Limits...
Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells.

Sevilla N, Kunz S, Holz A, Lewicki H, Homann D, Yamada H, Campbell KP, de La Torre JC, Oldstone MB - J. Exp. Med. (2000)

Bottom Line: In contrast, viral strains and variants that bind with low affinity to alpha-DG are associated with viral replication in the red pulp, display minimal replication in CD11c(+) and DEC-205(+) cells, and generate a robust anti-LCMV cytotoxic T lymphocyte response that clears the virus infection.Differences in binding affinities can be mapped to a single amino acid change in the viral glycoprotein 1 ligand that binds to alpha-DG.These findings indicate that receptor-virus interaction on dendritic cells in vivo can be an essential step in the initiation of virus-induced immunosuppression and viral persistence.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropharmacology, Division of Virology, The Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
Among cells of the immune system, CD11c(+) and DEC-205(+) splenic dendritic cells primarily express the cellular receptor (alpha-dystroglycan [alpha-DG]) for lymphocytic choriomeningitis virus (LCMV). By selection, strains and variants of LCMV that bind alpha-DG with high affinity are associated with virus replication in the white pulp, show preferential replication in a majority of CD11c(+) and DEC-205(+) cells, cause immunosuppression, and establish a persistent infection. In contrast, viral strains and variants that bind with low affinity to alpha-DG are associated with viral replication in the red pulp, display minimal replication in CD11c(+) and DEC-205(+) cells, and generate a robust anti-LCMV cytotoxic T lymphocyte response that clears the virus infection. Differences in binding affinities can be mapped to a single amino acid change in the viral glycoprotein 1 ligand that binds to alpha-DG. These findings indicate that receptor-virus interaction on dendritic cells in vivo can be an essential step in the initiation of virus-induced immunosuppression and viral persistence.

Show MeSH

Related in: MedlinePlus

VOPBA with purified α-DG and LCMV variants. Decreasing amounts (1, 0.1, and 0.01 μg) of purified α-DG were incubated with 107 PFU of each viral isolate and then with virus-specific antibody as described in Materials and Methods. The top panels show the VOPBA of CTL+P− LCMV isolates (ARM 53b, CD8-4, CD4-1, and TNFB2-1). The phenotype as well as the aa in position 260 of GP1 (F) is shown under each blot. The bottom panel shows the VOPBA of CTL−P+ LCMV isolates (Cl 13, PBL 7-1, PBL 36-4, PBL 50-1, PBL 67-3, and TNPBL4-2). The CTL P phenotype is indicated under the name of each isolate and the aa in position 260 of GP1 (L or I).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2193355&req=5

Figure 1: VOPBA with purified α-DG and LCMV variants. Decreasing amounts (1, 0.1, and 0.01 μg) of purified α-DG were incubated with 107 PFU of each viral isolate and then with virus-specific antibody as described in Materials and Methods. The top panels show the VOPBA of CTL+P− LCMV isolates (ARM 53b, CD8-4, CD4-1, and TNFB2-1). The phenotype as well as the aa in position 260 of GP1 (F) is shown under each blot. The bottom panel shows the VOPBA of CTL−P+ LCMV isolates (Cl 13, PBL 7-1, PBL 36-4, PBL 50-1, PBL 67-3, and TNPBL4-2). The CTL P phenotype is indicated under the name of each isolate and the aa in position 260 of GP1 (L or I).

Mentions: To establish the role of aa 260 in the binding to α-DG, several virus isolates with either a CTL−P+ or a CTL+P− phenotype were quantitatively assayed for their binding affinity to α-DG. All LCMV variants with an L or I in position 260 of GP1 showed high binding affinity to α-DG, comparable to that of Cl 13, with binding of at least 1 log and often 2–3 logs greater than that observed with CTL+P− viruses that contained F at GP1 aa 260 (Fig. 1). Competitive inhibition binding assays using soluble α-DG and 10 different viral strains or variants showed that high affinity virus binders were routinely blocked by 1–4 nM soluble α-DG (33% blocking) whereas in contrast, low affinity viral binders required >400 nM soluble α-DG to block binding to α-DG cells (data not shown). Taken together, these findings indicated that an aliphatic aa–like L or I in position 260 of GP1 of LCMV viruses is associated with high affinity binding to α-DG, whereas those viruses containing an aromatic (F) aa at this position bound at least 1 and most often at 2–3 logs lower affinity to α-DG.


Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells.

Sevilla N, Kunz S, Holz A, Lewicki H, Homann D, Yamada H, Campbell KP, de La Torre JC, Oldstone MB - J. Exp. Med. (2000)

VOPBA with purified α-DG and LCMV variants. Decreasing amounts (1, 0.1, and 0.01 μg) of purified α-DG were incubated with 107 PFU of each viral isolate and then with virus-specific antibody as described in Materials and Methods. The top panels show the VOPBA of CTL+P− LCMV isolates (ARM 53b, CD8-4, CD4-1, and TNFB2-1). The phenotype as well as the aa in position 260 of GP1 (F) is shown under each blot. The bottom panel shows the VOPBA of CTL−P+ LCMV isolates (Cl 13, PBL 7-1, PBL 36-4, PBL 50-1, PBL 67-3, and TNPBL4-2). The CTL P phenotype is indicated under the name of each isolate and the aa in position 260 of GP1 (L or I).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193355&req=5

Figure 1: VOPBA with purified α-DG and LCMV variants. Decreasing amounts (1, 0.1, and 0.01 μg) of purified α-DG were incubated with 107 PFU of each viral isolate and then with virus-specific antibody as described in Materials and Methods. The top panels show the VOPBA of CTL+P− LCMV isolates (ARM 53b, CD8-4, CD4-1, and TNFB2-1). The phenotype as well as the aa in position 260 of GP1 (F) is shown under each blot. The bottom panel shows the VOPBA of CTL−P+ LCMV isolates (Cl 13, PBL 7-1, PBL 36-4, PBL 50-1, PBL 67-3, and TNPBL4-2). The CTL P phenotype is indicated under the name of each isolate and the aa in position 260 of GP1 (L or I).
Mentions: To establish the role of aa 260 in the binding to α-DG, several virus isolates with either a CTL−P+ or a CTL+P− phenotype were quantitatively assayed for their binding affinity to α-DG. All LCMV variants with an L or I in position 260 of GP1 showed high binding affinity to α-DG, comparable to that of Cl 13, with binding of at least 1 log and often 2–3 logs greater than that observed with CTL+P− viruses that contained F at GP1 aa 260 (Fig. 1). Competitive inhibition binding assays using soluble α-DG and 10 different viral strains or variants showed that high affinity virus binders were routinely blocked by 1–4 nM soluble α-DG (33% blocking) whereas in contrast, low affinity viral binders required >400 nM soluble α-DG to block binding to α-DG cells (data not shown). Taken together, these findings indicated that an aliphatic aa–like L or I in position 260 of GP1 of LCMV viruses is associated with high affinity binding to α-DG, whereas those viruses containing an aromatic (F) aa at this position bound at least 1 and most often at 2–3 logs lower affinity to α-DG.

Bottom Line: In contrast, viral strains and variants that bind with low affinity to alpha-DG are associated with viral replication in the red pulp, display minimal replication in CD11c(+) and DEC-205(+) cells, and generate a robust anti-LCMV cytotoxic T lymphocyte response that clears the virus infection.Differences in binding affinities can be mapped to a single amino acid change in the viral glycoprotein 1 ligand that binds to alpha-DG.These findings indicate that receptor-virus interaction on dendritic cells in vivo can be an essential step in the initiation of virus-induced immunosuppression and viral persistence.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropharmacology, Division of Virology, The Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
Among cells of the immune system, CD11c(+) and DEC-205(+) splenic dendritic cells primarily express the cellular receptor (alpha-dystroglycan [alpha-DG]) for lymphocytic choriomeningitis virus (LCMV). By selection, strains and variants of LCMV that bind alpha-DG with high affinity are associated with virus replication in the white pulp, show preferential replication in a majority of CD11c(+) and DEC-205(+) cells, cause immunosuppression, and establish a persistent infection. In contrast, viral strains and variants that bind with low affinity to alpha-DG are associated with viral replication in the red pulp, display minimal replication in CD11c(+) and DEC-205(+) cells, and generate a robust anti-LCMV cytotoxic T lymphocyte response that clears the virus infection. Differences in binding affinities can be mapped to a single amino acid change in the viral glycoprotein 1 ligand that binds to alpha-DG. These findings indicate that receptor-virus interaction on dendritic cells in vivo can be an essential step in the initiation of virus-induced immunosuppression and viral persistence.

Show MeSH
Related in: MedlinePlus