Polyclonal B-cell activation reveals antibodies against human immunodeficiency virus type 1 (HIV-1) in HIV-1-seronegative individuals.

ABSTRACT Abnormal activation of B lymphocytes is a feature commonly seen in human immunodeficiency virus type 1 (HIV-1)-infected persons. However, the mechanism(s) responsible for this dysfunction is still poorly understood. Having recently shown that CD40L, the ligand for CD40, is inserted within emerging HIV-1 particles, we hypothesized that the contact between virus-anchored host CD40L and CD40 on the surface of B lymphocytes might result in the activation of this cell type. We report here that CD40L-bearing viruses, but not isogenic virions lacking host-derived CD40L, can induce immunoglobulin G and interleukin-6 production. Furthermore, such viral entities were found to induce B-cell homotypic adhesion. These effects were paralleled at the intracellular level by the nuclear translocation of the ubiquitous transcription factor NF-κB. The presence of host-derived CD40L within virions resulted in an increased virus attachment to B cells and a more-efficient B-cell-mediated transfer of HIV-1 to autologous CD4+ T lymphocytes. All the above processes were independent of the virus-encoded envelope glycoproteins. Altogether, the data gathered from this series of investigations suggest that the incorporation of host-encoded CD40L in HIV-1 is likely to play a role in the B-cell abnormalities that are seen in infected individuals.

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Sex-Based Differences in Human Immunodeficiency Virus Type 1 Reservoir Activity and Residual Immune Activation

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy617 ◽

2018 ◽

Vol 219 (7) ◽

pp. 1084-1094 ◽

Cited By ~ 22

Author(s):

Eileen P Scully ◽

Monica Gandhi ◽

Rowena Johnston ◽

Rebecca Hoh ◽

Ainsley Lockhart ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

T Cell Activation ◽

Immune Activation ◽

Cell Activation ◽

Immunodeficiency Virus ◽

Hiv 1

Abstract Plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in women are lower early in untreated HIV-1 infection compared with those in men, but women have higher T-cell activation and faster disease progression when adjusted for viral load. It is not known whether these sex differences persist during effective antiretroviral therapy (ART), or whether they would be relevant for the evaluation and implementation of HIV-1 cure strategies. We prospectively enrolled a cohort of reproductive-aged women and matched men on suppressive ART and measured markers of HIV-1 persistence, residual virus activity, and immune activation. The frequency of CD4+ T cells harboring HIV-1 DNA was comparable between the sexes, but there was higher cell-associated HIV-1 RNA, higher plasma HIV-1 (single copy assay), and higher T-cell activation and PD-1 expression in men compared with women. These sex-related differences in immune phenotype and HIV-1 persistence on ART have significant implications for the design and measurement of curative interventions.

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Neutralizing Antibodies Associated with Viremia Control in a Subset of Individuals after Treatment of Acute Human Immunodeficiency Virus Type 1 Infection

Journal of Virology ◽

10.1128/jvi.75.21.10200-10207.2001 ◽

2001 ◽

Vol 75 (21) ◽

pp. 10200-10207 ◽

Cited By ~ 70

Author(s):

David C. Montefiori ◽

Tanya S. Hill ◽

Ha T. T. Vo ◽

Bruce D. Walker ◽

Eric S. Rosenberg

Keyword(s):

Human Immunodeficiency Virus ◽

B Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Treatment Interruption ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Immediate treatment of acute human immunodeficiency virus type 1 (HIV-1) infection has been associated with subsequent control of viremia in a subset of patients after therapy cessation, but the immune responses contributing to control have not been fully defined. Here we examined neutralizing antibodies as a correlate of viremia control following treatment interruption in HIV-1-infected individuals in whom highly active antiretriviral therapy (HAART) was initiated during early seroconversion and who remained on therapy for 1 to 3 years. Immediately following treatment interruption, neutralizing antibodies were undetectable with T-cell-line adapted strains and the autologous primary HIV-1 isolate in seven of nine subjects. Env- and Gag-specific antibodies as measured by enzyme-linked immunosorbent assay were also low or undetectable at this time. Despite this apparent poor maturation of the virus-specific B-cell response during HAART, autologous neutralizing antibodies emerged rapidly and correlated with a spontaneous downregulation in rebound viremia following treatment interruption in three subjects. Control of rebound viremia was seen in other subjects in the absence of detectable neutralizing antibodies. The results indicate that virus-specific B-cell priming occurs despite the early institution of HAART, allowing rapid secondary neutralizing-antibody production following treatment interruption in a subset of individuals. Since early HAART limits viral diversification, we hypothesize that potent neutralizing-antibody responses to autologous virus are able to mature and that in some persons these responses contribute to the control of plasma viremia after treatment cessation.

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Hexamethylbisacetamide Remodels the Human Immunodeficiency Virus Type 1 (HIV-1) Promoter and Induces Tat-Independent HIV-1 Expression but Blunts Cell Activation

Journal of Virology ◽

10.1128/jvi.80.9.4570-4579.2006 ◽

2006 ◽

Vol 80 (9) ◽

pp. 4570-4579 ◽

Cited By ~ 36

Author(s):

Vladimir Klichko ◽

Nancy Archin ◽

Rupinderjeet Kaur ◽

Ginger Lehrman ◽

David Margolis

Keyword(s):

Human Immunodeficiency Virus ◽

Hiv Infection ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Cell Activation ◽

Ex Vivo ◽

Immunodeficiency Virus ◽

Latently Infected ◽

Hiv 1

ABSTRACT Hexamethylbisacetamide (HMBA) induces human immunodeficiency virus type 1 (HIV-1) gene expression in latently infected T-cell and monocytoid cell lines. We find that HMBA activation of viral expression is Tat independent but, like Tat, increases the efficiency of elongation of the HIV-1 promoter (long terminal repeat [LTR]) transcripts. Further, exposure to HMBA induces chromatin remodeling at nucleosome 1 (Nuc-1) near the start site of LTR transcription but does so without increasing histone acetylation or altering histone methylation near Nuc-1. Of note, despite enhanced proviral expression, HMBA suppressed HIV infection ex vivo in primary blood mononuclear cell (PBMC) cultures. Treatment with HMBA did not alter expression of the HIV coreceptors, CCR5 and CXCR4, in PBMCs but down-regulated CD4. Finally, HMBA interferes with cell proliferation and activation; it suppressed expression of Ki67 and CD25 and in PBMCs exposed to mitogen. As HMBA has been tested in oncology trials, its unusual properties make it a useful reagent for future studies of HIV promoter regulation and a novel prototype molecule for therapeutics that abort the latent proviral state of chronic HIV infection.

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G-Protein Signaling Triggered by R5 Human Immunodeficiency Virus Type 1 Increases Virus Replication Efficiency in Primary T Lymphocytes

Journal of Virology ◽

10.1128/jvi.79.12.7938-7941.2005 ◽

2005 ◽

Vol 79 (12) ◽

pp. 7938-7941 ◽

Cited By ~ 19

Author(s):

Yea-Lih Lin ◽

Clément Mettling ◽

Pierre Portalès ◽

Brigitte Réant ◽

Jacques Clot ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Lymphocytes ◽

G Protein ◽

Virus Replication ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Cell Activation ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The binding of R5 envelope to CCR5 during human immunodeficiency virus type 1 (HIV-1) entry provokes cell activation, which has so far been considered to have no effect on virus replication, since signaling-defective CCR5 molecules have been shown to function normally as HIV-1 coreceptors on transformed cells or mitogen-stimulated T lymphocytes. As the background state of activation of these cells might have biased the results, we performed experiments using the same approach but with nonactivated primary T lymphocytes. We now report that the single R126N mutation in the DRY motif, involved in G-protein coupling, results in a signaling-defective CCR5 coreceptor with a drastically impaired capacity to support HIV-1 infection.

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TFII-I Regulates Induction of Chromosomally Integrated Human Immunodeficiency Virus Type 1 Long Terminal Repeat in Cooperation with USF

Journal of Virology ◽

10.1128/jvi.79.7.4396-4406.2005 ◽

2005 ◽

Vol 79 (7) ◽

pp. 4396-4406 ◽

Cited By ~ 28

Author(s):

Jiguo Chen ◽

Tom Malcolm ◽

Mario C. Estable ◽

Robert G. Roeder ◽

Ivan Sadowski

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

T Cell Activation ◽

Cell Activation ◽

Jurkat Cells ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) replication is coupled to T-cell activation through its dependence on host cell transcription factors. Despite the enormous sequence variability of these factors, several cis elements for host factors are highly conserved within the 5′ long terminal repeats (LTRs) of viruses from AIDS patients; among these is the RBEIII upstream element for the Ras response element binding factor 2 (RBF-2). Here we show that RBF-2 is comprised of a USF1/USF2 heterodimer and TFII-I, which bind cooperatively to RBEIII. Recombinant USF1/USF2 binds to the RBEIII core sequence 160-fold less efficiently than it binds to an E box element, but the interaction with RBEIII is stimulated by TFII-I. Chromosomally integrated HIV-1 LTRs bearing an RBEIII mutation have slightly elevated basal transcription in unstimulated Jurkat cells but are unresponsive to cross-linking of the T-cell receptor or stimulation with phorbol myristate acetate (PMA) and ionomycin. Induction is inhibited by dominant interfering USF and TFII-I but not by the dominant negative I-κB protein. USF1, USF2, and TFII-I bind to the integrated wild-type LTR in unstimulated cells and become phosphorylated during the induction of transcription upon stimulation with PMA. These results demonstrate that USF1/USF2 and TFII-I interact cooperatively at the upstream RBEIII element and are necessary for the induction of latent HIV-1 in response to T-cell activation signals.

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Adult AIDS-Like Disease in a Novel Inducible Human Immunodeficiency Virus Type 1 Nef Transgenic Mouse Model: CD4+ T-Cell Activation Is Nef Dependent and Can Occur in the Absence of Lymphophenia

Journal of Virology ◽

10.1128/jvi.01466-09 ◽

2009 ◽

Vol 83 (22) ◽

pp. 11830-11846 ◽

Cited By ~ 18

Author(s):

Mir Munir Ahmed Rahim ◽

Pavel Chrobak ◽

Chunyan Hu ◽

Zaher Hanna ◽

Paul Jolicoeur

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

T Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

T Cell Activation ◽

Cell Activation ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT CD4C/HIVnef transgenic (Tg) mice express Nef in CD4+ T cells and in the cells of the macrophage/monocyte/dendritic lineage, and they develop an AIDS-like disease similar to human AIDS. In these mice, Nef is constitutively expressed throughout life. To rule out the contribution of any developmental defects caused by early expression of Nef, we generated inducible human immunodeficiency virus type 1 (HIV-1) Nef Tg mice by using the tetracycline-inducible system. Faithful expression of the Nef transgene was induced in (CD4C/rtTA × TRE/HIVNef) or (CD4C/rtTA2S-M2 × TRE/HIVNef) double-Tg mice upon doxycycline (DOX) treatment in drinking water. Long-term treatment of these mice with DOX also led to loss, apoptosis, and activation of CD4+ T cells, this latter phenotype being observed even with low levels of Nef. These phenotypes could be transferred by bone marrow (BM) transplantation, indicating a hematopoietic cell autonomous effect. In addition, in mixed Tg:non-Tg BM chimeras, only Tg and not non-Tg CD4+ T cells exhibited an effector/memory phenotype in the absence of lymphopenia. Finally, the DOX-induced double-Tg mice developed nonlymphoid organ diseases similar to those of CD4C/HIVNef Tg mice and of humans infected with HIV-1. These results show for the first time that adult mice are susceptible to the detrimental action of Nef and that Nef-mediated T-cell activation can be independent of lymphopenia. These Tg mice represent a unique model which is likely to be instrumental for understanding the cellular and molecular pathways of Nef action as well as the main characteristics of immune reconstitution following DOX withdrawal.

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