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. 2014 Jan 31;9(1):e86997.
doi: 10.1371/journal.pone.0086997. eCollection 2014.

Variation of human immunodeficiency virus type-1 reverse transcriptase within the simian immunodeficiency virus genome of RT-SHIV

Debra A Wadford  1 , Robert C Kauffman  1 , Jesse D Deere  1 , Scott T Aoki  1 , Richard A Stanton  2 , Joanne Higgins  1 , Koen K A Van Rompay  3 , Andradi Villalobos  1 , James H Nettles  2 , Raymond F Schinazi  4 , Niels C Pedersen  5 , Thomas W North  6
Affiliations

Variation of human immunodeficiency virus type-1 reverse transcriptase within the simian immunodeficiency virus genome of RT-SHIV

Debra A Wadford et al. PLoS One. .

Abstract

RT-SHIV is a chimera of simian immunodeficiency virus (SIV) containing the reverse transcriptase (RT)-encoding region of human immunodeficiency virus type 1 (HIV-1) within the backbone of SIVmac239. It has been used in a non-human primate model for studies of non-nucleoside RT inhibitors (NNRTI) and highly active antiretroviral therapy (HAART). We and others have identified several mutations that arise in the "foreign" HIV-1 RT of RT-SHIV during in vivo replication. In this study we catalogued amino acid substitutions in the HIV-1 RT and in regions of the SIV backbone with which RT interacts that emerged 30 weeks post-infection from seven RT-SHIV-infected rhesus macaques. The virus set points varied from relatively high virus load, moderate virus load, to undetectable virus load. The G196R substitution in RT was detected from 6 of 7 animals at week 4 post-infection and remained in virus from 4 of 6 animals at week 30. Virus from four high virus load animals showed several common mutations within RT, including L74V or V75L, G196R, L214F, and K275R. The foreign RT from high virus load isolates exhibited as much variation as that of the highly variable envelope surface glycoprotein, and 10-fold higher than that of the native RT of SIVmac239. Isolates from moderate virus load animals showed much less variation in the foreign RT than the high virus load isolates. No variation was found in SIVmac239 genes known to interact with RT. Our results demonstrate substantial adaptation of the foreign HIV-1 RT in RT-SHIV-infected macaques, which most likely reflects selective pressure upon the foreign RT to attain optimal activity within the context of the chimeric RT-SHIV and the rhesus macaque host.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. HIV-1 Reverse Transcriptase (RT) showing amino acid substitutions detected in RT-SHIV high virus load rhesus macaques.
HIV-1 RT p66 subunit ribbon diagram depicted with the most frequently detected amino acid substitutions as cyan-colored spheres. The domains of the RT active site are colored to correspond to the model of RT analogous to a human right hand with the fingers domain as dark blue, the palm domain as red, and the thumb domain as green. The X-ray crystal structure PDB ID: 1RTD of pre-catalytic, wild type HIV-1 reverse transcriptase in complex with double stranded DNA and incoming nucleotide was used to make the image.
Figure 2
Figure 2. Plasma viral RNA levels in RT-SHIV-infected rhesus macaques.
By week 30 post-inoculation, virus loads had segregated the animals into 3 groups: A) animals with high virus loads (0.6–3.9×106 RNA copies/ml plasma); B) animals with moderate virus loads (2.5–6.0×103); and C) one animal with a virus load less than 50 RNA copies/ml plasma which is below the limit of detection (dashed line). The data displayed in this figure were obtained from North et al .
Figure 3
Figure 3. Replication kinetics of RT-SHIV isolated from rhesus macaques.
CEMx174 cells were infected with RT-SHIV isolates from animals or the inoculating RT-SHIV stock as a control (see Materials and Methods). Replication was evaluated by measuring viral RNA copies per ml of culture supernatant for 7 days following infection. For each isolate, three independent experiments were performed in triplicate. Each experiment showed similar replication trends for the isolates relative to each other and the RT-SHIV control, therefore only representative curves are shown. Error bars indicate standard error of the mean for that experiment. RT-SHIV isolates from (A) animal 33741; (B) animal 33917; (C) animal 33731; (D) animal 33810.
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