SIVsm quasispecies adaptation to a new simian host

Abstract

Despite the potential for infectious agents harbored by other species to become emerging human pathogens, little is known about why some agents establish successful cross-species transmission, while others do not. The simian immunodeficiency viruses (SIVs), certain variants of which gave rise to the human HIV-1 and HIV-2 epidemics, have demonstrated tremendous success in infecting new host species, both simian and human. SIVsm from sooty mangabeys appears to have infected humans on several occasions, and was readily transmitted to nonnatural Asian macaque species, providing animal models of AIDS. Here we describe the first in-depth analysis of the tremendous SIVsm quasispecies sequence variation harbored by individual sooty mangabeys, and how this diverse quasispecies adapts to two different host species-new nonnatural rhesus macaque hosts and natural sooty mangabey hosts. Viral adaptation to rhesus macaques was associated with the immediate amplification of a phylogenetically related subset of envelope (env) variants. These variants contained a shorter variable region 1 loop and lacked two specific glycosylation sites, which may be selected for during acute infection. In contrast, transfer of SIVsm to its natural host did not subject the quasispecies to any significant selective pressures or bottleneck. After 100 d postinfection, variants more closely representative of the source inoculum reemerged in the macaques. This study describes an approach for elucidating how pathogens adapt to new host species, and highlights the particular importance of SIVsm env diversity in enabling cross-species transmission. The replicative advantage of a subset of SIVsm variants in macaques may be related to features of target cells or receptors that are specific to the new host environment, and may involve CD4-independent engagement of a viral coreceptor conserved among primates.

Figure 1. Phylogenetic Tree of V1V2 Variants

An NJ tree of all day 14 and SI V1V2 variants, constructed using a GTR model of evolution. Bootstrap support values greater than 50% are shown in italics at nodes and the number of multiple clones from the same animal at the ends of branches is indicated beside the symbol.

Figure 2. Pattern and Temporal Dynamics of Protein Sequence Evolution in Envelope

V1V2 amino acid sequence for SI, SM1, and RM1 at days 10 and 578. The consensus of all sequences is indicated at the top with amino acid positions labeled above. Glycosylation consensus motifs (NXT/S) are highlighted in yellow.

Figure 3. Evidence for Greater Positive Selection in SIV env at Later Times Postinfection

(A–E) Calculations for dN and dS were performed along the 124 amino acids of the V1V2 region using SNAP (http://hiv-web.lanl.gov/). The average dN and dS at each codon is shown for SMs at day 14 (A) and day 578 (B), as well as for RMs at day 14 (C) and day 578 (D), and for the SI (E). Yellow boxes indicate predicted N-gly sites, and asterisks indicate N-gly sites not present at early time points in RMs. (F) Cumulative dN and dS are shown across all sites for each animal at day 14 and day 578. Raw values of cumulative dN and cumulative dS are indicated below the graph.

Figure 4. Reemergence of Donor-Related Variants in Late Infection of Nonnatural Hosts

ML tree of sequences from the SI and RM1 at days 10 and 100. Bootstrap values greater than 50% are shown at nodes. The SI variants are identified by the legend.

Figure 5. Temporal Changes in Nucleotide Sequence Evolution in SMs and RMs

Mean pairwise nucleotide diversity of the V1V2 sequences for each animal at each time point, calculated using the Tamura-Nei model of nucleotide substitution in MEGA 2.1 [52]. The diversity of the SI is indicated on the y-axis. Trend lines are drawn for RMs (red) and SMs (blue).

Figure 6. Phylogenetic Analysis of SIVsmm gag Variants in Natural and Nonnatural Hosts

An NJ unrooted phylogenetic tree of all day-10 gag variants was constructed in PAUP* [43] using the GTR model with a gamma rate distribution of shape α = 1.0. The SI variants are represented by triangles and identified by the legend. Bootstrap values greater than 50% are shown at nodes, and the number of multiple clones from the same animal at the ends of branches is indicated within the symbol.