scholarly journals Ineffectual Targeting of HIV-1 Nef by Cytotoxic T Lymphocytes in Acute Infection Results in No Functional Impairment or Viremia Reduction

2014 ◽  
Vol 88 (14) ◽  
pp. 7881-7892 ◽  
Author(s):  
Justin De La Cruz ◽  
Thomas Vollbrecht ◽  
Patricia Frohnen ◽  
Hwee L. Ng ◽  
Eric S. Daar ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Receptor Gene ◽  
Acute Infection ◽  
Cell Receptor ◽  
Immunodeficiency Virus ◽  
Successful Control ◽  
And Function ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACTThe human immunodeficiency virus type 1 (HIV-1) accessory protein Nef is heavily targeted by CD8+T lymphocytes (CTLs) during acute infection and therefore is included in many candidate vaccines. We investigated whether CTL targeting of Nef during acute infection contributes to immune control by disrupting the function of Nef. The sequence and function of Nef in parallel with CTL responses were assessed longitudinally from peak viremia until the viremia set point in a cohort of six subjects with acute infection. All but one individual had a single founder strain. Nef-specific CTL responses were detected in all subjects and declined in magnitude over time. These responses were associated with mutations, but none of the mutations were detected in important functional motifs. Nef-mediated downregulation of CD4 and major histocompatibility complex (MHC) class I molecules was better preserved in acute infection than in chronic infection. Finally, Nef-specific CTL responses were not associated with a reduction in viremia from its acute-phase peak. Our results indicate that CTLs targeting Nef epitopes outside critical functional domains have little effect on the pathogenic functions of Nef, rendering these responses ineffective in acute infection.IMPORTANCEThese data indicate that using the whole Nef protein as a vaccine immunogen likely allows immunodominance that leads to targeting of CTL responses that are rapidly escaped with little effect on Nef-mediated pathogenic functions. Pursuing vaccination approaches that can more precisely direct responses to vulnerable areas would maximize efficacy. Until vaccine-induced targeting can be optimized, other approaches, such as the use of Nef function inhibitors or the pursuit of immunotherapies such as T cell receptor gene therapy or adoptive transfer, may be more likely to result in successful control of viremia.

scholarly journals Enhanced Infectivity of an R5-Tropic Simian/Human Immunodeficiency Virus Carrying Human Immunodeficiency Virus Type 1 Subtype C Envelope after Serial Passages in Pig-Tailed Macaques (Macaca nemestrina)

2000 ◽  
Vol 74 (14) ◽  
pp. 6501-6510 ◽  
Author(s):  
Zhiwei Chen ◽  
Yaoxing Huang ◽  
Xiuqing Zhao ◽  
Eva Skulsky ◽  
Dorothy Lin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
Acute Infection ◽  
Macaca Nemestrina ◽  
Subtype C ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The increasing prevalence of human immunodeficiency virus type 1 (HIV-1) subtype C infection worldwide calls for efforts to develop a relevant animal model for evaluating strategies against the transmission of the virus. A chimeric simian/human immunodeficiency virus (SHIV), SHIVCHN19, was generated with a primary, non-syncytium-inducing HIV-1 subtype C envelope from a Chinese strain in the background of SHIV33. Unlike R5-tropic SHIV162, SHIVCHN19 was not found to replicate in rhesus CD4+ T lymphocytes. SHIVCHN19 does, however, replicate in CD4+ T lymphocytes of pig-tailed macaques (Macaca nemestrina). The observed replication competence of SHIVCHN19 requires the fulltat/rev genes and partial gp41 region derived from SHIV33. To evaluate in vivo infectivity, SHIVCHN19 was intravenously inoculated, at first, into two pig-tailed and two rhesus macaques. Although all four animals became infected, the virus replicated preferentially in pig-tailed macaques with an earlier plasma viral peak and a faster seroconversion. To determine whether in vivo adaptation would enhance the infectivity of SHIVCHN19, passages were carried out serially in three groups of two pig-tailed macaques each, via intravenous blood-bone marrow transfusion. The passages greatly enhanced the infectivity of the virus as shown by the increasingly elevated viral loads during acute infection in animals with each passage. Moreover, the doubling time of plasma virus during acute infection became much shorter in passage 4 (P4) animals (0.2 day) in comparison to P1 animals (1 to 2 days). P2 to P4 animals all became seropositive around 2 to 3 weeks postinoculation and had a decline in CD4/CD8 T-cell ratio during the early phase of infection. In P4 animals, a profound depletion of CD4 T cells in the lamina propria of the jejunum was observed. Persistent plasma viremia has been found in most of the infected animals with sustained viral loads ranging from 103 to 105per ml up to 6 months postinfection. Serial passages did not change the viral phenotype as confirmed by the persistence of the R5 tropism of SHIVCHN19 isolated from P4 animals. In addition, the infectivity of SHIVCHN19 in rhesus peripheral blood mononuclear cells was also increased after in vivo passages. Our data indicate that SHIVCHN19 has adapted well to grow in macaque cells. This established R5-tropic SHIVCHN19/macaque model would be very useful for HIV-1 subtype C vaccine and pathogenesis studies.

scholarly journals Lentiviral Vectors Encoding Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Receptor Genes Efficiently Convert Peripheral Blood CD8 T Lymphocytes into Cytotoxic T Lymphocytes with Potent In Vitro and In Vivo HIV-1-Specific Inhibitory Activity

2008 ◽  
Vol 82 (6) ◽  
pp. 3078-3089 ◽  
Author(s):  
Aviva Joseph ◽  
Jian Hua Zheng ◽  
Antonia Follenzi ◽  
Teresa DiLorenzo ◽  
Kaori Sango ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Ex Vivo ◽  
Lentiviral Vectors ◽  
Cell Receptor ◽  
Specific Ctls ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1)-specific CD8 cytotoxic T-lymphocyte (CTL) response plays a critical role in controlling HIV-1 replication. Augmenting this response should enhance control of HIV-1 replication and stabilize or improve the clinical course of the disease. Although cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection in immunocompromised patients can be treated by adoptive transfer of ex vivo-expanded CMV- or EBV-specific CTLs, adoptive transfer of ex vivo-expanded, autologous HIV-1-specific CTLs had minimal effects on HIV-1 replication, likely a consequence of the inherently compromised qualitative function of HIV-1-specific CTLs derived from HIV-1-infected individuals. We hypothesized that this limitation could be circumvented by using as an alternative source of HIV-1-specific CTLs, autologous peripheral CD8+ T lymphocytes whose antigen specificity is redirected by transduction with lentiviral vectors encoding HIV-1-specific T-cell receptor (TCR) α and β chains, an approach used successfully in cancer therapy. To efficiently convert peripheral CD8 lymphocytes into HIV-1-specific CTLs that potently suppress in vivo HIV-1 replication, we constructed lentiviral vectors encoding the HIV-1-specific TCR α and TCR β chains cloned from a CTL clone specific for an HIV Gag epitope, SL9, as a single transcript linked with a self-cleaving peptide. We demonstrated that transduction with this lentiviral vector efficiently converted primary human CD8 lymphocytes into HIV-1-specific CTLs with potent in vitro and in vivo HIV-1-specific activity. Using lentiviral vectors encoding an HIV-1-specific TCR to transform peripheral CD8 lymphocytes into HIV-1-specific CTLs with defined specificities represents a new immunotherapeutic approach to augment the HIV-1-specific immunity of infected patients.

scholarly journals Persistence of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Clones in a Subject with Rapid Disease Progression

2001 ◽  
Vol 75 (10) ◽  
pp. 4907-4911 ◽  
Author(s):  
Sabina A. Islam ◽  
Christine M. Hay ◽  
Kelly E. Hartman ◽  
Suqin He ◽  
Amy K. Shea ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Clonal Deletion ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACT We longitudinally measured T-cell receptor transcript frequencies of human immunodeficiency virus type 1 (HIV-1) specific cytotoxic T lymphocytes (CTL) in an individual with rapidly progressive disease and high levels of viremia. CTL clones elicited during acute HIV-1 infection were present at the time of death, despite absent functional CTL responses, arguing against clonal deletion as a mechanism for the decline of CTL responses observed during HIV-1 infection.

scholarly journals Comprehensive Analysis of Human Immunodeficiency Virus Type 1-Specific CD4 Responses Reveals Marked Immunodominance of gag and nef and the Presence of Broadly Recognized Peptides

2004 ◽  
Vol 78 (9) ◽  
pp. 4463-4477 ◽  
Author(s):  
Daniel E. Kaufmann ◽  
Paul M. Bailey ◽  
John Sidney ◽  
Bradford Wagner ◽  
Philip J. Norris ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Consensus Sequence ◽  
Acute Infection ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Total Magnitude ◽  
Hiv 1

ABSTRACT Increasing evidence suggests that human immunodeficiency virus type 1 (HIV-1)-specific CD4 T-cell responses contribute to effective immune control of HIV-1 infection. However, the breadths and specificities of these responses have not been defined. We screened fresh CD8-depleted peripheral blood mononuclear cells (PBMC) from 36 subjects at different stages of HIV-1 infection for virus-specific CD4 responses by gamma interferon enzyme-linked immunospot assay, using 410 overlapping peptides spanning all HIV-1 proteins (based on the clade B consensus sequence). HIV-1-specific CD4 responses were identified in 30 of the 36 individuals studied, with the strongest and broadest responses detected in persons treated in acute infection who underwent treatment interruption. In individuals with identified responses, the total number of recognized HIV-1 peptides ranged from 1 to 36 (median, 7) and the total magnitude of responses ranged from 80 to >14,600 (median, 990) spot-forming cells/106 CD8-depleted PBMC. Neither the total magnitude nor the number of responses correlated with viremia. The most frequent and robust responses were directed against epitopes within the Gag and Nef proteins. Peptides targeted by ≥25% of individuals were then tested for binding to a panel of common HLA-DR molecules. All bound broadly to at least four of the eight alleles tested, and two bound to all of the HLA-DR molecules studied. Fine mapping and HLA restriction of the responses against four of these peptides showed a combination of clustering of epitopes and promiscuous presentation of the same epitopes by different HLA class II alleles. These findings have implications for the design of immunotherapeutic strategies and for testing candidate HIV vaccines.

scholarly journals Human immunodeficiency virus type 1-infected individuals make autoantibodies that bind to CD43 on normal thymic lymphocytes.

1990 ◽  
Vol 172 (4) ◽  
pp. 1151-1158 ◽  
Author(s):  
B Ardman ◽  
M A Sikorski ◽  
M Settles ◽  
D E Staunton
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Lymphocytes ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Lupus Erythematosus ◽  
Viral Infections ◽  
Immunodeficiency Virus ◽  
Hiv 1

Sera from human immunodeficiency virus type 1 (HIV-1)-infected and -noninfected individuals were screened for antibodies that could bind to native T cell differentiation antigens. Antibodies that could immunoprecipitate CD43 (sialophorin, leukosialin) from a T cell lymphoma line were detected in sera from 27% of patients, and antibodies that could bind specifically to transfected cells expressing CD43 were detected in 47% of patients. The anti-CD43 antibodies were related to HIV-1 infection in that no patients with other chronic viral infections or systemic lupus erythematosus contained such antibodies in their sera. The anti-CD43 autoantibodies bound to a partially sialylated form of CD43 expressed by normal human thymocytes, but not by normal, circulating T lymphocytes. However, the determinant(s) recognized by the anti-CD43 autoantibodies was present on a large proportion of circulating T lymphocytes, but masked from antibody recognition by sialic acid residues. These results demonstrate that HIV-1 infection is specifically associated with the production of autoantibodies that bind to a native T cell surface antigen.

scholarly journals Inhibition of CD3/CD28-Mediated Activation of the MEK/ERK Signaling Pathway Represses Replication of X4 but Not R5 Human Immunodeficiency Virus Type 1 in Peripheral Blood CD4+T Lymphocytes

2000 ◽  
Vol 74 (6) ◽  
pp. 2558-2566 ◽  
Author(s):  
Waldemar Popik ◽  
Paula M. Pitha
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
Human Immunodeficiency Virus Type ◽  
Peripheral Blood ◽  
Erk Signaling ◽  
Erk Pathway ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
In Cells

ABSTRACT Binding of human immunodeficiency virus type 1 (HIV-1) to CD4 receptors induces multiple cellular signaling pathways, including the MEK/ERK cascade. While the interaction of X4 HIV-1 with CXCR4 does not seem to activate this pathway, viruses using CCR5 for entry efficiently activate MEK/ERK kinases (W. Popik, J. E. Hesselgesser, and P. M. Pitha, J. Virol. 72:6406–6413, 1998; W. Popik and P. M. Pitha, Virology 252:210–217, 1998). Since the importance of MEK/ERK in the initial steps of viral replication is poorly understood, we have examined the role of MEK/ERK signaling in the CD3- and CD28 (CD3/CD28)-mediated activation of HIV-1 replication in resting peripheral blood CD4+ T lymphocytes infected with X4 or R5 HIV-1. We have found that the MEK/ERK inhibitor U0126 selectively inhibited CD3/CD28-stimulated replication of X4 HIV-1, while it did not affect the replication of R5 HIV-1. Inhibition of the CD3/CD28-stimulated MEK/ERK pathway did not affect the formation of the early proviral transcripts in cells infected with either X4 or R5 HIV-1, indicating that virus reverse transcription is not affected in the absence of MEK/ERK signaling. In contrast, the levels of nuclear provirus in cells infected with X4 HIV-1, detected by the formation of circular proviral DNA, was significantly lower in cells stimulated in the presence of MEK/ERK inhibitor than in the absence of the inhibitor. However, in cells infected with R5 HIV-1, the inhibition of the MEK/ERK pathway did not affect nuclear localization of the proviral DNA. These data suggest that the nuclear import of X4, but not R5, HIV-1 is dependent on a CD3/CD28-stimulated MEK/ERK pathway.

scholarly journals Effects of the SOS (A501C/T605C) and DS (I201C/A433C) Disulfide Bonds on HIV-1 Membrane Envelope Glycoprotein Conformation and Function

2019 ◽  
Vol 93 (12) ◽  
Author(s):  
Hanh T. Nguyen ◽  
Nirmin Alsahafi ◽  
Andrés Finzi ◽  
Joseph G. Sodroski
Keyword(s):  
Envelope Glycoprotein ◽  
Disulfide Bonds ◽  
Virus Entry ◽  
Envelope Proteins ◽  
Immunodeficiency Virus ◽  
Membrane Envelope ◽  
And Function ◽  
State 1 ◽  
Hiv 1

ABSTRACTMost broadly neutralizing antibodies and many entry inhibitors target the pretriggered (state 1) conformation of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env). Here we examine two previously reported Env mutants designed to be stabilized in this conformation by the introduction of artificial disulfide bonds: A501C/T605C (called SOS) and I201C/A433C (called DS). SOS Env supported virus entry and cell-cell fusion only after exposure to a reducing agent, dithiothreitol (DTT). Deletion of the Env cytoplasmic tail improved the efficiency with which the SOS Env supported virus infection in a reducing environment. The antigenicity of the SOS Env was similar to that of the unmodified Env, except for greater sensitivity to some state 1-preferring ligands. In contrast, viruses with the DS Env were not infectious, even after DTT treatment. The proteolytic maturation of the DS Env on both cell surfaces and virions was severely compromised compared with that of the unmodified Env. The DS Env exhibited detectable cell-fusing activity when DTT was present. However, the profiles of cell-surface Env recognition and cell-cell fusion inhibition by antibodies differed for the DS Env and the unmodified Env. Thus, the DS Env appears to be stabilized in an off-pathway conformation that is nonfunctional on the virus. The SOS change exerted more subtle, context-dependent effects on Env conformation and function.IMPORTANCEThe human immunodeficiency virus type 1 (HIV-1) envelope proteins (Envs) bind receptors on the host cell and change shape to allow the virus to enter the cell. Most virus-inhibiting antibodies and drugs recognize a particular shape of Env called state 1. Disulfide bonds formed by cysteine residues have been introduced into soluble forms of the flexible envelope proteins in an attempt to lock them into state 1 for use in vaccines and as research tools. We evaluated the effect of these cysteine substitutions on the ability of the membrane Env to support virus entry and on susceptibility to inhibition by antibodies and small molecules. We found that the conformation of the envelope proteins with the cysteine substitutions differed from that of the unmodified membrane envelope proteins. Awareness of these effects can assist efforts to create stable HIV-1 Env complexes that more closely resemble the state 1 conformation.

scholarly journals Cell-Free versus Cell-to-Cell Infection by Human Immunodeficiency Virus Type 1 and Human T-Lymphotropic Virus Type 1: Exploring the Link among Viral Source, Viral Trafficking, and Viral Replication

2016 ◽  
Vol 90 (17) ◽  
pp. 7607-7617 ◽  
Author(s):  
Hélène Dutartre ◽  
Mathieu Clavière ◽  
Chloé Journo ◽  
Renaud Mahieux
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Escape ◽  
Productive Infection ◽  
T Lymphotropic Virus ◽  
Immunodeficiency Virus ◽  
Hiv 1

Human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1) are complex retroviruses mainly infecting CD4+T lymphocytes. In addition, antigen-presenting cells such as dendritic cells (DCs) are targetedin vivoby both viruses, although to a lesser extent. Interaction of HIV-1 with DCs plays a key role in viral dissemination from the mucosa to CD4+T lymphocytes present in lymphoid organs. While similar mechanisms may occur for HTLV-1 as well, most HTLV-1 data were obtained from T-cell studies, and little is known regarding the trafficking of this virus in DCs. We first compared the efficiency of cell-free versus cell-associated viral sources of both retroviruses at infecting DCs. We showed that both HIV-1 and HTLV-1 cell-free particles are poorly efficient at productively infecting DCs, except when DC-SIGN has been engaged. Furthermore, while SAMHD-1 accounts for restriction of cell-free HIV-1 infection, it is not involved in HTLV-1 restriction. In addition, cell-free viruses lead mainly to a nonproductive DC infection, leading totrans-infection of T-cells, a process important for HIV-1 spread but not for that of HTLV-1. Finally, we show that T-DC cell-to-cell transfer implies viral trafficking in vesicles that may both increase productive infection of DCs (“cis-infection”) and allow viral escape from immune surveillance. Altogether, these observations allowed us to draw a model of HTLV-1 and HIV-1 trafficking in DCs.

scholarly journals Human Immunodeficiency Virus Type 1-Specific CD8+ T-Cell Responses during Primary Infection Are Major Determinants of the Viral Set Point and Loss of CD4+ T Cells

2009 ◽  
Vol 83 (15) ◽  
pp. 7641-7648 ◽  
Author(s):  
Hendrik Streeck ◽  
Jonathan S. Jolin ◽  
Ying Qi ◽  
Bader Yassine-Diab ◽  
Randall C. Johnson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Chronic Infection ◽  
Set Point ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Cell Decline ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACT Primary HIV-1 infection (PHI) is marked by a flu-like syndrome and high levels of viremia that decrease to a viral set point with the first emergence of virus-specific CD8+ T-cell responses. Here, we investigated in a large cohort of 527 subjects the immunodominance pattern of the first virus-specific cytotoxic T-lymphocyte (CTL) responses developed during PHI in comparison to CTL responses in chronic infection and demonstrated a distinct relationship between the early virus-specific CTL responses and the viral set point, as well as the slope of CD4+ T-cell decline. CTL responses during PHI followed clear hierarchical immunodominance patterns that were lost during the transition to chronic infection. Importantly, the immunodominance patterns of human immunodeficiency virus type 1 (HIV-1)-specific CTL responses detected in primary, but not in chronic, HIV-1 infection were significantly associated with the subsequent set point of viral replication. Moreover, the preservation of the initial CD8+ T-cell immunodominance patterns from the acute into the chronic phase of infection was significantly associated with slower CD4+ T-cell decline. Taken together, these data show that the specificity of the initial CTL response to HIV is critical for the subsequent control of viremia and have important implications for the rational selection of antigens for future HIV-1 vaccines.

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