The Role of the Antiviral APOBEC3 Gene Family in Protecting Chimpanzees against Lentiviruses from Monkeys - PubMed (original) (raw)

The Role of the Antiviral APOBEC3 Gene Family in Protecting Chimpanzees against Lentiviruses from Monkeys

Lucie Etienne et al. PLoS Pathog. 2015.

Abstract

Cross-species transmissions of viruses from animals to humans are at the origin of major human pathogenic viruses. While the role of ecological and epidemiological factors in the emergence of new pathogens is well documented, the importance of host factors is often unknown. Chimpanzees are the closest relatives of humans and the animal reservoir at the origin of the human AIDS pandemic. However, despite being regularly exposed to monkey lentiviruses through hunting, chimpanzees are naturally infected by only a single simian immunodeficiency virus, SIVcpz. Here, we asked why chimpanzees appear to be protected against the successful emergence of other SIVs. In particular, we investigated the role of the chimpanzee APOBEC3 genes in providing a barrier to infection by most monkey lentiviruses. We found that most SIV Vifs, including Vif from SIVwrc infecting western-red colobus, the chimpanzee's main monkey prey in West Africa, could not antagonize chimpanzee APOBEC3G. Moreover, chimpanzee APOBEC3D, as well as APOBEC3F and APOBEC3H, provided additional protection against SIV Vif antagonism. Consequently, lentiviral replication in primary chimpanzee CD4(+) T cells was dependent on the presence of a lentiviral vif gene that could antagonize chimpanzee APOBEC3s. Finally, by identifying and functionally characterizing several APOBEC3 gene polymorphisms in both common chimpanzees and bonobos, we found that these ape populations encode APOBEC3 proteins that are uniformly resistant to antagonism by monkey lentiviruses.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. APOBEC3G protects chimpanzees from most SIV cross-species infections.

A, Phylogenetic analysis of Vif proteins from different primate lentiviruses as described in the Methods. B, Single-round infectivity assay performed in the presence or absence of chimpanzee APOBEC3G; infectivity in the absence of APOBEC3G was normalized to 100%. The graphs show the infectivity values for the average of six to nine infections; error bars indicate the SD from the mean of these replicates. The infectivity of HIV-1ΔVif (white, negative control), and HIV-1ΔVifΔEnvLuc2 plasmid with vif from SIVcpz_Pts_Tan3 or SIVcpz_Ptt_Gab1 (black, positive controls), or vif from SIVs from the given primate species (grey bars) were tested. Each of the Vif proteins was fully capable of antagonizing at least one APOBEC3 protein using identical proviral expression constructs to those in Fig 1B ([4,17,20] and Fig 2).

Fig 2. Chimpanzee APOBEC3D, APOBEC3F and APOBEC3H also have antiviral capacities that monkey SIV Vifs differentially antagonize.

Single-round infectivity assay performed in the presence or absence of chimpanzee APOBEC3D (A), APOBEC3F (B), and APOBEC3H (C), as described in Fig 1B. D, Heat map summarizing the antagonistic potential of Vif from various lentiviruses (shown on the left) against chimpanzee APOBEC3 genes (shown at the top). The intensity of the color corresponds to the level that a given SIV Vif could antagonize the corresponding chimpanzee APOBEC3 protein (darker is more antagonism, lighter is less antagonism). The colors were determined according to the infectivity value of the given viral Vif construct relative to the infectivity of the positive control bearing SIVcpz Vif: lightest green, less than 10% relative infectivity; intermediate green, between 10% and 60% relative infectivity; dark green, more than 60% relative infectivity.

Fig 3. Vif-dependent restriction of lentiviral replication in primary chimpanzee CD4+ T cells.

A, Primary CD4+ T cells from three chimpanzee donors were infected with replication-competent HIV-1 clones containing either no Vif (ΔVif) or Vif from different SIV lineages (SIVcpz, SIVsab, SIVrcm, or SIVsmm) as described in the methods. Viral replication was evaluated by measuring HIV p24 titers every 48h over a 9- or 10-day course of infection. B, The same experiment was performed, but cells were treated with 500 U/ml of IFNα (left) and 100 U/ml of IFNβ (right) 24h prior infection (data are shown here for cells from donor 1; data for donor 2 are shown in S5B Fig).

Fig 4. The chimpanzee and bonobo populations are uniformly resistant to lentiviruses with various Vifs.

A, Graphical representation of Pan species and subspecies phylogeny (top) and geographic ranges (bottom) with the number of individuals per (sub)species that were examined for their APOBEC3 genes (in red, before the study; in black, in this study). The virus diagrams depict the two chimpanzee subspecies known to be infected by SIVcpz. B, Expression of transient chimpanzee APOBEC3D, APOBEC3F, and APOBEC3G variants. Western-blot analyses against HA-tagged APOBEC3 proteins. Tubulin serves as a loading control. C, Chimpanzee APOBEC3D, APOBEC3F, and APOBEC3G variants have comparable activity against lentiviruses and are antagonized similarly by primate lentiviral Vifs. Single-round infectivity assays, as described in Fig 1B, in the presence or absence of chimpanzee APOBEC3 variants with HIVΔVifΔEnvLuc2: ΔVif, SIVcpz Vif, SIVsmm Vif, or SIVwrc Vif. Infectivity in the absence of APOBEC3 was normalized to 100%. APOBEC3D variants are in purple, APOBEC3F variants are in blue, and APOBEC3G variants are in green.

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The Role of the Antiviral APOBEC3 Gene Family in Protecting Chimpanzees against Lentiviruses from Monkeys - PubMed (original) (raw)