TY - JOUR
T1 - Impaired T-cell responses to sphingosine-1-phosphate in HIV-1 infected lymph nodes
AU - Mudd, Joseph C.
AU - Murphy, Patrick
AU - Manion, Maura
AU - Debernardo, Robert
AU - Hardacre, Jeffrey
AU - Ammori, John
AU - Hardy, Gareth A.
AU - Harding, Clifford V.
AU - Mahabaleshwar, Ganapati H.
AU - Jain, Mukesh K.
AU - Jacobson, Jeffrey M.
AU - Brooks, Ari D.
AU - Lewis, Sharon
AU - Schacker, Timothy W.
AU - Anderson, Jodi
AU - Haddad, Elias K.
AU - Cubas, Rafael A.
AU - Rodriguez, Benigno
AU - Sieg, Scott F.
AU - Lederman, Michael M.
PY - 2013/4/11
Y1 - 2013/4/11
N2 - The determinants of HIV-1-associated lymphadenopathy are poorly understood. We hypothesized that lymphocytes could be sequestered in the HIV-1+ lymph node (LN) through impairments in sphingosine-1-phosphate (S1P) responsiveness. To test this hypothesis, we developed novel assays for S1P-induced Akt phosphorylation and actin polymerization. In the HIV-1+ LN, naïve CD4 T cells and central memory CD4 and CD8 T cells had impaired Akt phosphorylation in response to S1P, whereas actin polymerization responses to S1P were impaired dramatically in all LN maturation subsets. These defects were improvedwith antiretroviral therapy. LN T cells expressing CD69 were unable to respond to S1P in either assay, yet impaired S1P responseswere also seen in HIV-1+ LN T cells lacking CD69 expression. Microbial elements, HIV-1, and interferon α - putative drivers of HIV-1associated immune activation all tended to increase CD69 expression and reduce T-cell responses to S1P in vitro. Impairment in T-cell egress from lymph nodes through decreased S1P responsiveness may contribute to HIV-1-associated LN enlargement and to immune dysregulation in a key organ of immune homeostasis.
AB - The determinants of HIV-1-associated lymphadenopathy are poorly understood. We hypothesized that lymphocytes could be sequestered in the HIV-1+ lymph node (LN) through impairments in sphingosine-1-phosphate (S1P) responsiveness. To test this hypothesis, we developed novel assays for S1P-induced Akt phosphorylation and actin polymerization. In the HIV-1+ LN, naïve CD4 T cells and central memory CD4 and CD8 T cells had impaired Akt phosphorylation in response to S1P, whereas actin polymerization responses to S1P were impaired dramatically in all LN maturation subsets. These defects were improvedwith antiretroviral therapy. LN T cells expressing CD69 were unable to respond to S1P in either assay, yet impaired S1P responseswere also seen in HIV-1+ LN T cells lacking CD69 expression. Microbial elements, HIV-1, and interferon α - putative drivers of HIV-1associated immune activation all tended to increase CD69 expression and reduce T-cell responses to S1P in vitro. Impairment in T-cell egress from lymph nodes through decreased S1P responsiveness may contribute to HIV-1-associated LN enlargement and to immune dysregulation in a key organ of immune homeostasis.
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UR - http://www.scopus.com/inward/citedby.url?scp=84879429159&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-07-445783
DO - 10.1182/blood-2012-07-445783
M3 - Article
C2 - 23422746
AN - SCOPUS:84879429159
SN - 0006-4971
VL - 121
SP - 2914
EP - 2922
JO - Blood
JF - Blood
IS - 15
ER -