title: Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection.
abstract: Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11 alpha, alpha(E)beta 7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.
authors.affiliation: Dept. of Medical Microbiology and Immunology, GBSF, Room 5511, University of California, Davis, CA 95616, USA.
authors.forename: Moraima
authors.initials: M
authors.lastname: Guadalupe
authors.forename: Sumathi
authors.initials: S
authors.lastname: Sankaran
authors.forename: Michael D
authors.initials: MD
authors.lastname: George
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Reay
authors.forename: David
authors.initials: D
authors.lastname: Verhoeven
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Shacklett
authors.forename: Jason
authors.initials: J
authors.lastname: Flamm
authors.forename: Jacob
authors.initials: J
authors.lastname: Wegelin
authors.forename: Thomas
authors.initials: T
authors.lastname: Prindiville
authors.forename: Satya
authors.initials: S
authors.lastname: Dandekar
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005753:Gastric Mucosa / Q000276:immunology / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D014779:Virus Replication