scholarly journals Replication-Defective Canarypox (ALVAC) Vectors Effectively Activate Anti–Human Immunodeficiency Virus-1 Cytotoxic T Lymphocytes Present in Infected Patients: Implications for Antigen-Specific Immunotherapy

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2406-2416 ◽  
Author(s):  
G. Ferrari ◽  
C. Berend ◽  
J. Ottinger ◽  
R. Dodge ◽  
J. Bartlett ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cd8 T Cells ◽  
Mammalian Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Cell Repertoire ◽  
Immunodeficiency Virus ◽  
Hiv 1

In the attempt to develop immunotherapeutic strategies for acquired immunodeficiency syndrome capable of activating effector cells in an antigen-specific manner while maintaining the broadest possible T-cell repertoire, we evaluated two canarypox (ALVAC)-based vectors for their capacity to induce ex vivo activation/expansion of human immunodeficiency virus (HIV)-specific CD8+ cytotoxic lymphocyte precursors (CTLp) obtained from HIV-1–infected donors. These two vectors, vCP205 encoding HIV-1 gp120 + TM (28 amino acid transmembrane anchor sequence) in addition to Gag/protease and vCP300 encoding gp120 + Gag/protease as well as Nef and Pol CTL determinants, are pancytotropic but replication incompetent in mammalian cells. Bulk peripheral blood mononuclear cells (PBMCs) or enriched CD8+ T cells were stimulated for 10 days with autologous ALVAC-infected PBMCs in the presence of different cytokine combinations (interleukin-2 [IL-2], IL-4, IL-7, and IL-12). Activation by ALVAC constructs was highly antigen-specific, because vCP205 elicited only Env and Gag CTL, whereas vCP300 elicited broader reactivities against Env, Gag, Pol, and Nef determinants. The ALVAC activation of CTLp was IL-2 dependent and enhanced by the addition of IL-7, whereas IL-4 and IL-12 failed to augment cytotoxic reactivities elicited by these constructs. The expansion of enriched CD8+ T cells after activation with vCP300 was higher in patients with CD4 counts greater than 400 cells/μL. Two rounds of in vitro stimulation (IVS) with vCP300 resulted in nearly an eightfold expansion of CD8+ lymphocytes over a 25-day period. After the second IVS, an average 3.2-fold increase among the different antigen-specific CTL frequencies was achieved. These studies clearly show that HIV-recombinant ALVAC vectors represent powerful polyvalent antigenic stimuli for activation and expansion of the CD8 lymphocyte response that occurs as a result of HIV infection.

scholarly journals Replication-Defective Canarypox (ALVAC) Vectors Effectively Activate Anti–Human Immunodeficiency Virus-1 Cytotoxic T Lymphocytes Present in Infected Patients: Implications for Antigen-Specific Immunotherapy

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2406-2416 ◽  
Author(s):  
G. Ferrari ◽  
C. Berend ◽  
J. Ottinger ◽  
R. Dodge ◽  
J. Bartlett ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cd8 T Cells ◽  
Mammalian Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Cell Repertoire ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract In the attempt to develop immunotherapeutic strategies for acquired immunodeficiency syndrome capable of activating effector cells in an antigen-specific manner while maintaining the broadest possible T-cell repertoire, we evaluated two canarypox (ALVAC)-based vectors for their capacity to induce ex vivo activation/expansion of human immunodeficiency virus (HIV)-specific CD8+ cytotoxic lymphocyte precursors (CTLp) obtained from HIV-1–infected donors. These two vectors, vCP205 encoding HIV-1 gp120 + TM (28 amino acid transmembrane anchor sequence) in addition to Gag/protease and vCP300 encoding gp120 + Gag/protease as well as Nef and Pol CTL determinants, are pancytotropic but replication incompetent in mammalian cells. Bulk peripheral blood mononuclear cells (PBMCs) or enriched CD8+ T cells were stimulated for 10 days with autologous ALVAC-infected PBMCs in the presence of different cytokine combinations (interleukin-2 [IL-2], IL-4, IL-7, and IL-12). Activation by ALVAC constructs was highly antigen-specific, because vCP205 elicited only Env and Gag CTL, whereas vCP300 elicited broader reactivities against Env, Gag, Pol, and Nef determinants. The ALVAC activation of CTLp was IL-2 dependent and enhanced by the addition of IL-7, whereas IL-4 and IL-12 failed to augment cytotoxic reactivities elicited by these constructs. The expansion of enriched CD8+ T cells after activation with vCP300 was higher in patients with CD4 counts greater than 400 cells/μL. Two rounds of in vitro stimulation (IVS) with vCP300 resulted in nearly an eightfold expansion of CD8+ lymphocytes over a 25-day period. After the second IVS, an average 3.2-fold increase among the different antigen-specific CTL frequencies was achieved. These studies clearly show that HIV-recombinant ALVAC vectors represent powerful polyvalent antigenic stimuli for activation and expansion of the CD8 lymphocyte response that occurs as a result of HIV infection.

scholarly journals Nef Enhances Human Immunodeficiency Virus Replication and Responsiveness to Interleukin-2 in Human Lymphoid Tissue Ex Vivo

1999 ◽  
Vol 73 (5) ◽  
pp. 3968-3974 ◽  
Author(s):  
Svetlana Glushakova ◽  
Jean-Charles Grivel ◽  
Kalachar Suryanarayana ◽  
Pascal Meylan ◽  
Jeffrey D. Lifson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Lymphoid Tissue ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Dependent Manner ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Human Lymphoid Tissue ◽  
Hiv 1

ABSTRACT The nef gene is important for the pathogenicity associated with simian immunodeficiency virus infection in rhesus monkeys and with human immunodeficiency virus type 1 (HIV-1) infection in humans. The mechanisms by which nef contributes to pathogenesis in vivo remain unclear. We investigated the contribution of nef to HIV-1 replication in human lymphoid tissue ex vivo by studying infection with parental HIV-1 strain NL4-3 and with anef mutant (ΔnefNL4-3). In human tonsillar histocultures, NL4-3 replicated to higher levels than ΔnefNL4-3 did. Increased virus production with NL4-3 infection was associated with increased numbers of productively infected cells and greater loss of CD4+ T cells over time. While the numbers of productively infected T cells were increased in the presence of nef, the levels of viral expression and production per infected T cell were similar whether the nefgene was present or not. Exogenous interleukin-2 (IL-2) increased HIV-1 production in NL4-3-infected tissue in a dose-dependent manner. In contrast, ΔnefNL4-3 production was enhanced only marginally by IL-2. Thus, Nef can facilitate HIV-1 replication in human lymphoid tissue ex vivo by increasing the numbers of productively infected cells and by increasing the responsiveness to IL-2 stimulation.

Prolonged survival and tissue trafficking following adoptive transfer of CD4ζ gene-modified autologous CD4+ and CD8+ T cells in human immunodeficiency virus–infected subjects

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 785-793 ◽  
Author(s):  
Ronald T. Mitsuyasu ◽  
Peter A. Anton ◽  
Steven G. Deeks ◽  
David T. Scadden ◽  
Elizabeth Connick ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Cd4 Counts ◽  
Hiv Rna ◽  
Immunodeficiency Virus

Abstract We have genetically engineered CD4+ and CD8+ T cells with human immunodeficiency virus (HIV) specificity by inserting a gene, CD4ζ, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (ζ) chain of the T-cell receptor (which mediates T-cell activation). Twenty-four HIV-positive subjects received a single infusion of 2 to 3 × 1010 autologous CD4ζ-modified CD4+and CD8+ T cells administered with (n = 11) or without (n = 13) interleukin-2 (IL-2). Subjects had CD4 counts greater than 50/μL and viral loads of at least 1000 copies/mL at entry. T cells were costimulated ex vivo through CD3 and CD28 and expanded for approximately 2 weeks. CD4ζ was detected in 1% to 3% of blood mononuclear cells at 8 weeks and 0.1% at 1 year after infusion, and survival was not enhanced by IL-2. Trafficking of gene-modified T cells to bulk rectal tissue and/or isolated lamina propria lymphocytes was documented in a subset of 5 of 5 patients at 14 days and 2 of 3 at 1 year. A greater than 0.5 log mean decrease in rectal tissue–associated HIV RNA was observed for at least 14 days, suggesting compartmental antiviral activity of CD4ζ T cells. CD4+ counts increased by 73/μL at 8 weeks in the group receiving IL-2. There was no significant mean change in plasma HIV RNA or blood proviral DNA in either treatment arm. This sustained, high-level persistence of gene-modified T cells demonstrates the feasibility of ex vivo T-cell gene therapy in HIV-infected adults and suggests the importance of providing HIV-specific T-helper function.

Prolonged survival and tissue trafficking following adoptive transfer of CD4ζ gene-modified autologous CD4+ and CD8+ T cells in human immunodeficiency virus–infected subjects

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 785-793 ◽  
Author(s):  
Ronald T. Mitsuyasu ◽  
Peter A. Anton ◽  
Steven G. Deeks ◽  
David T. Scadden ◽  
Elizabeth Connick ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Cd4 Counts ◽  
Hiv Rna ◽  
Immunodeficiency Virus

We have genetically engineered CD4+ and CD8+ T cells with human immunodeficiency virus (HIV) specificity by inserting a gene, CD4ζ, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (ζ) chain of the T-cell receptor (which mediates T-cell activation). Twenty-four HIV-positive subjects received a single infusion of 2 to 3 × 1010 autologous CD4ζ-modified CD4+and CD8+ T cells administered with (n = 11) or without (n = 13) interleukin-2 (IL-2). Subjects had CD4 counts greater than 50/μL and viral loads of at least 1000 copies/mL at entry. T cells were costimulated ex vivo through CD3 and CD28 and expanded for approximately 2 weeks. CD4ζ was detected in 1% to 3% of blood mononuclear cells at 8 weeks and 0.1% at 1 year after infusion, and survival was not enhanced by IL-2. Trafficking of gene-modified T cells to bulk rectal tissue and/or isolated lamina propria lymphocytes was documented in a subset of 5 of 5 patients at 14 days and 2 of 3 at 1 year. A greater than 0.5 log mean decrease in rectal tissue–associated HIV RNA was observed for at least 14 days, suggesting compartmental antiviral activity of CD4ζ T cells. CD4+ counts increased by 73/μL at 8 weeks in the group receiving IL-2. There was no significant mean change in plasma HIV RNA or blood proviral DNA in either treatment arm. This sustained, high-level persistence of gene-modified T cells demonstrates the feasibility of ex vivo T-cell gene therapy in HIV-infected adults and suggests the importance of providing HIV-specific T-helper function.

scholarly journals Distinct Transcriptional Profiles in Ex Vivo CD4+ and CD8+ T Cells Are Established Early in Human Immunodeficiency Virus Type 1 Infection and Are Characterized by a Chronic Interferon Response as Well as Extensive Transcriptional Changes in CD8+ T Cells

2007 ◽  
Vol 81 (7) ◽  
pp. 3477-3486 ◽  
Author(s):  
Martin D. Hyrcza ◽  
Colin Kovacs ◽  
Mona Loutfy ◽  
Roberta Halpenny ◽  
Lawrence Heisler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Interferon Response ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Changes in T-cell function are a hallmark of human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms leading to these changes are unclear. We examined the gene expression profiles in ex vivo human CD4+ and CD8+ T cells from untreated HIV-1-infected individuals at different clinical stages and rates of disease progression. Profiles of pure CD4+ and CD8+ T-cell subsets from HIV-1-infected nonprogressors with controlled viremia were indistinguishable from those of individuals not infected with HIV-1. Similarly, no gene clusters could distinguish T cells from individuals with early infection from those seen in chronic progressive HIV-1 infection, whereas differences were observed between uninfected individuals or nonprogressors versus early or chronic progressors. In early and chronic HIV-1 infection, three characteristic gene expression signatures were observed. (i) CD4+ and CD8+ T cells showed increased expression of interferon-stimulated genes (ISGs). However, some ISGs, including CXCL9, CXCL10, and CXCL11, and the interleukin-15 alpha receptor were not upregulated. (ii) CD4+ and CD8+ T cells showed a cluster similar to that observed in thymocytes. (iii) More genes were differentially regulated in CD8+ T cells than in CD4+ T cells, including a cluster of genes downregulated exclusively in CD8+ T cells. In conclusion, HIV-1 infection induces a persistent T-cell transcriptional profile, early in infection, characterized by a dramatic but potentially aberrant interferon response and a profile suggesting an active thymic output. These findings highlight the complexity of the host-virus relationship in HIV-1 infection.

scholarly journals Selective anergy of V beta 8+ T cells in human immunodeficiency virus-infected individuals.

1994 ◽  
Vol 179 (2) ◽  
pp. 413-424 ◽  
Author(s):  
G Dadaglio ◽  
S Garcia ◽  
L Montagnier ◽  
M L Gougeon
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Clinical Status ◽  
Interleukin 2 ◽  
Cell Subset ◽  
T Cell Subset ◽  
Immunodeficiency Virus

We have analyzed the V beta usage by CD4+ and CD8+ T cells from human immunodeficiency virus (HIV)-infected individuals in response to an in vitro stimulation with the superantigenic erythrogenic toxin A (ETA) of Streptococcus pyogenes. ETA amplifies specifically CD4+ and CD8+ T cells from control donors expressing the V beta 8 and the V beta 12 elements. When peripheral T cells from asymptomatic HIV-infected individuals were stimulated with ETA, there was a complete lack of activation of the V beta 8+ T cell subset, whereas the V beta 12+ T cell subset responded normally to the superantigen. This V beta-specific anergy, which was also observed in response to staphylococcal enterotoxin E (SEE), affected both CD4+ and CD8+ T cells and represented an intrinsic functional defect rather than a specific lack of response to bacterial superantigens since it was also observed after a stimulation with V beta 8 monoclonal antibodies. The V beta 8 anergic T cells did not express interleukin 2 receptors (IL-2Rs) and failed to proliferate in response to exogenous IL-2 or IL-4, suggesting that this anergy was not a reversible process, at least by the use of these cytokines. The unresponsiveness of the V beta 8 T cell subset is frequent since it was found in 56% of the patients studied, and comparison of the clinical status of responder vs. anergic patients indicated that the only known common factor between them was HIV infection. In addition, it is noteworthy that the anergy of the V beta 8 subset may be a very early phenomenon since it was found in a patient at Centers for Disease Control stage I of the disease. These data provide evidence that a dominant superantigen may be involved in the course of HIV infection and that the contribution of HIV has to be considered.

scholarly journals Selection following isolation of human immunodeficiency virus type 1 in peripheral blood mononuclear cells and herpesvirus saimiri-transformed T cells is comparable

2002 ◽  
Vol 83 (6) ◽  
pp. 1343-1352 ◽  
Author(s):  
Natalie N. Zheng ◽  
Cherelyn Vella ◽  
Philippa J. Easterbrook ◽  
Rod S. Daniels
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Cell Types ◽  
Herpesvirus Saimiri ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells ◽  
Hiv 1

In attempts to improve isolation rates and virus yields for human immunodeficiency virus (HIV), the use of herpesvirus saimiri-immortalized T cells (HVS T cells) has been investigated as an alternative to/improvement over peripheral blood mononuclear cells (PBMCs). Here we characterize isolates rescued, in the two cell types, from two asymptomatic, long-term non-progressing HIV-1-infected individuals. All rescued viruses replicated in PBMCs and HVS T cells only, displaying a non-syncytium inducing (NSI) phenotype, and using CCR5 as co-receptor. Furthemore, PBMC/HVS T cell virus pairs displayed similar neutralization profiles. Full-length, expression-competent env genes were rescued from all virus isolates and directly from the patient samples using proviral DNA and viral RNA as templates. Compared with the sequences retrieved directly from the patient samples, both cell types showed similar selection characteristics. Whilst the selections were distinct for individual patient samples, they shared a common characteristic in selecting for viruses with increased negative charge across the V2 domain of the viral glycoproteins. The latter was observed at the env gene sequencing level for three other patients whose HIV strains were isolated in PBMCs only. This further supports a common selection for viral sequences that display a macrophage-tropic/NSI phenotype and shows that HVS T cells are a viable alternative to PBMCs for HIV-1 isolation.

scholarly journals WFDC1/ps20 Is a Novel Innate Immunomodulatory Signature Protein of Human Immunodeficiency Virus (HIV)-Permissive CD4+ CD45RO+ Memory T Cells That Promotes Infection by Upregulating CD54 Integrin Expression and Is Elevated in HIV Type 1 Infection

2007 ◽  
Vol 82 (1) ◽  
pp. 471-486 ◽  
Author(s):  
R. Alvarez ◽  
J. Reading ◽  
D. F. L. King ◽  
M. Hayes ◽  
P. Easterbrook ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Integrin Expression ◽  
Small Interference Rna ◽  
Immunodeficiency Virus

ABSTRACT Understanding why human immunodeficiency virus (HIV) preferentially infects some CD4+ CD45RO+ memory T cells has implications for antiviral immunity and pathogenesis. We report that differential expression of a novel secreted factor, ps20, previously implicated in tissue remodeling, may underlie why some CD4 T cells are preferentially targeted. We show that (i) there is a significant positive correlation between endogenous ps20 mRNA in diverse CD4 T-cell populations and in vitro infection, (ii) a ps20+ permissive cell can be made less permissive by antibody blockade- or small-interference RNA-mediated knockdown of endogenous ps20, and (iii) conversely, a ps20low cell can be more permissive by adding ps20 exogenously or engineering stable ps20 expression by retroviral transduction. ps20 expression is normally detectable in CD4 T cells after in vitro activation and interleukin-2 expansion, and such oligoclonal populations comprise ps20positive and ps20low/negative isogenic clones at an early differentiation stage (CD45RO+/CD25+/CD28+/CD57−). This pattern is altered in chronic HIV infection, where ex vivo CD4+ CD45RO+ T cells express elevated ps20. ps20 promoted HIV entry via fusion and augmented CD54 integrin expression; both of these effects were reversed by anti-ps20 antibody. We therefore propose ps20 to be a novel signature of HIV-permissive CD4 T cells that promotes infection in an autocrine and paracrine manner and that HIV has coopted a fundamental role of ps20 in promoting cell adhesion for its benefit. Disrupting the ps20 pathway may therefore provide a novel anti-HIV strategy.

Changes in human immunodeficiency virus type 1 virus load during mobilization and harvesting of hemopoietic progenitor cells

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 48-55
Author(s):  
Thomas B. Campbell ◽  
Anne Sevin ◽  
Robert W. Coombs ◽  
Gregory C. Peterson ◽  
Mary Rosandich ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Hemopoietic Stem Cell ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Hemopoietic Progenitor ◽  
Hemopoietic Progenitor Cells ◽  
Rna Levels

Genetic modification of hemopoietic progenitor cells ex vivo, followed by the infusion of the genetically modified cells into the human immunodeficiency virus-1 (HIV-1) infected donor, has been proposed as a treatment for HIV-1 infection. The current study was undertaken to evaluate the effect of hemopoietic stem cell mobilization and harvesting on HIV-1 replication in persons with HIV-1 infection. Eighteen HIV-1–infected persons received recombinant granulocyte colony-stimulating factor (G-CSF; Filgrastim) 10 μg/kg per day, for 7 days. On days 4 and 5, peripheral blood mononuclear cells were harvested by leukapheresis. The CD4+ lymphocyte count at entry was >500/μL for 6 subjects, 200 to 500/μL for 6 subjects, and <200/μL for 6 subjects. For 9 of 18 subjects, plasma HIV-1 RNA levels increased 4- to 100-fold (>0.6 log10) above baseline between days 4 and 7 and returned to baseline by day 27. Significant increases of plasma HIV-1 RNA levels occurred in 5 subjects despite 3-drug antiretroviral therapy. Changes in CD4+ and CD34+ cells during mobilization and harvesting were similar in all subjects whether they had or did not have increased plasma HIV-1 RNA levels. Thus, mobilization and harvesting of bone marrow progenitor cells from persons infected with HIV-1 induced a transient increase in viral replication in some patients but was not associated with adverse effects. (Blood. 2000;95: 48-55)

scholarly journals Disseminated human immunodeficiency virus 1 (HIV-1) infection in SCID-hu mice after peripheral inoculation with HIV-1.

1994 ◽  
Vol 179 (2) ◽  
pp. 513-522 ◽  
Author(s):  
T R Kollmann ◽  
M Pettoello-Mantovani ◽  
X Zhuang ◽  
A Kim ◽  
M Hachamovitch ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Lymph Nodes ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Human T Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Human Immunodeficiency Virus 1

A small animal model that could be infected with human immunodeficiency virus 1 (HIV-1) after peripheral inoculation would greatly facilitate the study of the pathophysiology of acute HIV-1 infection. The utility of SCID mice implanted with human fetal thymus and liver (SCID-hu mice) for studying peripheral HIV-1 infection in vivo has been hampered by the requirement for direct intraimplant injection of HIV-1 and the continued restriction of the resultant HIV-1 infection to the human thymus and liver (hu-thy/liv) implant. This may have been due to the very low numbers of human T cells present in the SCID-hu mouse peripheral lymphoid compartment. Since the degree of the peripheral reconstitution of SCID-hu mice with human T cells may be a function of the hu-thy/liv implant size, we increased the quantity of hu-thy/liv tissue implanted under the renal capsule and implanted hu-thy/liv tissue under the capsules of both kidneys. This resulted in SCID-hu mice in which significant numbers of human T cells were detected in the peripheral blood, spleens, and lymph nodes. After intraimplant injection of HIV-1 into these modified SCID-hu mice, significant HIV-1 infection was detected by quantitative coculture not only in the hu-thy/liv implant, but also in the spleen and peripheral blood. This indicated that HIV-1 infection can spread from the thymus to the peripheral lymphoid compartment. More importantly, a similar degree of infection of the hu-thy/liv implant and peripheral lymphoid compartment occurred after peripheral intraperitoneal inoculation with HIV-1. Active viral replication was indicated by the detection of HIV-1 gag DNA, HIV-1 gag RNA, and spliced tat/rev RNA in the hu-thy/liv implants, peripheral blood mononuclear cells (PBMC), spleens, and lymph nodes of these HIV-1-infected SCID-hu mice. As a first step in using our modified SCID-hu mouse model to investigate the pathophysiological consequences of HIV-1 infection, the effect of HIV-1 infection on the expression of human cytokines shown to enhance HIV-1 replication was examined. Significantly more of the HIV-1-infected SCID-hu mice expressed mRNA for human tumor necrosis factors alpha and beta, and interleukin 2 in their spleens, lymph nodes, and PBMC than did uninfected SCID-hu mice. This suggested that HIV-1 infection in vivo can stimulate the expression of cytokine mRNA by human T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Sign in / Sign up

Export Citation Format

Share Document