title: Impaired T-cell responses to sphingosine-1-phosphate in HIV-1 infected lymph nodes.
abstract: 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 improved with antiretroviral therapy. LN T cells expressing CD69 were unable to respond to S1P in either assay, yet impaired S1P responses were also seen in HIV-1+ LN T cells lacking CD69 expression. Microbial elements, HIV-1, and interferon α - putative drivers of HIV-1 associated 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.
authors: Division of Infectious Diseases, Center for AIDS Research, Case Western Reserve University/UniversityHospitals Case Medical Center, Cleveland, OH 44106, USA.
authors: Joseph C
authors: JC
authors: Mudd
authors: Patrick
authors: P
authors: Murphy
authors: Maura
authors: M
authors: Manion
authors: Robert
authors: R
authors: Debernardo
authors: Jeffrey
authors: J
authors: Hardacre
authors: John
authors: J
authors: Ammori
authors: Gareth A
authors: GA
authors: Hardy
authors: Clifford V
authors: CV
authors: Harding
authors: Ganapati H
authors: GH
authors: Mahabaleshwar
authors: Mukesh K
authors: MK
authors: Jain
authors: Jeffrey M
authors: JM
authors: Jacobson
authors: Ari D
authors: AD
authors: Brooks
authors: Sharon
authors: S
authors: Lewis
authors: Timothy W
authors: TW
authors: Schacker
authors: Jodi
authors: J
authors: Anderson
authors: Elias K
authors: EK
authors: Haddad
authors: Rafael A
authors: RA
authors: Cubas
authors: Benigno
authors: B
authors: Rodriguez
authors: Scott F
authors: SF
authors: Sieg
authors: Michael M
authors: MM
authors: Lederman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008196:Lymph / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D044966:Anti-Retroviral Agents; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D008246:Lysophospholipids; D051057:Proto-Oncogene Proteins c-akt; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099192:CD69 Antigens; C477362:S1PR1 protein, human; C060506:sphingosine 1-phosphate