency virus (SIV). We identified single amino acid changes within A3G in two AGM subspecies that render it resistant to Vif proteins, except for Vif from the viruses that naturally infect these subspecies. Moreover, experimental infection of AGMs shows that Vif can rapidly adapt to these arising Vif-resistant A3G genotypes. These data suggest that despite being generally nonpathogenic in its natural host, SIV infection selects for Vif-resistant forms of A3G in AGM populations, driving Vif counterevolution and functional divergence.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gorillas in Southwest Cameroon Are the Reservoir of HIV-1 Group P Ancestors. Mirela D’arc 1,2, Ahidjo Ayouba 1, Amandine Esteban1, Lucie Etienne1, Sabrina Locatelli1, Avelin Aghokeng1,3, Eric Delaporte1, Eitel Mpoudi Ngole3, Martine Peeters1. 1 UMI 233, IRD and University of Montpellier 1, Montpellier, France. 2 Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 3 Projet PRESICA and IMPM/CREMER, Yaoundé, Cameroon BACKGROUND: In west central Africa, western lowland gorillas (Gorilla gorilla gorilla) are infected with a simian immunodeficiency virus, SIVgor, that is related to HIV-1 groups O and P. In order to better document the gorilla populations that could be at the origin of some HIV-1 strains, we extended our non-invasive studies on wild gorilla populations in southern Cameroon. METHODS: Fecal samples, preserved in RNA-later, were collected from wild gorilla populations at 11 different sites in southern Cameroon, especially around areas where we previously identified SIVgor infected gorillas. All samples were tested for the presence of HIV cross-reactive antibodies using the INNO-LIA HIV I/II confirmation test. Nucleic acids were extracted from all antibody reactive samples. RT-PCR amplifications were done using SIVcpz/SIVgor/HIV-1 consensus and specific primers in gag, pol, gp41 and LTR. The host species was confirmed using mitochondrial DNA analysis and the individuals were determined by microsatellite analysis. Phylogenetic analyses with reference sequences were performed using PhyML. RESULTS: A total of 855 fecal samples were collected, and 29 with SIV/HIV cross-reactive antibodies were detected in two sites in southwest Cameroon. SIVgor infection was confirmed in six samples from two gorillas in pol (280 bp) and/or gp41 (490 bp). Phylogenetic analyses showed that these viruses form a monophyletic lineage with previously characterized SIVgor and HIV-1 group P and that they are more closely related to HIV-1 group P than any other SIV. Additional sequence analyses of partial gag (400 bp) and LTR (330 bp) confirmed this observation. Overall, the genetic distance of the new SIVgor strains to HIV-1 P was smaller (0.138 vs 0.229) than for the previously reported SIVgor strains. Most importantly, the genetic distance between SIVgor and HIV-1 group P was smaller or comparable to the distance between SIVcpz and their HIV-1 counterparts, groups M (0.221) or N (0.136), respectively. CONCLUSIONS: It is the first clear evidence that SIVgor has been transmitted to humans and that gorilla populations from southwest Cameroon were the source of HIV-1 group P. The new data confirm that even if SIVgor in gorillas is less widespread than SIVcpz in chimpanzees, it can be a potential risk for new zoonotic infections in humans. Thus, the ongoing contact between humans and infected apes represents a continuous source of inter-species viral transmission. Keywords: HIV-1/P, SIVgor, Gorilla, Cameroon, Fecal samples.
    20th Conference on Retroviruses and Opportunistic Infections (CROI) 2013, Georgia World Congress Center, Atlanta, USA; 03/2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intrinsic restriction factors and viral nucleic acid sensors are important for the anti-viral response. Here, we show how upstream sensing of retroviral reverse transcripts integrates with the downstream effector APOBEC3, an IFN-induced cytidine deaminase that introduces lethal mutations during retroviral reverse transcription. Using a murine leukemia virus (MLV) variant with an unstable capsid that induces a strong IFNβ antiviral response, we identify three sensors, IFI203, DDX41, and cGAS, required for MLV nucleic acid recognition. These sensors then signal using the adaptor STING, leading to increased production of IFNβ and other targets downstream of the transcription factor IRF3. Using knockout and mutant mice, we show that APOBEC3 limits the levels of reverse transcripts that trigger cytosolic sensing, and that nucleic acid sensing in vivo increases expression of IFN-regulated restriction factors like APOBEC3 that in turn reduce viral load. These studies underscore the importance of the multiple layers of protection afforded by host factors. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 03/2015; DOI:10.1016/j.chom.2015.02.021 · 12.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV-1, the cause of AIDS, is composed of four phylogenetic lineages, groups M, N, O, and P, each of which resulted from an independent cross-species transmission event of simian immunodeficiency viruses (SIVs) infecting African apes. Although groups M and N have been traced to geographically distinct chimpanzee communities in southern Cameroon, the reservoirs of groups O and P remain unknown. Here, we screened fecal samples from western lowland (n = 2,611), eastern lowland (n = 103), and mountain (n = 218) gorillas for gorilla SIV (SIVgor) antibodies and nucleic acids. Despite testing wild troops throughout southern Cameroon (n = 14), northern Gabon (n = 16), the Democratic Republic of Congo (n = 2), and Uganda (n = 1), SIVgor was identified at only four sites in southern Cameroon, with prevalences ranging from 0.8–22%. Amplification of partial and full-length SIVgor sequences revealed extensive genetic diversity, but all SIVgor strains were derived from a single lineage within the chimpanzee SIV (SIVcpz) radiation. Two fully sequenced gorilla viruses from southwestern Cameroon were very closely related to, and likely represent the source population of, HIV-1 group P. Most of the genome of a third SIVgor strain, from central Cameroon, was very closely related to HIV-1 group O, again pointing to gorillas as the immediate source. Functional analyses identified the cytidine deaminase APOBEC3G as a barrier for chimpanzee-to-gorilla, but not gorilla-to-human, virus transmission. These data indicate that HIV-1 group O, which spreads epidemically in west central Africa and is estimated to have infected around 100,000 people, originated by cross-species transmission from western lowland gorillas.
    Proceedings of the National Academy of Sciences 03/2015; 112(11). DOI:10.1073/pnas.1502022112 · 9.81 Impact Factor