ABSTRACT
Genetic, epidemiological and experimental evidence suggest that the major histocompatibility complex (MHC) is critical in controlling human immunodeficiency virus (HIV) infection. The objectives of this study were to determine whether novel recombinant Mamu MHC constructs would elicit protection against rectal challenge with heterologous simian-human immunodeficiency virus (SHIV) strain SF162.P4 in rhesus macaques. Mamu class I and II gene products were linked together with HIV gp140, simian immunodeficiency virus (SIV) p27 and heat-shock protein 70 to dextran. The vaccine was administered to two groups, each consisting of nine macaques, either subcutaneously (SC), or rectally and boosted by SC immunization. The controls were untreated or adjuvant-treated animals. Repetitive rectal challenges with up to ten doses of SHIV SF162.P4 showed a significant decrease in the peak and sequential viral RNA concentrations, and three macaques remained uninfected, in the nine SC-immunized animals, compared with infection in all nine controls. Macaques immunized rectally followed by SC boosters showed a less significant decrease in both sequential and peak viral loads compared with the SC-immunized animals, and all were infected following rectal challenge with SHIV SF162.P4. Plasma and mucosal IgG and IgA antibodies to Mamu class I alleles and HIV gp120, as well as to RANTES (regulated upon activation, normal T-cell expressed, and secreted; CCR5) were increased, and showed significant inverse correlations with the peak viral load. These results suggested that allo-immunization with recombinant MHC constructs linked to HIV-SIV antigens merits further investigation in preventing HIV-1 infection.
Subject(s)
Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class I/immunology , SAIDS Vaccines/immunology , Simian Acquired Immunodeficiency Syndrome/prevention & control , Simian Immunodeficiency Virus/immunology , env Gene Products, Human Immunodeficiency Virus/immunology , Administration, Rectal , Animals , Antibodies, Viral/blood , Disease Models, Animal , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Injections, Subcutaneous , Macaca mulatta , SAIDS Vaccines/administration & dosage , Vaccination/methods , Viral LoadABSTRACT
CD1c+ myeloid dendritic cells (mDCs) in the peripheral blood of 30 SHIV-SF162p4 and SIVmac251 sequentially infected Chinese rhesus macaques were examined by flow cytometry to obtain further insight into mDC alterations in HIV/AIDS. The CD1c+ cells were found to be mononuclear leukocytes rather than granulocytes, and most of them expressed CD20. CD1c+mDCs (CD1c+CD20-) consisted of two morphological subsets: the granular and the large CD1c+mDCs. The expression of HLA-DR, CD86, and CD11b, but no CCR7, CD83 and CD123, together with their endocytotic capacity indicated that they were immature mDCs. Their frequency at weeks 10 and 12 post-infection was significantly higher than that of un-infected ones; the large CD1c+mDC level was significantly different between time points and almost absent from un-infected rhesus monkeys; significant correlations between CD1c+mDCs and plasma viral load levels were also observed. These data indicated a possible role for CD1c+mDCs in the pathophysiological process of SIV/HIV infection.
Subject(s)
Antigens, CD1/immunology , Dendritic Cells/immunology , HIV Infections/immunology , Leukocytes, Mononuclear/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Animals , Antigens, CD1/blood , Antigens, CD20/blood , Antigens, CD20/immunology , B7-2 Antigen/blood , B7-2 Antigen/immunology , CD11b Antigen/blood , CD11b Antigen/immunology , China , Dendritic Cells/metabolism , Endocytosis/immunology , Flow Cytometry , HIV Infections/blood , HIV Infections/virology , HLA-DR Antigens/blood , HLA-DR Antigens/immunology , Humans , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/virology , Macaca mulatta , Myeloid Cells/immunology , Myeloid Cells/metabolism , Simian Acquired Immunodeficiency Syndrome/blood , Simian Acquired Immunodeficiency Syndrome/virologyABSTRACT
Serotonin transporter (SERT, 5-HTT) is a key element in the serotonergic system which is probably involved in the psychiatric disorders commonly observed in people living with HIV/AIDS. However, no information is available about the effects of HIV infection on SERT expression. In this study, a TaqMan real-time RT-PCR method was established, levels of SERT mRNA in the peripheral blood mononuclear cells (PBMCs) and various tissues from normal Chinese rhesus macaques, in PBMCs from 32 SHIV-sf162p4 infected rhesus macaques and from 8 rhesus macaques before and 7, 14, 21, 28 and 196 days after SHIV-sf162p4 infection, and in PBMCs before and after in vitro phytohemagglutinin (PHA) stimulation were examined. It was found that SERT mRNA was widely distributed in lymphoid tissues; the level of SERT mRNA was significantly reduced in PBMCs from SHIV infected rhesus macaques and in PBMCs stimulated with PHA. The most evident decrease (to about one-tenth) in SERT mRNA level was observed at day 7 after SHIV infection. Difference in PBMC SERT mRNA level between 5-HTTLPR genotypes was not statistically significant. These data indicated that, in addition to previously observed abnormality in serotonin metabolism, SERT expression might be affected in HIV/AIDS, which might be associated with depression and other psychiatric disorders in HIV/AIDS. Besides, this study provided a basis for quantitative analysis of SERT gene expression under effects of host and environmental factors, such as 5-HTTLPR genotypes, SERT targeting drugs or other infectious agents.
