Human Immunodeficiency Virus Type 1 Nef Protein Sensitizes CD4+ T Lymphoid Cells to Apoptosis via Functional Upregulation of the CD95/CD95 Ligand Pathway

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 1000-1010 ◽  
Author(s):  
Giorgio Zauli ◽  
Davide Gibellini ◽  
Paola Secchiero ◽  
Hélène Dutartre ◽  
Daniel Olive ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Death ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cd95 Ligand ◽  
Immunodeficiency Virus ◽  
Hiv 1

Many viruses have evolved genes encoding proteins that regulate cell death by apoptosis. The human immunodeficiency virus type 1 (HIV-1) Nef protein alters T-cell development and signaling and is required for optimal viral replication and pathogenicity in vivo. To analyze the interference of Nef with cell survival, we used both regulated and constitutively expressed nef alleles in stably transfected T-cell lines. Nef-expressing cells were sensitized to cell death by apoptosis, which was specifically exacerbated by an anti-CD95 IgM monoclonal antibody (MoAb). Flow cytometric analysis showed that the surface expression of both CD95 and CD95 ligand (CD95L) was upregulated by endogenous Nef expression. Nef-mediated apoptosis was almost completely suppressed by the addition in culture of an anti-CD95 Fab′ IgG MoAb, which specifically blocks CD95/CD95L interactions. Lastly, mutation of a proline motif in the core region of the nef gene, which disrupts its ability to interact with cellular kinases and reduces HIV-1 replication in vitro, completely abrogated the Nef-mediated induction of apoptosis as well as its ability to upregulate surface CD95 and CD95L. These findings may provide molecular insight into the role of endogenous Nef in the T-cell depletion observed in vivo, particularly HIV-specific cytotoxic CD8+ T cells.

Human Immunodeficiency Virus Type 1 Nef Protein Sensitizes CD4+ T Lymphoid Cells to Apoptosis via Functional Upregulation of the CD95/CD95 Ligand Pathway

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 1000-1010 ◽  
Author(s):  
Giorgio Zauli ◽  
Davide Gibellini ◽  
Paola Secchiero ◽  
Hélène Dutartre ◽  
Daniel Olive ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Death ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cd95 Ligand ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Many viruses have evolved genes encoding proteins that regulate cell death by apoptosis. The human immunodeficiency virus type 1 (HIV-1) Nef protein alters T-cell development and signaling and is required for optimal viral replication and pathogenicity in vivo. To analyze the interference of Nef with cell survival, we used both regulated and constitutively expressed nef alleles in stably transfected T-cell lines. Nef-expressing cells were sensitized to cell death by apoptosis, which was specifically exacerbated by an anti-CD95 IgM monoclonal antibody (MoAb). Flow cytometric analysis showed that the surface expression of both CD95 and CD95 ligand (CD95L) was upregulated by endogenous Nef expression. Nef-mediated apoptosis was almost completely suppressed by the addition in culture of an anti-CD95 Fab′ IgG MoAb, which specifically blocks CD95/CD95L interactions. Lastly, mutation of a proline motif in the core region of the nef gene, which disrupts its ability to interact with cellular kinases and reduces HIV-1 replication in vitro, completely abrogated the Nef-mediated induction of apoptosis as well as its ability to upregulate surface CD95 and CD95L. These findings may provide molecular insight into the role of endogenous Nef in the T-cell depletion observed in vivo, particularly HIV-specific cytotoxic CD8+ T cells.

scholarly journals Exclusive and Persistent Use of the Entry Coreceptor CXCR4 by Human Immunodeficiency Virus Type 1 from a Subject Homozygous for CCR5 Δ32

1998 ◽  
Vol 72 (7) ◽  
pp. 6040-6047 ◽  
Author(s):  
Nelson L. Michael ◽  
Julie A. E. Nelson ◽  
Vineet N. KewalRamani ◽  
George Chang ◽  
Stephen J. O’Brien ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Compartment ◽  
Gene Coding ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Individuals who are homozygous for the 32-bp deletion in the gene coding for the chemokine receptor and major human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 (CCR5 −/−) lack functional cell surface CCR5 molecules and are relatively resistant to HIV-1 infection. HIV-1 infection in CCR5 −/− individuals, although rare, has been increasingly documented. We now report that the viral quasispecies from one such individual throughout disease is homogenous, T cell line tropic, and phenotypically syncytium inducing (SI); exclusively uses CXCR4; and replicates well in CCR5−/− primary T cells. The recently discovered coreceptors BOB and Bonzo are not used. Although early and persistent SI variants have been described in longitudinal studies, this is the first demonstration of exclusive and persistent CXCR4 usage. With the caveat that the earliest viruses available from this subject were from approximately 4 years following primary infection, these data suggest that HIV-1 infection can be mediated and persistently maintained by viruses which exclusively utilize CXCR4. The lack of evolution toward the available minor coreceptors in this subject underscores the dominant biological roles of the major coreceptors CCR5 and CXCR4. This and two similar subjects (R. Biti, R. Ffrench, J. Young, B. Bennetts, G. Stewart, and T. Liang, Nat. Med. 3:252–253, 1997; I. Theodoreu, L. Meyer, M. Magierowska, C. Katlama, and C. Rouzioux, Lancet 349:1219–1220, 1997) showed relatively rapid CD4+ T-cell declines despite average or low initial viral RNA load. Since viruses which use CXCR4 exclusively cannot infect macrophages, these data have implications for the relative infection of the T-cell compartment versus the macrophage compartment in vivo and for the development of CCR5-based therapeutics.

scholarly journals Human Lymphoblastoid CD4+ T Cells Become Permissive to Macrophage-Tropic Strains of Human Immunodeficiency Virus Type 1 after Passage into Severe Combined Immunodeficient Mice through In Vivo Upregulation of CCR5: In Vivo Dynamics of CD4+ T-Cell Differentiation in Pathogenesis of AIDS

1998 ◽  
Vol 72 (12) ◽  
pp. 10323-10327 ◽  
Author(s):  
Caterina Lapenta ◽  
Stefania Parlato ◽  
Massimo Spada ◽  
Stefano M. Santini ◽  
Paola Rizza ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Chemokine Receptors ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT In this article, we show that passage in SCID mice rendered a human CD4+ T-cell line (CEM cells) highly susceptible to infection by macrophage-tropic (M-tropic) strains and primary clinical isolates of human immunodeficiency virus type 1 (HIV-1). This in vivo-acquired permissiveness of CEM cells was associated with the induction of a CD45RO+ phenotype as well as of some β-chemokine receptors. Regulated upon activation, normal T-cell expressed and secreted chemokine entirely inhibited the ability of M-tropic HIV-1 strains to infect these cells. These findings may lead to new approaches in investigating in vivo the capacity of different HIV strains to exploit chemokine receptors in relation to the dynamics of the activation and/or differentiation state of human CD4+ T cells.

scholarly journals Allogeneic leukocytes but not therapeutic blood elements induce reactivation and dissemination of latent human immunodeficiency virus type 1 infection: implications for transfusion support of infected patients

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 2128-2135 ◽  
Author(s):  
MP Busch ◽  
TH Lee ◽  
J Heitman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Blood Components ◽  
Route Of Transmission ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Donor Lymphocytes

Abstract Various immunologic stimuli and heterologous viral regulatory elements have been shown to increase susceptibility to, and replication of, human immunodeficiency virus type 1 (HIV-1) in lymphocytes and monocytes in vitro. Transfusion of allogeneic blood components from heterologous donors constitutes a profound immunologic stimulus to the recipient, in addition to being a potential route of transmission of lymphotropic viral infections. To investigate the hypothesis that transfusions, and particularly those containing leukocytes, activate HIV-1 replication in infected recipient cells, we cocultured peripheral blood mononuclear cells (PBMC) from three anti-HIV-1-positive individuals with allogeneic donor PBMC, as well as partially purified populations of donor lymphocytes, monocytes, granulocytes, platelets, and red blood cells (RBC) and allogeneic cell-free plasma. Allogeneic PBMC induced a dose-related activation of HIV-1 expression in in vivo infected cells, followed by dissemination of HIV-1 to previously uninfected patient cells. Activation of HIV-1 replication was observed with donor lymphocytes, monocytes, and granulocytes, whereas no effect was seen with leukocyte-depleted RBC, platelets, or plasma (ie, therapeutic blood constituents). Allogeneic donor PBMC were also shown to upregulate HIV-1 expression in a “latently” infected cell line, and to increase susceptibility of heterologous donor PBMC to acute HIV-1 infection. Studies should be performed to evaluate whether transfusions of leukocyte-containing blood components accelerate HIV-1 dissemination and disease progression in vivo. If so, HIV-1-infected patients should be transfused as infrequently as possible and leukocyte-depleted (filtered) blood components should be used to avoid this complication.

scholarly journals Mutually Exclusive T-Cell Receptor Induction and Differential Susceptibility to Human Immunodeficiency Virus Type 1 Mutational Escape Associated with a Two-Amino-Acid Difference between HLA Class I Subtypes

2006 ◽  
Vol 81 (4) ◽  
pp. 1619-1631 ◽  
Author(s):  
Xu G. Yu ◽  
Mathias Lichterfeld ◽  
Senica Chetty ◽  
Katie L. Williams ◽  
Stanley K. Mui ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Hla Class I ◽  
Viral Escape ◽  
Class I ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The relative contributions of HLA alleles and T-cell receptors (TCRs) to the prevention of mutational viral escape are unclear. Here, we examined human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses restricted by two closely related HLA class I alleles, B*5701 and B*5703, that differ by two amino acids but are both associated with a dominant response to the same HIV-1 Gag epitope KF11 (KAFSPEVIPMF). When this epitope is presented by HLA-B*5701, it induces a TCR repertoire that is highly conserved among individuals, cross-recognizes viral epitope variants, and is rarely associated with mutational escape. In contrast, KF11 presented by HLA-B*5703 induces an entirely different, more heterogeneous TCR β-chain repertoire that fails to recognize specific KF11 escape variants which frequently arise in clade C-infected HLA-B*5703+ individuals. These data show the influence of HLA allele subtypes on TCR selection and indicate that extensive TCR diversity is not a prerequisite to prevention of allowable viral mutations.

scholarly journals Enhanced immunogenicity using an alphavirus replicon DNA vaccine against human immunodeficiency virus type 1

2005 ◽  
Vol 86 (2) ◽  
pp. 349-354 ◽  
Author(s):  
Eva K. L. Nordström ◽  
Mattias N. E. Forsell ◽  
Christina Barnfield ◽  
Eivor Bonin ◽  
Tomas Hanke ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Dna Vaccine ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Semliki Forest Virus ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

With the human immunodeficiency virus type 1 (HIV-1) epidemic expanding at increasing speed, development of a safe and effective vaccine remains a high priority. One of the most central vaccine platforms considered is plasmid DNA. However, high doses of DNA and several immunizations are typically needed to achieve detectable T-cell responses. In this study, a Semliki Forest virus replicon DNA vaccine designed for human clinical trials, DREP.HIVA, encoding an antigen that is currently being used in human trials in the context of a conventional DNA plasmid, pTHr.HIVA, was generated. It was shown that a single immunization of DREP.HIVA stimulated HIV-1-specific T-cell responses in mice, suggesting that the poor immunogenicity of conventional DNA vaccines may be enhanced by using viral replicon-based plasmid systems. The results presented here support the evaluation of Semliki Forest virus replicon DNA vaccines in non-human primates and in clinical studies.

scholarly journals Ontogeny and Specificities of Mucosal and Blood Human Immunodeficiency Virus Type 1-Specific CD8+ Cytotoxic T Lymphocytes

2003 ◽  
Vol 77 (1) ◽  
pp. 291-300 ◽  
Author(s):  
L. Musey ◽  
Y. Ding ◽  
J. Cao ◽  
J. Lee ◽  
C. Galloway ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cytotoxic T Lymphocyte ◽  
Infected Individual ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Induction of adaptive immunity to human immunodeficiency virus type 1 (HIV-1) at the mucosal site of transmission is poorly understood but crucial in devising strategies to control and prevent infection. To gain further understanding of HIV-1-specific T-cell mucosal immunity, we established HIV-1-specific CD8+ cytotoxic T-lymphocyte (CTL) cell lines and clones from the blood, cervix, rectum, and semen of 12 HIV-1-infected individuals and compared their specificities, cytolytic function, and T-cell receptor (TCR) clonotypes. Blood and mucosal CD8+ CTL had common HIV-1 epitope specificities and major histocompatibility complex restriction patterns. Moreover, both systemic and mucosal CTL lysed targets with similar efficiency, primarily through the perforin-dependent pathway in in vitro studies. Sequence analysis of the TCRβ VDJ region revealed in some cases identical HIV-1-specific CTL clones in different compartments in the same HIV-1-infected individual. These results clearly establish that a subset of blood and mucosal HIV-1-specific CTL can have a common origin and can traffic between anatomically distinct compartments. Thus, these effectors can provide immune surveillance at the mucosa, where rapid responses are needed to contain HIV-1 infection.

scholarly journals The Interaction of Vpr with Uracil DNA Glycosylase Modulates the Human Immunodeficiency Virus Type 1 In Vivo Mutation Rate

2000 ◽  
Vol 74 (15) ◽  
pp. 7039-7047 ◽  
Author(s):  
Louis M. Mansky ◽  
Sandra Preveral ◽  
Luc Selig ◽  
Richard Benarous ◽  
Serge Benichou
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mutation Rate ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Dna Glycosylase ◽  
Uracil Dna Glycosylase ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The Vpr protein of human immunodeficiency virus type 1 (HIV-1) influences the in vivo mutation rate of the virus. Since Vpr interacts with a cellular protein implicated in the DNA repair process, uracil DNA glycosylase (UNG), we have explored the contribution of this interaction to the mutation rate of HIV-1. Single-amino-acid variants of Vpr were characterized for their differential UNG-binding properties and used to trans complement vpr null mutant HIV-1. A striking correlation was established between the abilities of Vpr to interact with UNG and to influence the HIV-1 mutation rate. We demonstrate that Vpr incorporation into virus particles is required to influence the in vivo mutation rate and to mediate virion packaging of the nuclear form of UNG. The recruitment of UNG into virions indicates a mechanism for how Vpr can influence reverse transcription accuracy. Our data suggest that distinct mechanisms evolved in primate and nonprimate lentiviruses to reconcile uracil misincorporation into lentiviral DNA.

scholarly journals In vivo characteristics of human immunodeficiency virus type 1 intersubtype recombination: determination of hot spots and correlation with sequence similarity

2003 ◽  
Vol 84 (10) ◽  
pp. 2715-2722 ◽  
Author(s):  
Gkikas Magiorkinis ◽  
Dimitrios Paraskevis ◽  
Anne-Mieke Vandamme ◽  
Emmanouil Magiorkinis ◽  
Vana Sypsa ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Recombination Frequency ◽  
Sequence Similarity ◽  
Virus Species ◽  
Immunodeficiency Virus ◽  
Hiv 1

Recombination plays a pivotal role in the evolutionary process of many different virus species, including retroviruses. Analysis of all human immunodeficiency virus type 1 (HIV-1) intersubtype recombinants revealed that they are more complex than described initially. Recombination frequency is higher within certain genomic regions, such as partial reverse transcriptase (RT), vif/vpr, the first exons of tat/rev, vpu and gp41. A direct correlation was observed between recombination frequency and sequence similarity across the HIV-1 genome, indicating that sufficient sequence similarity is required upstream of the recombination breakpoint. This finding suggests that recombination in vivo may occur preferentially during reverse transcription through the strand displacement-assimilation model rather than the copy-choice model.

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