scholarly journals Presence of Host ICAM-1 in Laboratory and Clinical Strains of Human Immunodeficiency Virus Type 1 Increases Virus Infectivity and CD4+-T-Cell Depletion in Human Lymphoid Tissue, a Major Site of Replication In Vivo

2002 ◽  
Vol 76 (3) ◽  
pp. 1004-1014 ◽  
Author(s):  
Salim Bounou ◽  
Jacques E. Leclerc ◽  
Michel J. Tremblay
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Lymphoid Tissue ◽  
Host Proteins ◽  
Major Site ◽  
Immunodeficiency Virus ◽  
Human Lymphoid Tissue ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) incorporates several host proteins. Earlier studies have indicated that such foreign constituents can modulate the virus life cycle, although the potential roles that these proteins might play in the viral pathology in vivo remain unclear. In an attempt to shed light on this issue, we first exposed explants of human lymphoid tissue to isogenic viruses except for the presence or absence of host-derived ICAM-1. Incorporation of ICAM-1 alone increased HIV-1 infectivity for human tonsillar tissue cultured ex vivo. This observation was made for viruses bearing distinct coreceptor utilization profiles. Conversion of LFA-1 to a high-affinity-high-avidity state for ICAM-1 further augmented the susceptibility of human tonsillar histocultures to infection by ICAM-1-bearing virions. A more massive depletion of CD4+ T lymphocytes was seen with X4 ICAM-1/POS viruses than with isogenic ICAM-1/NEG virions. Exposure of X4 and R5 primary isolates of HIV-1 to a blocking anti-ICAM-1 antibody resulted in a decrease of virus infection. Finally, X4 and R5 virions derived from a natural human lymphoid tissue microenvironment incorporated high levels of ICAM-1. Altogether, these results indicate that the incorporation of host ICAM-1 can significantly modulate the biology of HIV-1 in a cellular milieu recognized as the major site of replication in vivo and suggest that host proteins found in HIV-1 particles may participate in the pathogenesis of this disease.

scholarly journals Cytopathicity of Human Immunodeficiency Virus Type 1 Primary Isolates Depends on Coreceptor Usage and Not Patient Disease Status

2001 ◽  
Vol 75 (18) ◽  
pp. 8842-8847 ◽  
Author(s):  
Jason F. Kreisberg ◽  
David Kwa ◽  
Birgit Schramm ◽  
Verena Trautner ◽  
Ruth Connor ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Lymphoid Tissue ◽  
Disease Status ◽  
Immunodeficiency Virus ◽  
Human Lymphoid Tissue ◽  
Hiv 1

ABSTRACT It has been hypothesized that human immunodeficiency virus type 1 (HIV-1) evolves toward increased cytopathicity in conjunction with disease progression in infected patients. A viral property known to evolve in some but not all patients is coreceptor utilization, and it has been shown that a switch in coreceptor utilization is sufficient for the development of increased cytopathicity. To test the hypothesis that the evolution of other viral properties also contributes to accelerating cytopathicity in vivo, we used human lymphoid tissue explants to assay the cytopathicity of a panel of primary HIV-1 isolates derived from various stages of disease characterized by the presence or absence of changes in coreceptor preference. We found no evidence of coreceptor-independent increases in cytopathicity in isolates obtained either before coreceptor preference changes or from patients who progressed to AIDS despite an absence of coreceptor evolution. Instead, the cytopathicity of all HIV-1 isolates was determined solely by their coreceptor utilization. These results argue that HIV-1 does not evolve toward increased cytopathicity independently of changes in coreceptor utilization.

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 Viral Interactions in Human Lymphoid Tissue: Human Herpesvirus 7 Suppresses the Replication of CCR5-Tropic Human Immunodeficiency Virus Type 1 via CD4 Modulation

2006 ◽  
Vol 81 (2) ◽  
pp. 708-717 ◽  
Author(s):  
Andrea Lisco ◽  
Jean-Charles Grivel ◽  
Angélique Biancotto ◽  
Christophe Vanpouille ◽  
Francesco Origgi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Lymphoid Tissue ◽  
Human Herpesvirus ◽  
Hiv Disease ◽  
Immunodeficiency Virus ◽  
Human Lymphoid Tissue ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens that affect the clinical course of HIV disease. Here, we identified another virus, human herpesvirus 7 (HHV-7) that interferes with HIV type 1 (HIV-1) replication in human lymphoid tissue, where critical events of HIV disease occur. Like the closely related HHV-6, HHV-7 suppresses the replication of CCR5-tropic (R5) HIV-1 in coinfected blocks of human lymphoid tissue. Unlike HHV-6, which affects HIV-1 by upregulating RANTES, HHV-7 did not upregulate any CCR5-binding chemokine. Rather, the inhibition of R5 HIV-1 by HHV-7 was associated with a marked downregulation of CD4, the cellular receptor shared by HHV-7 and HIV-1. HHV-7-induced CD4 downregulation was sufficient for HIV-1 inhibition, since comparable downregulation of CD4 with cyclotriazadisulfonamide, a synthetic macrocycle that specifically modulates expression of CD4, resulted in the suppression of HIV infection similar to that seen in HHV-7-infected tissues. In contrast to R5 HIV-1, CXCR4-tropic (X4) HIV-1 was only minimally suppressed by HHV-7 coinfection. This selectivity in suppression of R5 and X4 HIV-1 is explained by a suppression of HHV-7 replication in X4- but not in R5-coinfected tissues. These results suggest that HIV-1 and HHV-7 may interfere in lymphoid tissue in vivo, thus potentially affecting the progression of HIV-1 disease. Knowledge of the mechanisms of interaction of HIV-1 with HHV-7, as well as with other pathogens that modulate HIV-1 replication, may provide new insights into HIV pathogenesis and lead to the development of new anti-HIV therapeutic strategies.

scholarly journals Cellular Compartments of Human Immunodeficiency Virus Type 1 Replication In Vivo: Determination by Presence of Virion-Associated Host Proteins and Impact of Opportunistic Infection

2000 ◽  
Vol 74 (1) ◽  
pp. 139-145 ◽  
Author(s):  
Stephen D. Lawn ◽  
Beverly D. Roberts ◽  
George E. Griffin ◽  
Thomas M. Folks ◽  
Salvatore T. Butera
Keyword(s):  
Human Immunodeficiency Virus ◽  
Opportunistic Infection ◽  
Human Immunodeficiency Virus Type ◽  
Host Proteins ◽  
Immunodeficiency Virus ◽  
Cellular Compartments ◽  
Hiv 1

ABSTRACT Antigens derived from host cells are detectable in the envelope of human immunodeficiency virus type 1 (HIV-1) and result in a distinctive viral phenotype reflecting that of the host cell. An immunomagnetic capture assay targeting discriminatory host proteins was developed to differentiate between HIV-1 derived from macrophages and lymphocytes. HIV-1 propagated in macrophages or lymphocytes in vitro was selectively captured by monoclonal antibodies directed against the virally incorporated cell-type-specific host markers CD36 (macrophages) and CD26 (lymphocytes). Furthermore, by targeting these markers, virus of defined cellular origin was selectively captured from a mixed pool of in vitro-propagated viruses. This technique was further refined in order to determine the impact of opportunistic infection on HIV-1 expression from these cellular compartments in vivo. Analysis of cell-free virus purified from plasma of patients with HIV-1 infection suggested that in those with an opportunistic infection, viral replication occurred in activated lymphocytes. Interestingly, there was also significant replication in activated macrophages in those patients with untreated pulmonary tuberculosis. Thus, in addition to lymphocytes, the macrophage cellular pool may serve as an important source of cell-free HIV-1 in patients with opportunistic infections that lead to marked macrophage activation. This novel viral capture technique may allow researchers to address a wide range of important questions regarding virus-host dynamics.

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.

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