Role of alveolar macrophage-T cell adherence in accessory cell function in human immunodeficiency virus-infected individuals.

Interleukin-12 (IL-12) is a potentially critical factor in the immune response against human immunodeficiency virus (HIV) because it is important for regulating proliferation and interferon-γ (IFN-γ) production by T cells and natural killer (NK) cells, antigen presentation and accessory cell function by macrophages and dendritic cells, and cytolytic activities of cytotoxic T-lymphocyte cells and NK cells, which are all functions known to be dysfunctional in patients with acquired immune deficiency syndrome. Peripheral blood mononuclear cells (PBMC) from HIV-infected patients have been previously shown to be deficient in the ability to produce IL-12 in response to the bacterial pathogen Staphylococcus aureus Cowan. In this study, impaired IL-12 production in cells from PBMC of HIV-infected patients compared with healthy donors was observed across a broad panel of stimuli derived from infectious pathogens with or without priming with cytokines such as IFN-γ and IL-4, which amplify the IL-12 induction signal. Analysis of p40 and p35 mRNA accumulation showed that reductions in both subunits contribute to the lower IL-12 secretion of cells from HIV-infected individuals. PBMC from HIV-infected donors also failed to upregulate the IL-12 receptor β2 chain (IL-12Rβ2) in response to mitogenic stimuli. The expression of the IL-12Rβ2 gene could, however, be restored by in vitro exposure to rIL-12. Thus, it is possible that a primary IL-12 defect may lead to secondary deficiencies in expression of the genes for IL-12Rβ2 and IFN-γ, thus amplifying immune deficiency during HIV infection.

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Impairment of Gag-Specific CD8+ T-Cell Function in Mucosal and Systemic Compartments of Simian Immunodeficiency Virus mac251- and Simian-Human Immunodeficiency Virus KU2-Infected Macaques

Journal of Virology ◽

10.1128/jvi.75.23.11483-11495.2001 ◽

2001 ◽

Vol 75 (23) ◽

pp. 11483-11495 ◽

Cited By ~ 58

Author(s):

Zdenek Hel ◽

Janos Nacsa ◽

Brian Kelsall ◽

Wen-Po Tsai ◽

Norman Letvin ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

T Cell ◽

Pilot Study ◽

Simian Immunodeficiency Virus ◽

Cell Function ◽

The Body ◽

Lymphoid Tissues ◽

T Cell Function ◽

Immunodeficiency Virus

ABSTRACT The identification of several simian immunodeficiency virus mac251 (SIVmac251) cytotoxic T-lymphocyte epitopes recognized by CD8+ T cells of infected rhesus macaques carrying the Mamu-A*01 molecule and the use of peptide-major histocompatibility complex tetrameric complexes enable the study of the frequency, breadth, functionality, and distribution of virus-specific CD8+ T cells in the body. To begin to address these issues, we have performed a pilot study to measure the virus-specific CD8+ and CD4+ T-cell response in the blood, lymph nodes, spleen, and gastrointestinal lymphoid tissues of eight Mamu-A*01-positive macaques, six of those infected with SIVmac251 and two infected with the pathogenic simian-human immunodeficiency virus KU2. We focused on the analysis of the response to peptide p11C, C-M (Gag 181), since it was predominant in most tissues of all macaques. Five macaques restricted viral replication effectively, whereas the remaining three failed to control viremia and experienced a progressive loss of CD4+ T cells. The frequency of the Gag 181 (p11C, C→M) immunodominant response varied among different tissues of the same animal and in the same tissues from different animals. We found that the functionality of this virus-specific CD8+ T-cell population could not be assumed based on the ability to specifically bind to the Gag 181 tetramer, particularly in the mucosal tissues of some of the macaques infected by SIVmac251 that were progressing to disease. Overall, the functionality of CD8+ tetramer-binding T cells in tissues assessed by either measurement of cytolytic activity or the ability of these cells to produce gamma interferon or tumor necrosis factor alpha was low and was even lower in the mucosal tissue than in blood or spleen of some SIVmac251-infected animals that failed to control viremia. The data obtained in this pilot study lead to the hypothesis that disease progression may be associated with loss of virus-specific CD8+ T-cell function.

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Stable expression of transdominant Rev protein in human T cells inhibits human immunodeficiency virus replication.

Journal of Experimental Medicine ◽

10.1084/jem.176.4.1197 ◽

1992 ◽

Vol 176 (4) ◽

pp. 1197-1201 ◽

Cited By ~ 113

Author(s):

M H Malim ◽

W W Freimuth ◽

J Liu ◽

T J Boyle ◽

H K Lyerly ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Hiv Infection ◽

Viral Replication ◽

Cell Lines ◽

Cell Function ◽

T Cell Function ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Rev Protein

The human immunodeficiency virus (HIV) Rev protein is essential for viral structural protein expression (Gag, Pol, and Env) and, hence, for viral replication. In transient transfection assays, mutant forms of Rev have been identified that inhibit wild-type Rev activity and therefore suppress viral replication. To determine whether such transdominant Rev proteins could provide long-term protection against HIV infection without affecting T cell function, T leukemia cell lines were stably transduced with a retroviral vector encoding a transdominant mutant of the Rev protein, M10. While all the M10-expressing cell lines remained infectable by HIV-1, these same cells failed to support a productive replication cycle when infected with a cloned isolate of HIV-1. In addition, two out of three M10-expressing CEM clones were also resistant to highly productive infection by a heterogeneous HIV-1 pool. Expression of M10 did not affect induction of HIV transcription mediated by the kappa B regulatory element or Tat. Importantly, constitutive expression of Rev M10 did not alter the secretion of interleukin 2 in response to mitogen stimulation of EL-4 and Jurkat cells. The inhibition of HIV infection in cells stably expressing a transdominant Rev protein, in the absence of any deleterious effect on T cell function, suggests that such a strategy could provide a therapeutic effect in the T lymphocytes of acquired immunodeficiency syndrome patients.

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B And T Cell Function Parameters During Zidovudine Treatment Of Human Immunodeficiency Virus-Infected Patients

The Journal of Infectious Diseases ◽

10.1093/infdis/170.5.1148 ◽

1994 ◽

Vol 170 (5) ◽

pp. 1148-1156 ◽

Cited By ~ 3

Author(s):

R. Zamarchi ◽

M. Panozzo ◽

A. Del Mistro ◽

A. Barelli ◽

A. Borri ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Cell Function ◽

T Cell Function ◽

Zidovudine Treatment ◽

Immunodeficiency Virus

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Vaccine protection from CD4+ T-cell loss caused by simian immunodeficiency virus (SIV) mac251 is afforded by sequential immunization with three unrelated vaccine vectors encoding multiple SIV antigens

Journal of General Virology ◽

10.1099/vir.0.80226-0 ◽

2004 ◽

Vol 85 (10) ◽

pp. 2915-2924 ◽

Cited By ~ 30

Author(s):

Gerrit Koopman ◽

Daniella Mortier ◽

Sam Hofman ◽

Henk Niphuis ◽

Zahra Fagrouch ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Cell Function ◽

Semliki Forest Virus ◽

Rhesus Macaques ◽

Cell Loss ◽

Inverse Association ◽

Immunodeficiency Virus

Candidate human immunodeficiency virus (HIV) vaccine strategies that induce strong cellular immune responses protect rhesus macaques that are infected with recombinant simian/human immunodeficiency virus SHIV89.6p from acute CD4+ T-cell loss and delay progression to AIDS. However, similar strategies have not proven as efficacious in the simian immunodeficiency virus (SIV)mac model of AIDS, an infection that causes a slow, steady loss of CD4+ T-cell function and numbers in rhesus macaques similar to that caused by HIV-1, the principal cause of AIDS in humans. Efforts to increase vaccine efficacy by repeated boosting with the same vector are quickly limited by rising anti-vector immune responses. Here, the sequential use of three different vectors (DNA, Semliki Forest virus and modified vaccinia virus Ankara) encoding the same SIVmac structural and regulatory antigens was investigated and demonstrated to prevent or slow the loss of CD4+ T-cells after mucosal challenge with the highly pathogenic SIVmac251 strain. Of particular interest was an inverse association between the extent of T-helper 2 cytokine responses and steady-state virus load. Although limited in the number of animals, this study provides important proof of the efficacy of the triple-vector vaccine strategy against chronic, progressive CD4+ T-cell loss in the rigorous SIVmac/rhesus macaque model of AIDS.

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