Virus subtype-specific features of natural simian immunodeficiency virus SIVsmm infection in sooty mangabeys

Abstract

Simian immunodeficiency virus (SIV) SIV(smm) naturally infects sooty mangabeys (SMs) and is the source virus of pathogenic infections with human immunodeficiency virus type 2 (HIV-2) and SIV(mac) of humans and macaques, respectively. In previous studies we characterized SIV(smm) diversity in naturally SIV-infected SMs and identified nine different phylogenetic subtypes whose genetic distances are similar to those reported for the different HIV-1 group M subtypes. Here we report that, within the colony of SMs housed at the Yerkes National Primate Research Center, at least four SIV(smm) subtypes cocirculate, with the vast majority of animals infected with SIV(smm) subtype 1, 2, or 3, resulting in the emergence of occasional recombinant forms. While SIV(smm)-infected SMs show a typically nonpathogenic course of infection, we have observed that different SIV(smm) subtypes are in fact associated with specific immunologic features. Notably, while subtypes 1, 2, and 3 are associated with a very benign course of infection and preservation of normal CD4+ T-cell counts, three out of four SMs infected with subtype 5 show a significant depletion of CD4+ T cells. The fact that virus replication in SMs infected with subtype 5 is similar to that in SMs infected with other SIV(smm) subtypes suggests that the subtype 5-associated CD4+ T-cell depletion is unlikely to simply reflect higher levels of virus-mediated direct killing of CD4+ T-cells. Taken together, this systematic analysis of the subtype-specific features of SIV(smm) infection in natural SM hosts identifies subtype-specific differences in the pathogenicity of SIV(smm) infection.

FIG. 1.

SIV_smm diversity in SMs from YNPRC. Subtypes are clusters of SIVs that are highly related and branch together. SIV_smm strains belonging to different subtypes are color coded: red, subtype 1; violet, subtype 2; turquoise, subtype 3; blue, subtype 4; orange, subtype 5; light green, subtype 6. Reference SIV_smm strains and strains from wild-caught SMs are shown in black, whereas HIV-2 strains are shown in light gray. The trees are based on gag (500-bp) (a), pol (592-bp) (b), and env (405-bp) (c) fragments after gap-containing sites have been removed. The phylogenetic trees were estimated by the neighbor-joining method on amino acid sequences. The reliability was estimated from 1,000 bootstrap replicates; only relevant bootstrap values are shown. The scale bar indicates amino acid replacements per site. Strain nomenclature includes the assigned lineage, the primate center of origin, the year of strain collection, and the monkey identification.

FIG. 1.

SIV_smm diversity in SMs from YNPRC. Subtypes are clusters of SIVs that are highly related and branch together. SIV_smm strains belonging to different subtypes are color coded: red, subtype 1; violet, subtype 2; turquoise, subtype 3; blue, subtype 4; orange, subtype 5; light green, subtype 6. Reference SIV_smm strains and strains from wild-caught SMs are shown in black, whereas HIV-2 strains are shown in light gray. The trees are based on gag (500-bp) (a), pol (592-bp) (b), and env (405-bp) (c) fragments after gap-containing sites have been removed. The phylogenetic trees were estimated by the neighbor-joining method on amino acid sequences. The reliability was estimated from 1,000 bootstrap replicates; only relevant bootstrap values are shown. The scale bar indicates amino acid replacements per site. Strain nomenclature includes the assigned lineage, the primate center of origin, the year of strain collection, and the monkey identification.

FIG. 1.

SIV_smm diversity in SMs from YNPRC. Subtypes are clusters of SIVs that are highly related and branch together. SIV_smm strains belonging to different subtypes are color coded: red, subtype 1; violet, subtype 2; turquoise, subtype 3; blue, subtype 4; orange, subtype 5; light green, subtype 6. Reference SIV_smm strains and strains from wild-caught SMs are shown in black, whereas HIV-2 strains are shown in light gray. The trees are based on gag (500-bp) (a), pol (592-bp) (b), and env (405-bp) (c) fragments after gap-containing sites have been removed. The phylogenetic trees were estimated by the neighbor-joining method on amino acid sequences. The reliability was estimated from 1,000 bootstrap replicates; only relevant bootstrap values are shown. The scale bar indicates amino acid replacements per site. Strain nomenclature includes the assigned lineage, the primate center of origin, the year of strain collection, and the monkey identification.

FIG. 2.

Cross-sectional analysis of plasma VL levels in 137 SMs infected with different SIV_smm subtypes. Subtypes are color coded as follows: red, subtype 1; violet, subtype 2; turquoise, subtype 3; blue, subtype 4; orange, subtype 5; light green, subtype 6. VL was quantified by bDNA (detection limit, 125 copies/ml) and real-time PCR (detection limit, 100 copies/ml). Box-and-whisker plots show the boxes that extend from the 25th percentile to the 75th percentile, with a horizontal line at the median, and the whiskers extend down to the 10th percentile and up to the 90th percentile. Each outlier is shown as an individual point outside the plots.

FIG. 3.

Retrospective analysis of the dynamics of VL in SMs infected with different SIV_smm subtypes over a 20-year period showed no statistically significant difference in viral replication between subtype 1 (a) and non-subtype 1 (b) infections. Subtypes are color coded as follows: red, subtype 1; violet, subtype 2; turquoise, subtype 3; blue, subtype 4; orange, subtype 5; light green, subtype 6. Black lines show the dynamics of VLs in an SM that progressed to AIDS (36). VL was quantified by bDNA (detection limit, 125 copies/ml) on serum samples stored at −80°C.

FIG. 4.

Prospective analysis of the dynamics of viral replication of different SIV_smm subtypes over 6 years. No statistical difference in VLs between subtype 1 (red), subtype 2 (violet); subtype 3 (turquoise), subtype 4 (blue), subtype 5 (orange), and subtype 6 (light green) was seen. VL was quantified by bDNA (detection limit, 125 copies/ml).

FIG. 5.

Cross-sectional analysis of CD4⁺ T-cell levels in SMs infected with different SIV_smm subtypes. Subtypes are color coded: subtype 1, red; subtype 2, violet; subtype 3, turquoise; subtype 4, blue; subtype 5, orange; subtype 6, light green. Statistically significant lower CD4⁺ T-cell counts were observed in subtype 5-infected SMs. Box-and-whisker plots show the boxes that extend from the 25th percentile to the 75th percentile, with a horizontal line at the median, and the whiskers extend down to the 10th percentile and up to the 90th percentile. Each outlier is shown as an individual point outside the plots.