scholarly journals Candidate Microbicide PPCM Blocks Human Immunodeficiency Virus Type 1 Infection in Cell and Tissue Cultures and Prevents Genital Herpes in a Murine Model

2008 ◽  
Vol 82 (13) ◽  
pp. 6576-6584 ◽  
Author(s):  
Pedro M. M. Mesquita ◽  
Sarah S. Wilson ◽  
Philippe Manlow ◽  
Lucia Fischetti ◽  
Marla J. Keller ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Genital Herpes ◽  
Murine Model ◽  
Human Seminal Plasma ◽  
Clade B ◽  
Immunodeficiency Virus ◽  
Clade C ◽  
Simplex Virus

ABSTRACT A structurally novel candidate microbicide, PPCM, which is formed from the reaction of d,l-mandelic acid with sulfuric acid, provides activity against human immunodeficiency virus (HIV) and herpes simplex virus (HSV) and is not cytotoxic. The objectives of the current studies were to comprehensively evaluate the activity of PPCM in cell and explant cultures, explore the possibility of combining PPCM with HIV-specific reverse transcriptase inhibitors, and evaluate the efficacy of a formulated gel against genital herpes in a murine model. PPCM inhibited infection by laboratory and clinical R5 and X4 clade B and clade C HIV strains in cell culture. Ectocervical and endocervical tissue explants exposed to HIV-1BaL in the presence of PPCM were protected (50% inhibitory concentrations [IC50] of 3.9 μg/ml for ectocervix and 3.1 μg/ml for endocervix), and transfer of virus to target T cells via migratory cells was significantly impaired (IC50 of 35.7 μg/ml for ectocervix and 54.6 μg/ml for endocervix). The drug also blocked infection by cell-associated virus. Combinations of PPCM with UC-781 or PMPA in vitro exhibited additive anti-HIV activity. PPCM was incorporated into stable, low-pH gel formulations at concentrations of 0.4% and 4%. Both gels prevented genital herpesvirus infection in mice, even when virus was introduced in human seminal plasma. The abilities of PPCM to inhibit primary HIV isolates, reduce infection by cell-associated virus, and transfer of HIV from migratory to T cells, combined with the complete protection provided by formulated gel against genital herpes, indicate that this drug is an excellent candidate for inclusion in a combination microbicide and would provide protection against both HIV and HSV.

scholarly journals Follicular Helper T Cells Are Major Human Immunodeficiency Virus-2 Reservoirs and Support Productive Infection

2019 ◽  
Vol 221 (1) ◽  
pp. 122-126 ◽  
Author(s):  
Ana Godinho-Santos ◽  
Russell B Foxall ◽  
Ana V Antão ◽  
Bárbara Tavares ◽  
Tiago Ferreira ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Ex Vivo ◽  
Immune Deficiency Syndrome ◽  
Productive Infection ◽  
Helper T Cells ◽  
Follicular Helper T Cells ◽  
Follicular Helper ◽  
Immunodeficiency Virus

Abstract Follicular helper T cells (Tfh), CD4 lymphocytes critical for efficient antibody responses, have been shown to be key human immunodeficiency virus (HIV)-1 reservoirs. Human immunodeficiency virus-2 infection represents a unique naturally occurring model for investigating Tfh role in HIV/acquired immune deficiency syndrome, given its slow rate of CD4 decline, low to undetectable viremia, and high neutralizing antibody titers throughout the disease course. In this study, we investigated, for the first time, Tfh susceptibility to HIV-2 infection by combining in vitro infection of tonsillar Tfh with the ex vivo study of circulating Tfh from HIV-2-infected patients. We reveal that Tfh support productive HIV-2 infection and are preferential viral targets in HIV-2-infected individuals.

scholarly journals WFDC1/ps20 Is a Novel Innate Immunomodulatory Signature Protein of Human Immunodeficiency Virus (HIV)-Permissive CD4+ CD45RO+ Memory T Cells That Promotes Infection by Upregulating CD54 Integrin Expression and Is Elevated in HIV Type 1 Infection

2007 ◽  
Vol 82 (1) ◽  
pp. 471-486 ◽  
Author(s):  
R. Alvarez ◽  
J. Reading ◽  
D. F. L. King ◽  
M. Hayes ◽  
P. Easterbrook ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Integrin Expression ◽  
Small Interference Rna ◽  
Immunodeficiency Virus

ABSTRACT Understanding why human immunodeficiency virus (HIV) preferentially infects some CD4+ CD45RO+ memory T cells has implications for antiviral immunity and pathogenesis. We report that differential expression of a novel secreted factor, ps20, previously implicated in tissue remodeling, may underlie why some CD4 T cells are preferentially targeted. We show that (i) there is a significant positive correlation between endogenous ps20 mRNA in diverse CD4 T-cell populations and in vitro infection, (ii) a ps20+ permissive cell can be made less permissive by antibody blockade- or small-interference RNA-mediated knockdown of endogenous ps20, and (iii) conversely, a ps20low cell can be more permissive by adding ps20 exogenously or engineering stable ps20 expression by retroviral transduction. ps20 expression is normally detectable in CD4 T cells after in vitro activation and interleukin-2 expansion, and such oligoclonal populations comprise ps20positive and ps20low/negative isogenic clones at an early differentiation stage (CD45RO+/CD25+/CD28+/CD57−). This pattern is altered in chronic HIV infection, where ex vivo CD4+ CD45RO+ T cells express elevated ps20. ps20 promoted HIV entry via fusion and augmented CD54 integrin expression; both of these effects were reversed by anti-ps20 antibody. We therefore propose ps20 to be a novel signature of HIV-permissive CD4 T cells that promotes infection in an autocrine and paracrine manner and that HIV has coopted a fundamental role of ps20 in promoting cell adhesion for its benefit. Disrupting the ps20 pathway may therefore provide a novel anti-HIV strategy.

Detection and characterization of apoptotic peripheral blood lymphocytes in human immunodeficiency virus infection and cancer chemotherapy by a novel flow immunocytometric method

Blood ◽  
1994 ◽  
Vol 83 (5) ◽  
pp. 1268-1277 ◽  
Author(s):  
M Carbonari ◽  
M Cibati ◽  
M Cherchi ◽  
D Sbarigia ◽  
AM Pesce ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Hiv Infection ◽  
Peripheral Blood ◽  
Peripheral Blood Leukocytes ◽  
Blood Leukocytes ◽  
Cell Counts ◽  
Immunodeficiency Virus

We have developed a quantitative and sensitive flow cytometric method for the detection of human apoptotic lymphocytes that, unlike previously described assays, allows their identification in mixed populations of peripheral blood leukocytes as well as their immunophenotyping. Apoptotic lymphocytes are identified on the basis of peculiar light scatter changes, reflecting their smaller size and their modified nucleus/cytoplasm organization, and of the decreased expression of surface CD45 molecules. Based on these criteria, apoptotic lymphocytes generated by exposure to ionizing radiation can be easily distinguished from viable cells and from necrotic lymphocytes generated by treatment with antibody and complement. Using this assay, we reappraised the phenomenon of the in vitro apoptosis of lymphocytes from patients with human immunodeficiency virus (HIV) infection. Lymphocytes from HIV patients, unlike those from normal HIV-negative subjects, undergo apoptosis upon simple in vitro culture. We found that the percentages of lymphocytes undergoing apoptosis were significantly higher in patients with low CD4 cell counts (< 400/microL) than in patients at earlier stages (> 400 CD4 cells/microL). However, phenotypic analysis disclosed that apoptotic lymphocytes generated in these cultures were mostly CD8+ T cells and CD19+ B cells. Thus, in contrast to what has been previously suggested, the phenomenon of in vitro lymphocyte apoptosis might not be pathogenetically related to the depletion of CD4+ T cells in acquired immunodeficiency syndrome. Nevertheless, it might represent an useful marker of disease progression. Our assay allows the analysis of unfractionated peripheral blood leukocytes and thus the identification of apoptotic lymphocytes circulating in vivo. Apoptotic lymphocytes could indeed be detected in the circulation of a patient with cancer shortly after high-dose cytotoxic chemotherapy. By contrast, no apoptotic lymphocytes could be detected in vivo in patients with early or advanced HIV infection.

scholarly journals Restoration of Anti-Human Immunodeficiency Virus Type 1 (HIV-1) Responses in CD8+ T Cells from Late-Stage Patients on Prolonged Antiretroviral Therapy by Stimulation In Vitro with HIV-1 Protein-Loaded Dendritic Cells

2001 ◽  
Vol 75 (9) ◽  
pp. 4413-4419 ◽  
Author(s):  
Zheng Fan ◽  
Xiao-Li Huang ◽  
Luann Borowski ◽  
John W. Mellors ◽  
Charles R. Rinaldo
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Antiretroviral Therapy ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT We demonstrate that dendritic cells loaded in vitro with human immunodeficiency virus type 1 (HIV-1) protein-liposome complexes activate HLA class I-restricted anti-HIV-1 cytotoxic T-lymphocyte and gamma interferon (IFN-γ) responses in autologous CD8+ T cells from late-stage HIV-1-infected patients on prolonged combination drug therapy. Interleukin-12 enhanced this effect through an interleukin-2- and IFN-γ-mediated pathway. This suggests that dendritic cells from HIV-1-infected persons can be engineered to evoke stronger anti-HIV-1 CD8+ T-cell reactivity as a strategy to augment antiretroviral therapy.

scholarly journals Exogenous Interleukin-2 Administration Corrects the Cell Cycle Perturbation of Lymphocytes from Human Immunodeficiency Virus-Infected Individuals

2001 ◽  
Vol 75 (22) ◽  
pp. 10843-10855 ◽  
Author(s):  
Mirko Paiardini ◽  
Domenico Galati ◽  
Barbara Cervasi ◽  
Giuseppe Cannavo ◽  
Luca Galluzzi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Cycle Control ◽  
Interleukin 2 ◽  
Protein Ubiquitination ◽  
Immunodeficiency Virus ◽  
Cell Cycle Perturbation ◽  
Cycle Dependent

ABSTRACT Human immunodeficiency virus (HIV)-induced immunodeficiency is characterized by progressive loss of CD4+ T cells associated with functional abnormalities of the surviving lymphocytes. Increased susceptibility to apoptosis and loss of proper cell cycle control can be observed in lymphocytes from HIV-infected individuals and may contribute to the lymphocyte dysfunction of AIDS patients. To better understand the relation between T-cell activation, apoptosis, and cell cycle perturbation, we studied the effect of exogenous interleukin-2 (IL-2) administration on the intracellular turnover of phase-dependent proteins. Circulating T cells from HIV-infected patients display a marked discrepancy between a metabolic profile typical of G0 and a pattern of expression of phase-dependent proteins that indicates a more-advanced position within the cell cycle. This discrepancy is enhanced by in vitro activation with ConA and ultimately results in a marked increase of apoptotic events. Conversely, treatment of lymphocytes with IL-2 alone restores the phase-specific pattern of expression of cell cycle-dependent proteins and is associated with low levels of apoptosis. Interestingly, exogenous IL-2 administration normalizes the overall intracellular protein turnover, as measured by protein synthesis, half-life of newly synthesised proteins, and total protein ubiquitination, thus providing a possible explanation for the effect of IL-2 on the intracellular kinetics of cell cycle-dependent proteins. The beneficial effect of IL-2 administration is consistent with the possibility of defective IL-2 function in vivo, which is confirmed by the observation that lymphocytes from HIV-infected patients show abnormal endogenous IL-2 paracrine/autocrine function upon in vitro mitogen stimulation. Overall these results confirm that perturbation of cell cycle control contributes to HIV-related lymphocyte dysfunction and, by showing that IL-2 administration can revert this perturbation, suggest a new mechanism of action of IL-2 therapy in HIV-infected patients.

scholarly journals Replication of the human immunodeficiency virus 1 and impaired differentiation of T cells after in vitro infection of bone marrow immature T cells.

1989 ◽  
Vol 83 (2) ◽  
pp. 610-615 ◽  
Author(s):  
Y Lunardi-Iskandar ◽  
M T Nugeyre ◽  
V Georgoulias ◽  
F Barré-Sinoussi ◽  
C Jasmin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Virus 1

scholarly journals Vaccines against Genital Herpes: Where Are We?

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 420
Author(s):  
Hyeon Cheol Kim ◽  
Heung Kyu Lee
Keyword(s):  
Human Immunodeficiency Virus ◽  
Genital Herpes ◽  
Vaccine Development ◽  
Venereal Disease ◽  
Current Status ◽  
Neonatal Herpes ◽  
Entire Life ◽  
High Burden ◽  
Immunodeficiency Virus ◽  
Simplex Virus

Genital herpes is a venereal disease caused by herpes simplex virus (HSV). Although HSV symptoms can be reduced with antiviral drugs, there is no cure. Moreover, because HSV infected individuals are often unaware of their infection, it is highly likely that they will transmit HSV to their sexual partner. Once infected, an individual has to live with HSV for their entire life, and HSV infection can lead to meningitis, encephalitis, and neonatal herpes as a result of vertical transmission. In addition, HSV infection increases the rates of human immunodeficiency virus (HIV) infection and transmission. Because of the high burden of genital herpes, HSV vaccines have been developed, but none have been very successful. In this review, we discuss the current status of genital herpes vaccine development.

CD8+ cell noncytotoxic anti-human immunodeficiency virus response inhibits expression of viral RNA but not reverse transcription or provirus integration

Microbiology ◽  
2000 ◽  
Vol 81 (5) ◽  
pp. 1261-1264 ◽  
Author(s):  
Carl E. Mackewicz ◽  
Bruce K. Patterson ◽  
Sandra A. Lee ◽  
Jay A. Levy
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Interleukin 2 ◽  
Viral Rna ◽  
Hiv Replication ◽  
Immunodeficiency Virus ◽  
Cd8 Cell ◽  
Provirus Integration ◽  
Replicative Cycle

CD8+ T cells from human immunodeficiency virus (HIV)-infected individuals can suppress HIV replication in CD4+ cells by a noncytotoxic mechanism that inhibits the expression of viral RNA. The present study examined whether other step(s) in the virus replicative cycle could be affected by the CD8+ cells. Culturing HIV-infected CD4+ T cells with antiviral CD8+ T cells did not significantly reduce the amounts of (i) early HIV DNA reverse transcripts (detected by LTR-U3/R), (ii) total nuclear HIV gag DNA, or (iii) integrated proviral DNA. However, exposure to the CD8+ T cells did cause a reduction in the amount of multiply spliced tat and full-length gag mRNA expressed by the infected CD4+ T cells, confirming previous observations. The levels of glyceraldehyde-3-phosphate dehydrogenase and interleukin-2 receptor-α mRNA were not affected. The results support the conclusion that the noncytotoxic anti-HIV response of CD8+ T cells, demonstrable in vitro, does not affect any of the virus replication steps leading to the integration of proviral HIV, but specifically interrupts the expression of viral RNA.

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