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1.
Clin Pharmacol Ther ; 99(6): 600-11, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26940481

ABSTRACT

Human immunodeficiency virus (HIV) infection is associated with an altered gut microbiome that is not consistently restored with effective antiretroviral therapy (ART). Interpretation of the specific microbiome changes observed during HIV infection is complicated by factors like population, sample type, and ART-each of which may have dramatic effects on gut bacteria. Understanding how these factors shape the microbiome during HIV infection (which we refer to as the HIV-associated microbiome) is critical for defining its role in HIV disease, and for developing therapies that restore gut health during infection.


Subject(s)
Antiretroviral Therapy, Highly Active/adverse effects , Antiretroviral Therapy, Highly Active/methods , Dysbiosis/microbiology , Gastrointestinal Microbiome , HIV Infections/drug therapy , HIV Infections/microbiology , Animals , Anti-HIV Agents/therapeutic use , Dysbiosis/immunology , Humans , Microbiota
2.
J Virol ; 76(12): 5925-36, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12021325

ABSTRACT

One hallmark of uncontrolled, chronic human immunodeficiency virus type 1 (HIV-1) infection is the absence of strong HIV-1-specific, CD4(+) T-cell-proliferative responses, yet the mechanism underlying this T helper (Th)-cell defect remains controversial. To better understand the impact of HIV-1 replication on Th-cell function, we compared the frequency of CD4(+) Th-cell responses based on production of gamma interferon to lymphoproliferative responses directed against HIV-1 proteins in HIV-1-infected subjects with active in vivo viral replication versus those on suppressed highly active antiretroviral therapy (HAART). No statistically significant differences in the frequencies of cytokine-secreting, HIV-1-specific CD4(+) T cells between the donor groups were found, despite differences in viral load and treatment status. However, HIV-1-specific lymphoproliferative responses were significantly greater in the subjects with HAART suppression than in subjects with active viral replication. Similar levels of HIV-1 RNA were measured in T-cell cultures stimulated with HIV-1 antigens regardless of donor in vivo viral loads, but only HIV-1-specific CD4(+) T cells from subjects with HAART suppression proliferated in vitro, suggesting that HIV-1 replication in vitro does not preclude HIV-1-specific lymphoproliferation. This study demonstrates a discordance between the frequency and proliferative capacity of HIV-1-specific CD4(+) T cells in subjects with ongoing in vivo viral replication and suggests that in vivo HIV-1 replication contributes to the observed defect in HIV-1-specific CD4(+) T-cell proliferation.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/virology , HIV-1/immunology , Interferon-gamma/biosynthesis , Lymphocyte Activation/immunology , Virus Replication , Adult , Antigens, CD/immunology , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/immunology , Antigens, Differentiation, T-Lymphocyte/metabolism , Antiretroviral Therapy, Highly Active , CD4-Positive T-Lymphocytes/metabolism , HIV Core Protein p24/immunology , HIV Core Protein p24/metabolism , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/drug effects , HIV-1/physiology , Humans , Lectins, C-Type , RNA, Viral/blood , Viral Load
3.
Immunogenetics ; 49(3): 206-14, 1999 Mar.
Article in English | MEDLINE | ID: mdl-9914334

ABSTRACT

We analyzed nucleotide and deduced amino acid sequence heterogeneity of sheep T-cell receptor beta-chain cDNAs isolated from an anchored-polymerase chain reaction library. Evaluation of 34 individual rearrangements has defined 18 new beta-chain variable region sequences which have been clustered into 13 families. Presumptive allelic polymorphisms of four of these variable regions have been defined, as well as ten distinct beta-chain joining region sequences. The present analysis indicates that sheep T-cell receptor beta-chains are composed of characteristic leader, variable, joining, and constant region sequences, and that imprecise joining and N-region addition contribute significantly to diversity in the third hypervariable region. Thus, it appears that sheep, like all other mammals studied to date, employ somatic rearrangement of multiple germline genes to create beta-chain heterogeneity. These findings have allowed us to estimate the diversity of the sheep T-cell receptor beta-chain variable region repertoire, and they provide information that will permit the evaluation of the role that specific T-cell populations play in naturally occurring and experimental diseases of sheep.


Subject(s)
Gene Rearrangement, beta-Chain T-Cell Antigen Receptor , Genes, T-Cell Receptor beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/chemistry , Sheep/immunology , Alleles , Amino Acid Sequence , Animals , Base Sequence , Cloning, Molecular , Consensus Sequence/genetics , DNA, Complementary/genetics , Genetic Variation/genetics , Germ Cells , Humans , Molecular Sequence Data , Polymerase Chain Reaction , Polymorphism, Genetic/genetics , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/immunology , Sequence Alignment , Sequence Analysis, DNA , Sequence Homology, Amino Acid , Sheep/genetics
4.
J Lab Clin Med ; 128(5): 477-87, 1996 Nov.
Article in English | MEDLINE | ID: mdl-8900290

ABSTRACT

An improved understanding of host defense against Pneumocystis carinii could provide novel therapeutic modalities directed against this opportunistic pathogen. Immunodeficient mouse models confirm the role of CD4+ lymphocytes in defense against P. carinii, but the role of CD8+ lymphocytes is controversial. BALB/c mice specifically depleted of CD4+ lymphocytes are susceptible to P. carinii, recruiting large numbers of CD8+ lymphocytes to their lungs during infection. Because of this recruitment, we hypothesized that CD8+ lymphocytes could participate in host defense against P. carinii. BALB/c mice were depleted of CD4+ lymphocytes, CD8+ lymphocytes, or both CD4+ and CD8+ lymphocytes. All mice were then inoculated intratracheally with P. carinii. Mice depleted of CD4+ lymphocytes became moderately infected with P. carinii. Mice depleted of CD8+ lymphocytes cleared the inoculum, indicating that CD8+ lymphocytes are unnecessary for defense when CD4+ lymphocytes are available. However, mice depleted of both CD4+ and CD8+ lymphocytes became significantly more intensely infected than mice depleted of CD4+ lymphocytes alone. Therefore, CD8+ lymphocytes participate in defense against P. carinii in vivo during depletion of CD4+ lymphocytes. To determine the mechanisms of this protection, CD8+ lymphocytes were purified from the lungs of CD4-depleted mice during infection. Lung CD8+ lymphocytes proliferated in response to P. carinii antigen and elaborated interferon-gamma in vitro. Thus CD8+ lymphocytes provide defense against P. carinii in vivo, and the elaboration of interferon-gamma likely represents one important mechanism of defense. During states of CD4+ lymphocyte depletion, the modulation of CD8+ lymphocyte function may provide alternative approaches to the host defense against opportunistic pathogens.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Pneumocystis/immunology , Animals , Antibodies, Monoclonal , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Disease Models, Animal , Interferon-gamma/biosynthesis , Lung/cytology , Lung/immunology , Lung/pathology , Lymphocyte Activation , Lymphocyte Depletion , Male , Mice , Mice, Inbred BALB C , Opportunistic Infections/immunology , Opportunistic Infections/pathology , Opportunistic Infections/therapy , Pneumonia, Pneumocystis/immunology , Pneumonia, Pneumocystis/pathology , Pneumonia, Pneumocystis/therapy
5.
Infect Immun ; 64(11): 4643-7, 1996 Nov.
Article in English | MEDLINE | ID: mdl-8890219

ABSTRACT

Pneumocystis carinii pneumonia remains a major cause of morbidity and mortality in human immunodeficiency virus-infected individuals, despite the widespread use of prophylaxis and the development of new chemotherapeutic agents. The study of P. carinii and of pulmonary host defenses directed against it has been limited by lack of reliable, reproducible methods to obtain pure populations of organisms in useful quantities. While recent success has been achieved with cultures of rat P. carinii organisms, cultures of mouse P. carinii organisms have not been successful. Experiments were performed to determine whether P. carinii organisms derived from mice could be propagated in vitro. Mouse P. carinii organisms, obtained from the lungs of chronically infected athymic mice, were inoculated into spinner flasks containing HEL299 feeder cells seated on microcarrier beads. The numbers of mouse P. carinii organisms increased significantly over 7 days in culture. To test the viability and pathogenicity of these cultured organisms, P. carinii organisms were harvested after 7 days of culture and were inoculated intratracheally into susceptible scid mice. Four weeks after inoculation, scid mice developed uniformly severe P. carinii pneumonia. These studies demonstrate for the first time that mouse P. carinii organisms can be propagated in vitro. Furthermore, cultured mouse P. carinii organisms maintain their pathogenicity in an in vivo model system. This culture system will have important applications in the study of P. carinii biology and in the study of host defenses directed against this important opportunistic pathogen.


Subject(s)
Pneumocystis/growth & development , Pneumonia, Pneumocystis/microbiology , Animals , Cell Line , Disease Models, Animal , Humans , Lung/pathology , Mice , Mice, Nude , Mice, SCID , Pneumocystis/pathogenicity , Pneumonia, Pneumocystis/pathology , Virulence
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