scholarly journals Conformation of HIV-1 Envelope Governs Rhesus CD4 Usage and Simian-Human Immunodeficiency Virus Replication

mBio ◽  
2022 ◽  
Author(s):  
Geraldine Vilmen ◽  
Anna C. Smith ◽  
Hector Cervera Benet ◽  
Rajni Kant Shukla ◽  
Ross C. Larue ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Animal Model ◽  
Virus Replication ◽  
Rhesus Macaques ◽  
Envelope Glycoproteins ◽  
Human Immunodeficiency Virus Replication ◽  
Preclinical Testing ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Viruses ◽  
Hiv 1

Rhesus macaques are a critical animal model for preclinical testing of HIV-1 vaccine and prevention approaches. However, HIV-1 does not replicate in rhesus macaques, and thus, chimeric simian-human immunodeficiency viruses (SHIVs), which encode HIV-1 envelope glycoproteins (Envs), are used as surrogate challenge viruses to infect rhesus macaques for modeling HIV-1 infection.

scholarly journals Regulation of Human Immunodeficiency Virus Replication by 2′,5′-Oligoadenylate-Dependent RNase L

1998 ◽  
Vol 72 (2) ◽  
pp. 1146-1152 ◽  
Author(s):  
Ratan K. Maitra ◽  
Robert H. Silverman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Virus Replication ◽  
Virus Production ◽  
Jurkat Cells ◽  
Alpha Interferon ◽  
Human Immunodeficiency Virus Replication ◽  
Rnase L ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Activation of RNase L by 2′,5′-linked oligoadenylates (2-5A) is one of the antiviral pathways of interferon action. To determine the involvement of the 2-5A system in the control of human immunodeficiency virus type 1 (HIV-1) replication, a segment of the HIV-1nef gene was replaced with human RNase L cDNA. HIV-1 provirus containing sense orientation RNase L cDNA caused increased expression of RNase L and 500- to 1,000-fold inhibition of virus replication in Jurkat cells for a period of about 2 weeks. Subsequently, a partial deletion of the RNase L cDNA which coincided with increases in virus production occurred. The anti-HIV activity of RNase L correlated with decreases in HIV-1 RNA and with an acceleration in cell death accompanied by DNA fragmentation. Replication of HIV-1 encoding RNase L was also transiently suppressed in peripheral blood lymphocytes (PBL). In contrast, recombinant HIV containing reverse orientation RNase L cDNA caused decreased levels of RNase L, increases in HIV yields, and reductions in the anti-HIV effect of alpha interferon in PBL and in Jurkat cells. To obtain constitutive and continuous expression of RNase L cDNA, Jurkat cells were cotransfected with HIV-1 proviral DNA and with plasmid containing a cytomegalovirus promoter driving expression of RNase L cDNA. The RNase L plasmid suppressed HIV-1 replication by eightfold, while an antisense RNase L construct enhanced virus production by twofold. These findings demonstrate that RNase L can severely impair HIV replication and suggest involvement of the 2-5A system in the anti-HIV effect of alpha interferon.

scholarly journals Co-expression of interleukin-5 influences replication of simian/human immunodeficiency viruses in vivo

2002 ◽  
Vol 83 (5) ◽  
pp. 1183-1188 ◽  
Author(s):  
Iouri L. Kozyrev ◽  
Tomoyuki Miura ◽  
Taichiro Takemura ◽  
Takeo Kuwata ◽  
Masahiro Ui ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Virus Replication ◽  
Rhesus Macaques ◽  
Interleukin 5 ◽  
Th Cell ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Viruses

The positive effect of the co-expression of T helper (Th) cell type 2 cytokine interleukin-5 (IL-5) on nef-deleted simian/human immunodeficiency virus (SHIV) replication in vitro has been observed previously. To analyse whether the growth advantage of IL-5-containing SHIV (NI-IL5) in vitro would be relevant in vivo, the virus was inoculated into monkeys. Three rhesus macaques were inoculated intravenously with 104 TCID50 of NI-IL5. Results were compared with those obtained previously from SHIV NM-3rN (intact) and SHIV-dn (nef-deleted)-infected monkeys. Cytokine production, analysed by IL-5 ELISA, showed a twofold increase in IL-5 concentration in the plasma soon after the peak of virus replication. Virus replication and antibody production were greater in monkeys inoculated with IL-5-expressing SHIV than in monkeys inoculated with nef-deleted SHIV without IL-5. These findings show a stimulation of SHIV replication by co-expression of IL-5 and suggest the important role of Th2-type cytokines in human immunodeficiency virus type 1 infection.

scholarly journals Membrane-Fusing Capacity of the Human Immunodeficiency Virus Envelope Proteins Determines the Efficiency of CD4+ T-Cell Depletion in Macaques Infected by a Simian-Human Immunodeficiency Virus

2001 ◽  
Vol 75 (12) ◽  
pp. 5646-5655 ◽  
Author(s):  
Bijan Etemad-Moghadam ◽  
Daniela Rhone ◽  
Tavis Steenbeke ◽  
Ying Sun ◽  
Judith Manola ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Lymphocytes ◽  
Virus Replication ◽  
Single Amino Acid ◽  
Envelope Glycoproteins ◽  
Virus Envelope ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The mechanism of the progressive loss of CD4+ T lymphocytes, which underlies the development of AIDS in human immunodeficiency virus (HIV-1)-infected individuals, is unknown. Animal models, such as the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae, can assist studies of HIV-1 pathogenesis. Serial in vivo passage of the nonpathogenic SHIV-89.6 generated a virus, SHIV-89.6P, that causes rapid depletion of CD4+ T lymphocytes and AIDS-like illness in monkeys. SHIV-KB9, a molecularly cloned virus derived from SHIV-89.6P, also caused CD4+ T-cell decline and AIDS in inoculated monkeys. It has been demonstrated that changes in the envelope glycoproteins of SHIV-89.6 and SHIV-KB9 determine the degree of CD4+ T-cell loss that accompanies a given level of virus replication in the host animals (G. B. Karlsson et. al., J. Exp. Med. 188:1159–1171, 1998). The envelope glycoproteins of the pathogenic SHIV mediated membrane fusion more efficiently than those of the parental, nonpathogenic virus. Here we show that the minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity is sufficient to convert SHIV-89.6 into a virus that causes profound CD4+ T-lymphocyte depletion in monkeys. We also studied two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins by different mechanisms. Each of these changes attenuated the CD4+ T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4+ T lymphocytes in vivo.

scholarly journals Novel Transmitted/Founder Simian-Human Immunodeficiency Viruses for Human Immunodeficiency Virus Latency and Cure Research

2020 ◽  
Vol 94 (8) ◽  
Author(s):  
Anya M. Bauer ◽  
Widade Ziani ◽  
Emily Lindemuth ◽  
Leticia Kuri-Cervantes ◽  
Hui Li ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Chronic Infection ◽  
Rhesus Macaques ◽  
Treatment Interruption ◽  
Viral Kinetics ◽  
Macaque Model ◽  
Cart Initiation ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Viruses ◽  
Hiv 1

ABSTRACT A robust simian-human immunodeficiency virus (SHIV)-macaque model of latency is critical to investigate eradicative and suppressive strategies that target HIV-1 Env. To this end, we previously reported a novel strategy for constructing SHIVs that bear primary or transmitted/founder (TF) Envs with modifications at Env residue 375 that enable efficient replication in Indian rhesus macaques (RM). Such TF SHIVs, however, have not been examined for their suitability for HIV-1 latency and cure research. Here, we evaluate two promising TF SHIVs, SHIV.D.191859 and SHIV.C.CH848, which encode TF subtype D and C HIV-1 Envs, respectively, for their viral kinetics and persistence during suppressive combination antiretroviral therapy (cART) and treatment interruption in RM. Our results suggest that the viral kinetics of these SHIVs in RM during acute, early, and chronic infection, and upon cART initiation, maintenance and discontinuation, mirror those of HIV-1 infection. We demonstrate consistent early peak and set point viremia, rapid declines in viremia to undetectable plasma titers following cART initiation, infection of long-lived cellular subsets and establishment of viral latency, and viral rebound with return to pretreatment set point viremia following treatment interruption. The viral dynamics and reservoir biology of SHIV.D.191859, and to a lesser extent SHIV.C.CH848, during chronic infection, cART administration, and upon treatment interruption suggest that these TF SHIVs are promising reagents for a SHIV model of HIV-1 latency and cure. IMPORTANCE Simian-human immunodeficiency viruses (SHIVs) have been successfully used for over 2 decades to study virus-host interactions, transmission, and pathogenesis in rhesus macaques. The majority of Env trimers of most previously studied SHIVs, however, do not recapitulate key properties of transmitted/founder (TF) or primary HIV-1 isolates, such as CCR5 tropism, tier 2 neutralization resistance, and native trimer conformation. Here, we test two recently generated TF SHIVs, SHIV.D.191859 and SHIV.C.CH848, which were designed to address these issues as components of a nonhuman primate model of HIV-1 latency. We conclude that the TF SHIV-macaque model reflects several hallmarks of HIV and SIV infection and latency. Results suggest that this model has broad applications for evaluating eradicative and suppressive strategies against the HIV reservoir, including Env-specific interventions, therapeutic vaccines, and engineered T cells.

Metabolism of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine in Combination in Human Immunodeficiency Virus Infected Lymphoblastoid Cells

1992 ◽  
Vol 3 (3) ◽  
pp. 165-170 ◽  
Author(s):  
S. Cox
Keyword(s):  
Human Immunodeficiency Virus ◽  
Virus Replication ◽  
Cell Types ◽  
Human Immunodeficiency Virus Replication ◽  
Lymphoblastoid Cells ◽  
Synergistic Inhibition ◽  
Immunodeficiency Virus ◽  
Deoxynucleoside Triphosphate ◽  
The Individual

A combination of 3′-azido-3′-deoxythymidine (AZT) with 3′-fluoro-3′-deoxythymidine (FLT) has been shown previously to give synergistic inhibition of human immunodeficiency virus replication and greatly reduced cytotoxicity in vitro. The phosphorylation of the compounds, and their effect upon the natural deoxynucleoside triphosphate pools, were compared in CEM, H9, and HIV-infected H9 lymphoblastoid cells, both for the compounds when used alone and when combined together. Higher levels of FLT triphosphate than AZT triphosphate, and higher levels of AZT monophosphate than FLT monosphosphate, were formed in all cell types. Both compounds were phosphorylated most efficiently in CEM cells, whereas they were least efficiently phosphorylated in infected H9 cells. Owing to competition, the phosphorylation of both analogues was reduced when used in combination, compared to the phosphorylation of the separate compounds. The phosphorylation of the separate compounds was therefore at a maximum and was not increased by combining the compounds. The two compounds competed equally with each other for phosphorylation when used at a ratio of AZT: FLT of 5: 1. Both analogues severely reduced the deoxynucleoside triphosphate pools in uninfected and human immunodeficiency virus-infected H9 cells, but not in CEM cells. The effects of the two compounds were similar to those found when the compounds were combined, and thus H9 cells were shown to be much more sensitive to the effects of the analogues upon deoxynucleoside triphosphate pools than CEM cells were. Thus the synergistic combination of 3′-azido-3′-deoxythymidine and 3′-fluoro-3′-deoxythymidine was shown to have a similar metabolism and a similar effect upon cellular deoxynucleoside triphosphate pools to the individual compounds.

scholarly journals Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist

2004 ◽  
Vol 78 (23) ◽  
pp. 12996-13006 ◽  
Author(s):  
Katrien Princen ◽  
Sigrid Hatse ◽  
Kurt Vermeire ◽  
Stefano Aquaro ◽  
Erik De Clercq ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Entry ◽  
Mononuclear Cells ◽  
Human Immunodeficiency Virus Replication ◽  
Cxcr4 Antagonist ◽  
Peripheral Blood Mononuclear ◽  
Transfected Cells ◽  
Immunodeficiency Virus ◽  
Intracellular Ca ◽  
Hiv 1

ABSTRACT Here we report that the N-pyridinylmethyl cyclam analog AMD3451 has antiviral activity against a wide variety of R5, R5/X4, and X4 strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% inhibitory concentration [IC50] ranging from 1.2 to 26.5 μM) in various T-cell lines, CCR5- or CXCR4-transfected cells, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. AMD3451 also inhibited R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs (IC50, 1.8 to 7.3 μM). A PCR-based viral entry assay revealed that AMD3451 blocks R5 and X4 HIV-1 infection at the virus entry stage. AMD3451 dose-dependently inhibited the intracellular Ca2+ signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca2+ flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca2+ signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca2+ signaling by itself at concentrations up to 400 μM. In freshly isolated monocytes, AMD3451 inhibited the Ca2+ flux induced by CXCL12 and CCL4 but not that induced by CCL2, CCL3, CCL5, and CCL7. The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451. Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells. AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4. AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction.

scholarly journals A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus Envelope Glycoprotein Trimer

2010 ◽  
Vol 84 (7) ◽  
pp. 3147-3161 ◽  
Author(s):  
Shi-Hua Xiang ◽  
Andrés Finzi ◽  
Beatriz Pacheco ◽  
Kevin Alexander ◽  
Wen Yuan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Receptor Binding ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Envelope Glycoproteins ◽  
V3 Loop ◽  
Virus Envelope ◽  
Hydrophobic Patch ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus (HIV-1) entry into cells is mediated by a trimeric complex consisting of noncovalently associated gp120 (exterior) and gp41 (transmembrane) envelope glycoproteins. The binding of gp120 to receptors on the target cell alters the gp120-gp41 relationship and activates the membrane-fusing capacity of gp41. Interaction of gp120 with the primary receptor, CD4, results in the exposure of the gp120 third variable (V3) loop, which contributes to binding the CCR5 or CXCR4 chemokine receptors. We show here that insertions in the V3 stem or polar substitutions in a conserved hydrophobic patch near the V3 tip result in decreased gp120-gp41 association (in the unliganded state) and decreased chemokine receptor binding (in the CD4-bound state). Subunit association and syncytium-forming ability of the envelope glycoproteins from primary HIV-1 isolates were disrupted more by V3 changes than those of laboratory-adapted HIV-1 envelope glycoproteins. Changes in the gp120 β2, β19, β20, and β21 strands, which evidence suggests are proximal to the V3 loop in unliganded gp120, also resulted in decreased gp120-gp41 association. Thus, a gp120 element composed of the V3 loop and adjacent beta strands contributes to quaternary interactions that stabilize the unliganded trimer. CD4 binding dismantles this element, altering the gp120-gp41 relationship and rendering the hydrophobic patch in the V3 tip available for chemokine receptor binding.

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