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Transmitted/founder simian immunodeficiency virus envelope sequences in vesicular stomatitis and Semliki forest virus vector immunized rhesus macaques.

Gambhira R, Keele BF, Schell JB, Hunter MJ, Dufour JP, Montefiori DC, Tang H, Rose JK, Rose N, Marx PA - PLoS ONE (2014)

Bottom Line: We used single genome amplification and phylogenetic analyses to characterize transmitted/founder SIVs both in the inoculum and in immunized-infected rhesus monkeys.We obtained 246 full-length envelope sequences from SIVsmE660 infected macaques at the peak of infection and determined the number of transmitted/founder variants per animal.Because there were only 2 infected animals in the gag-env vaccinated rhesus compared to 10 infected rhesus in the other 2 groups, the significance of finding single env variants in the gag-env vaccinated group could not be established.

View Article: PubMed Central - PubMed

Affiliation: Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, Louisiana, United States of America.

ABSTRACT
Identification of transmitted/founder simian immunodeficiency virus (SIV) envelope sequences responsible for infection may prove critical for understanding HIV/SIV mucosal transmission. We used single genome amplification and phylogenetic analyses to characterize transmitted/founder SIVs both in the inoculum and in immunized-infected rhesus monkeys. Single genome amplification of the SIVsmE660 inoculum revealed a maximum diversity of 1.4%. We also noted that the consensus sequence of the challenge stock differed from the vaccine construct in 10 amino acids including 3 changes in the V4 loop. Viral env was prepared from rhesus plasma in 3 groups of 6 immunized with vesicular stomatitis virus (VSV) vectors and boosted with Semliki forest virus (SFV) replicons expressing (a) SIVsmE660 gag-env (b) SIVsmE660 gag-env plus rhesus GM-CSF and (c) control influenza hemagglutinin protein. Macaques were immunized twice with VSV-vectors and once with SFV vector and challenged intrarectally with 4000 TCID50. Single genome amplification characterized the infections of 2 unprotected animals in the gag-env immunized group, both of which had reduced acute plasma viral loads that ended as transient infections indicating partial immune control. Four of 6 rhesus were infected in the gag-env + GM-CSF group which demonstrated that GM-CSF abrogated protection. All 6 animals from the control group were infected having high plasma viral loads. We obtained 246 full-length envelope sequences from SIVsmE660 infected macaques at the peak of infection and determined the number of transmitted/founder variants per animal. Our analysis found that 2 of 2 gag-env vaccinated but infected macaques exhibited single but distinct virus envelope lineages whereas rhesus vaccinated with gag-env-GM-CSF or HA control exhibited both single and multiple env lineages. Because there were only 2 infected animals in the gag-env vaccinated rhesus compared to 10 infected rhesus in the other 2 groups, the significance of finding single env variants in the gag-env vaccinated group could not be established.

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Plasma virus loads (PVLs) in immunized and control rhesus macaques challenged with SIVsmE660.The PVLs were assayed from serial plasma samples collected from rhesus vaccinated with vesicular stomatitis-semliki forest virus vectors and challenged with SIVsmE660. The graphs depict the PVLs in Log10 scale. (A) In SIVe660 gag-env immunized group (Group I). (B) SIVe660 gag-env immunized plus GM-CSF group (Group II) and (C) the Influenza HA control group (Group III).
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pone-0109678-g001: Plasma virus loads (PVLs) in immunized and control rhesus macaques challenged with SIVsmE660.The PVLs were assayed from serial plasma samples collected from rhesus vaccinated with vesicular stomatitis-semliki forest virus vectors and challenged with SIVsmE660. The graphs depict the PVLs in Log10 scale. (A) In SIVe660 gag-env immunized group (Group I). (B) SIVe660 gag-env immunized plus GM-CSF group (Group II) and (C) the Influenza HA control group (Group III).

Mentions: In total, 3 groups of 18 rhesus macaques were IR challenged with 4000 TCID50 SIVsmE660. In gag-env immunized macaques, 2 of 6 animals had transient viral loads above the baseline level (DG21 and DF38). Both rhesus had reduced peak viral loads at day 14 post-challenge 103.9 to 105.8 compared to the control group (Fig. 1). The plasma viral loads were undetectable by day 21 in DG21 and by day 42 in DF38 (Fig. 1A). The remaining four macaques, in the gag-env group had undetectable viral loads throughout the study period. Importantly, after the depletion of CD8+ T cells, both transiently infected macaques (DF38, DF21) but not the 4 completely protected macaques exhibited rebound in viral loads confirming low-level systemic infection. The Gag-env-GM-CSF group immunized animals had 5 of 6 rhesus infected, with peak PVLs ranging from 104.7 to 107.8 on days 10 to 21 post-infection (Fig. 1B). All HA-vaccinated-control macaques were infected and had the highest peaks (106.0 to 108.3) (Fig. 1C. While some reached peak by days 10 (EN82) or 14 (FG05, DD04, EP84, FT80) others showed peak viral loads by day 21 (N288) (Fig. 1C). PVLs of the efficacy experiment (Fig. 1) were published [27] and are also shown here for clarity.


Transmitted/founder simian immunodeficiency virus envelope sequences in vesicular stomatitis and Semliki forest virus vector immunized rhesus macaques.

Gambhira R, Keele BF, Schell JB, Hunter MJ, Dufour JP, Montefiori DC, Tang H, Rose JK, Rose N, Marx PA - PLoS ONE (2014)

Plasma virus loads (PVLs) in immunized and control rhesus macaques challenged with SIVsmE660.The PVLs were assayed from serial plasma samples collected from rhesus vaccinated with vesicular stomatitis-semliki forest virus vectors and challenged with SIVsmE660. The graphs depict the PVLs in Log10 scale. (A) In SIVe660 gag-env immunized group (Group I). (B) SIVe660 gag-env immunized plus GM-CSF group (Group II) and (C) the Influenza HA control group (Group III).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215841&req=5

pone-0109678-g001: Plasma virus loads (PVLs) in immunized and control rhesus macaques challenged with SIVsmE660.The PVLs were assayed from serial plasma samples collected from rhesus vaccinated with vesicular stomatitis-semliki forest virus vectors and challenged with SIVsmE660. The graphs depict the PVLs in Log10 scale. (A) In SIVe660 gag-env immunized group (Group I). (B) SIVe660 gag-env immunized plus GM-CSF group (Group II) and (C) the Influenza HA control group (Group III).
Mentions: In total, 3 groups of 18 rhesus macaques were IR challenged with 4000 TCID50 SIVsmE660. In gag-env immunized macaques, 2 of 6 animals had transient viral loads above the baseline level (DG21 and DF38). Both rhesus had reduced peak viral loads at day 14 post-challenge 103.9 to 105.8 compared to the control group (Fig. 1). The plasma viral loads were undetectable by day 21 in DG21 and by day 42 in DF38 (Fig. 1A). The remaining four macaques, in the gag-env group had undetectable viral loads throughout the study period. Importantly, after the depletion of CD8+ T cells, both transiently infected macaques (DF38, DF21) but not the 4 completely protected macaques exhibited rebound in viral loads confirming low-level systemic infection. The Gag-env-GM-CSF group immunized animals had 5 of 6 rhesus infected, with peak PVLs ranging from 104.7 to 107.8 on days 10 to 21 post-infection (Fig. 1B). All HA-vaccinated-control macaques were infected and had the highest peaks (106.0 to 108.3) (Fig. 1C. While some reached peak by days 10 (EN82) or 14 (FG05, DD04, EP84, FT80) others showed peak viral loads by day 21 (N288) (Fig. 1C). PVLs of the efficacy experiment (Fig. 1) were published [27] and are also shown here for clarity.

Bottom Line: We used single genome amplification and phylogenetic analyses to characterize transmitted/founder SIVs both in the inoculum and in immunized-infected rhesus monkeys.We obtained 246 full-length envelope sequences from SIVsmE660 infected macaques at the peak of infection and determined the number of transmitted/founder variants per animal.Because there were only 2 infected animals in the gag-env vaccinated rhesus compared to 10 infected rhesus in the other 2 groups, the significance of finding single env variants in the gag-env vaccinated group could not be established.

View Article: PubMed Central - PubMed

Affiliation: Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, Louisiana, United States of America.

ABSTRACT
Identification of transmitted/founder simian immunodeficiency virus (SIV) envelope sequences responsible for infection may prove critical for understanding HIV/SIV mucosal transmission. We used single genome amplification and phylogenetic analyses to characterize transmitted/founder SIVs both in the inoculum and in immunized-infected rhesus monkeys. Single genome amplification of the SIVsmE660 inoculum revealed a maximum diversity of 1.4%. We also noted that the consensus sequence of the challenge stock differed from the vaccine construct in 10 amino acids including 3 changes in the V4 loop. Viral env was prepared from rhesus plasma in 3 groups of 6 immunized with vesicular stomatitis virus (VSV) vectors and boosted with Semliki forest virus (SFV) replicons expressing (a) SIVsmE660 gag-env (b) SIVsmE660 gag-env plus rhesus GM-CSF and (c) control influenza hemagglutinin protein. Macaques were immunized twice with VSV-vectors and once with SFV vector and challenged intrarectally with 4000 TCID50. Single genome amplification characterized the infections of 2 unprotected animals in the gag-env immunized group, both of which had reduced acute plasma viral loads that ended as transient infections indicating partial immune control. Four of 6 rhesus were infected in the gag-env + GM-CSF group which demonstrated that GM-CSF abrogated protection. All 6 animals from the control group were infected having high plasma viral loads. We obtained 246 full-length envelope sequences from SIVsmE660 infected macaques at the peak of infection and determined the number of transmitted/founder variants per animal. Our analysis found that 2 of 2 gag-env vaccinated but infected macaques exhibited single but distinct virus envelope lineages whereas rhesus vaccinated with gag-env-GM-CSF or HA control exhibited both single and multiple env lineages. Because there were only 2 infected animals in the gag-env vaccinated rhesus compared to 10 infected rhesus in the other 2 groups, the significance of finding single env variants in the gag-env vaccinated group could not be established.

Show MeSH
Related in: MedlinePlus