scholarly journals CD4+ T-Lymphocyte Depletion in Human Lymphoid Tissue Ex Vivo Is Not Induced by Noninfectious Human Immunodeficiency Virus Type 1 Virions

1998 ◽  
Vol 72 (11) ◽  
pp. 9345-9347 ◽  
Author(s):  
A. W. Sylwester ◽  
J.-C. Grivel ◽  
W. Fitzgerald ◽  
J. L. Rossio ◽  
J. D. Lifson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Ex Vivo ◽  
Productive Infection ◽  
Lymphoid Tissues ◽  
Immunodeficiency Virus ◽  
Human Lymphoid Tissue ◽  
Hiv 1

ABSTRACT We tested infectious human immunodeficiency virus type 1 (HIV-1), noninfectious but conformationally authentic inactivated whole HIV-1 virions, and purified gp120 for the ability to induce depletion of CD4+ T cells in human lymphoid tissues ex vivo. Infectious CXCR4-tropic HIV-1, but not matched inactivated virions or gp120, mediated CD4+ T-cell depletion, consistent with mechanisms requiring productive infection.

scholarly journals Human Immunodeficiency Virus Type 1 Variants Resistant to First- and Second-Version Fusion Inhibitors and Cytopathic in Ex Vivo Human Lymphoid Tissue

2007 ◽  
Vol 81 (12) ◽  
pp. 6563-6572 ◽  
Author(s):  
Raghavan Chinnadurai ◽  
Devi Rajan ◽  
Jan Münch ◽  
Frank Kirchhoff
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Lymphoid Tissue ◽  
Ex Vivo ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Human Lymphoid Tissue ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) fusion inhibitors blocking viral entry by binding the gp41 heptad repeat 1 (HR1) region offer great promise for antiretroviral therapy, and the first of these inhibitors, T20 (Fuzeon; enfuvirtide), is successfully used in the clinic. It has been reported previously that changes in the 3-amino-acid GIV motif at positions 36 to 38 of gp41 HR1 mediate resistance to T20 but usually not to second-version fusion inhibitors, such as T1249, which target an overlapping but distinct region in HR1 including a conserved hydrophobic pocket (HP). Based on the common lack of cross-resistance and the difficulty of selecting T1249-resistant HIV-1 variants, it has been suggested that the determinants of resistance to first- and second-version fusion inhibitors may be different. To further assess HIV-1 resistance to fusion inhibitors and to analyze where changes in HR1 are tolerated, we randomized 16 codons in the HR1 region, including those making contact with HR2 codons and/or encoding residues in the GIV motif and the HP. We found that changes only at positions 37I, 38V, and 40Q near the N terminus of HR1 were tolerated. The propagation of randomly gp41-mutated HIV-1 variants in the presence of T1249 allowed the effective selection of highly resistant forms, all containing changes in the IV residues. Overall, the extent of T1249 resistance was inversely correlated to viral fitness and cytopathicity. Notably, one HIV-1 mutant showing ∼10-fold-reduced susceptibility to T1249 inhibition replicated with wild type-like kinetics and caused substantial CD4+-T-cell depletion in ex vivo-infected human lymphoid tissue in the presence and absence of an inhibitor. Taken together, our results show that the GIV motif also plays a key role in resistance to second-version fusion inhibitors and suggest that some resistant HIV-1 variants may be pathogenic in vivo.

scholarly journals Proline 35 of Human Immunodeficiency Virus Type 1 (HIV-1) Vpr Regulates the Integrity of the N-Terminal Helix and the Incorporation of Vpr into Virus Particles and Supports the Replication of R5-Tropic HIV-1 in Human Lymphoid Tissue Ex Vivo

2007 ◽  
Vol 81 (17) ◽  
pp. 9572-9576 ◽  
Author(s):  
Jörg Votteler ◽  
Nicole Studtrucker ◽  
Stefan Sörgel ◽  
Jan Münch ◽  
Elke Rücker ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Lymphoid Tissue ◽  
Mutational Analysis ◽  
Ex Vivo ◽  
Immunodeficiency Virus ◽  
Human Lymphoid Tissue ◽  
Hiv 1

ABSTRACT Mutational analysis of the four conserved proline residues in human immunodeficiency virus type 1 (HIV-1) Vpr reveals that only Pro-35 is required for efficient replication of R5-tropic, but not of X4-tropic, viruses in human lymphoid tissue (HLT) cultivated ex vivo. While Vpr-mediated apoptosis and G2 cell cycle arrest, as well as the expression and subcellular localization of Vpr, were independent, the capacity for encapsidation of Vpr into budding virions was dependent on Pro-35. 1H nuclear magnetic resonance data suggest that mutation of Pro-35 causes a conformational change in the hydrophobic core of the molecule, whose integrity is required for the encapsidation of Vpr, and thus, Pro-35 supports the replication of R5-tropic HIV-1 in HLT.

scholarly journals Vpr and Vpu Are Important for Efficient Human Immunodeficiency Virus Type 1 Replication and CD4+ T-Cell Depletion in Human Lymphoid Tissue Ex Vivo

2004 ◽  
Vol 78 (22) ◽  
pp. 12689-12693 ◽  
Author(s):  
Elke Rücker ◽  
Jean-Charles Grivel ◽  
Jan Münch ◽  
Frank Kirchhoff ◽  
Leonid Margolis
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Lymphoid Tissue ◽  
Ex Vivo ◽  
Immunodeficiency Virus ◽  
Human Lymphoid Tissue ◽  
Hiv 1

ABSTRACT The relevance of the accessory vpr, vpu, and nef genes for human immunodeficiency virus type 1 (HIV-1) replication in human lymphoid tissue (HLT), the major site of viral replication in vivo, is largely unknown. Here, we show that an individual deletion of nef, vpr, or vpu significantly decreases HIV-1 replication and prevents CD4+ T-cell depletion in ex vivo HLT. However, only combined defects in all three accessory genes entirely disrupt the replicative capacity of HIV-1. Our results demonstrate that nef, vpr, and vpu are all essential for efficient viral spread in HLT, suggesting an important role in AIDS pathogenesis.

scholarly journals CD4 Down-Modulation by Human Immunodeficiency Virus Type 1 Nef Correlates with the Efficiency of Viral Replication and with CD4+ T-Cell Depletion in Human Lymphoid Tissue Ex Vivo

2001 ◽  
Vol 75 (21) ◽  
pp. 10113-10117 ◽  
Author(s):  
Svetlana Glushakova ◽  
Jan Münch ◽  
Silke Carl ◽  
Thomas C. Greenough ◽  
John L. Sullivan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Lymphoid Tissue ◽  
Ex Vivo ◽  
Immunodeficiency Virus ◽  
Human Lymphoid Tissue ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Nef protein is an important virulence factor. Nef has several functions, including down-modulation of CD4 and class I major histocompatibility complex cell surface expression, enhancement of virion infectivity, and stimulation of viral replication in peripheral blood mononuclear cells. Nef also increases HIV-1 replication in human lymphoid tissue (HLT) ex vivo. We analyzed recombinant and primarynef alleles with highly divergent activity in different in vitro assays to clarify which of these Nef activities are functionally linked. Our results demonstrate that Nef activity in CD4 down-regulation correlates significantly with the efficiency of HIV-1 replication and with the severity of CD4+ T-cell depletion in HLT. In conclusion, HIV-1 Nef variants with increased activity in CD4 down-modulation would cause severe depletion of CD4+ T cells in lymphoid tissues and accelerate AIDS progression.

scholarly journals Human Immunodeficiency Virus Type 1 (HIV-1) Non-B Subtypes Are Similar to HIV-1 Subtype B in that Coreceptor Specificity Is a Determinant of Cytopathicity in Human Lymphoid Tissue Infected Ex Vivo

2001 ◽  
Vol 75 (21) ◽  
pp. 10520-10522 ◽  
Author(s):  
Nina Malkevich ◽  
Chad Womack ◽  
Punita Pandya ◽  
Jean-Charles Grivel ◽  
Anthony S. Fauci ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Lymphoid Tissue ◽  
Ex Vivo ◽  
Immunodeficiency Virus ◽  
Human Lymphoid Tissue ◽  
Hiv 1

ABSTRACT We sought to determine the relationship between virus-mediated CD4+ T-lymphocyte cytopathicity and viral coreceptor preference among various human immunodeficiency virus type 1 (HIV-1) subtypes in an ex vivo-infected human lymphoid tissue model. Our data show that all R5 HIV-1 infections resulted in mild depletion of CD4+ T lymphocytes, whereas all X4 HIV-1 infections caused severe depletion of CD4+ T lymphocytes regardless of their subtype origin. Thus, at least for the viruses within subtypes A, B, C, and E that were tested, coreceptor specificity is a critical factor that determines the ability of HIV-1 to deplete CD4+ T cells in human lymphoid tissue infected ex vivo.

scholarly journals Human Immunodeficiency Virus Type 1 Coreceptor Preferences Determine Target T-Cell Depletion and Cellular Tropism in Human Lymphoid Tissue

2000 ◽  
Vol 74 (11) ◽  
pp. 5347-5351 ◽  
Author(s):  
Jean-Charles Grivel ◽  
Michael L. Penn ◽  
Daniel A. Eckstein ◽  
Birgit Schramm ◽  
Roberto F. Speck ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Ex Vivo ◽  
Lymphoid Tissues ◽  
Cell Tropism ◽  
Immunodeficiency Virus ◽  
Cellular Tropism ◽  
Human Lymphoid Tissue

ABSTRACT The present study sought to determine how usage of coreceptors by human immunodeficiency virus type 1 dictates cell tropism and depletion of CD4+ T cells in human lymphoid tissues cultured ex vivo. We found that coreceptor preferences control the marked, preferential depletion of coreceptor-expressing CD4+ lymphocytes. In addition, there was a strong, but not absolute, preference shown by CXCR4-using strains for lymphocytes and by CCR5-using strains for macrophages.

scholarly journals Differential Susceptibility to Human Immunodeficiency Virus Type 1 Infection of Myeloid and Plasmacytoid Dendritic Cells

2005 ◽  
Vol 79 (14) ◽  
pp. 8861-8869 ◽  
Author(s):  
Anna Smed-Sörensen ◽  
Karin Loré ◽  
Jayanand Vasudevan ◽  
Mark K. Louder ◽  
Jan Andersson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Ex Vivo ◽  
Productive Infection ◽  
Necrosis Factor Alpha ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection of dendritic cells (DCs) plays an important role in HIV-1 transmission and pathogenesis. Here, we studied the susceptibility of ex vivo-isolated CD11c+ myeloid DCs (MDCs) and CD123+ plasmacytoid DCs (PDCs) to HIV-1 infection and the function of these cells early after infection. Both DC subsets were susceptible to CCR5- and CXCR4-using HIV-1 isolates (BaL and IIIB, respectively). However, MDCs were more susceptible to HIV-1BaL infection than donor-matched PDCs. In addition, HIV-1BaL infected MDCs more efficiently than HIV-1IIIB, whereas PDCs were equally susceptible to both isolates. While exposure to HIV-1 alone resulted in only weak maturation of DCs, Toll-like receptor 7/8 ligation induced full maturation in both infected and uninfected DCs. Maturation did not increase HIV-1 replication in infected DCs, and infected DCs retained their ability to produce tumor necrosis factor alpha after stimulation. Both HIV-1 isolates induced alpha interferon production exclusively in PDCs, irrespective of productive infection. In conclusion, PDCs and MDCs were susceptible to HIV-1 infection, but neither displayed functional defects as a consequence of infection. The difference in susceptibility of PDCs and MDCs to HIV-1 may have implications for HIV-1 transmission and DC-mediated transfer of HIV-1 to T cells.

scholarly journals CCR5- and CXCR4-Tropic Subtype C Human Immunodeficiency Virus Type 1 Isolates Have a Lower Level of Pathogenic Fitness than Other Dominant Group M Subtypes: Implications for the Epidemic

2009 ◽  
Vol 83 (11) ◽  
pp. 5592-5605 ◽  
Author(s):  
Awet Abraha ◽  
Immaculate L. Nankya ◽  
Richard Gibson ◽  
Korey Demers ◽  
Denis M. Tebit ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Ex Vivo ◽  
Sub Saharan Africa ◽  
Subtype C ◽  
Immunodeficiency Virus ◽  
Subtype A ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) subtype C is the dominant subtype globally, due largely to the incidence of subtype C infections in sub-Saharan Africa and east Asia. We compared the relative replicative fitness (ex vivo) of the major (M) group of HIV-1 subtypes A, B, C, D, and CRF01_AE and group O isolates. To estimate pathogenic fitness, pairwise competitions were performed between CCR5-tropic (R5) or CXCR4-tropic (X4) virus isolates in peripheral blood mononuclear cells (PBMC). A general fitness order was observed among 33 HIV-1 isolates; subtype B and D HIV-1 isolates were slightly more fit than the subtype A and dramatically more fit than the 12 subtype C isolates. All group M isolates were more fit (ex vivo) than the group O isolates. To estimate ex vivo transmission fitness, a subset of primary HIV-1 isolates were examined in primary human explants from penile, cervical, and rectal tissues. Only R5 isolates and no X4 HIV-1 isolates could replicate in these tissues, whereas the spread to PM1 cells was dependent on active replication and passive virus transfer. In tissue competition experiments, subtype C isolates could compete with and, in some cases, even win over subtype A and D isolates. However, when the migratory cells from infected tissues were mixed with a susceptible cell line, the subtype C isolates were outcompeted by other subtypes, as observed in experiments with PBMC. These findings suggest that subtype C HIV-1 isolates might have equal transmission fitness but reduced pathogenic fitness relative to other group M HIV-1 isolates.

scholarly journals A Human Nuclear Shuttling Protein That Interacts with Human Immunodeficiency Virus Type 1 Matrix Is Packaged into Virions

2000 ◽  
Vol 74 (24) ◽  
pp. 11811-11824 ◽  
Author(s):  
Kalpana Gupta ◽  
David Ott ◽  
Thomas J. Hope ◽  
Robert F. Siliciano ◽  
Jef D. Boeke
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nuclear Import ◽  
Productive Infection ◽  
Genomic Rna ◽  
Virion Production ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Active nuclear import of the human immunodeficiency virus type 1 (HIV-1) preintegration complex (PIC) is essential for the productive infection of nondividing cells. Nuclear import of the PIC is mediated by the HIV-1 matrix protein, which also plays several critical roles during viral entry and possibly during virion production facilitating the export of Pr55Gag and genomic RNA. Using a yeast two-hybrid screen, we identified a novel human virion-associated matrix-interacting protein (VAN) that is highly conserved in vertebrates and expressed in most human tissues. Its expression is upregulated upon activation of CD4+ T cells. VAN is efficiently incorporated into HIV-1 virions and, like matrix, shuttles between the nucleus and cytoplasm. Furthermore, overexpression of VAN significantly inhibits HIV-1 replication in tissue culture. We propose that VAN regulates matrix nuclear localization and, by extension, both nuclear import of the PIC and export of Pr55Gag and viral genomic RNA during virion production. Our data suggest that this regulatory mechanism reflects a more global process for regulation of nucleocytoplasmic transport.

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.

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