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ABSTRACT: We examined the effect of immune stimulation by a human immunodeficiency virus type 1 (HIV-1) immunogen (Remune) compared to a non-HIV vaccine (influenza) on HIV-1-specific immune responses in HIV-1-seropositive subjects. HIV-1 p24 antigen-stimulated lymphocyte proliferation was not augmented after immunization with the influenza vaccine. In contrast, subjects increased their lymphocyte proliferative responses to p24 antigen after one immunization with HIV-1 immunogen (Remune) (gp120-depleted inactivated HIV-1 in incomplete Freund's adjuvant). Furthermore, p24 antigen-stimulated beta-chemokine production (RANTES, MIP-1alpha, MIP-1beta) was also augmented after immunization with the HIV-1 immunogen but not influenza vaccine. Taken together, these results suggest that in this cohort, HIV-specific immune responses to p24 antigen can be augmented after immunization with an HIV-1 immunogen. The ability to upregulate immune responses to the more conserved core proteins may have important implications in the development of immunotherapeutic interventions for HIV-1 infection.
Clinical and Diagnostic Laboratory Immunology 06/1998; 5(3):308-12. · 2.51 Impact Factor
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ABSTRACT: In this study, the effects were examined of dose and adjuvant of whole-killed gp120-depleted HIV-1 antigen on antibody and cytokine responses in a murine model. Immunization with increasing doses of inactivated HIV-1 antigen in Incomplete Freund's Adjuvant (IFA) resulted in increased production of IL-4 and IgG1 antibody with decreased production of interferon gamma. Immunization with inactivated HIV-1 antigen in Detox PC adjuvant produced TH1 type predominant cytokine patterns along with IgG2a subclass antibody. Higher levels of interferon gamma were associated with immunization with inactivated HIV-1 antigen in Detox PC compared with inactivated HIV-1 in IFA or inactivated HIV-1 in saline. Inactivated HIV-1 antigen in Detox PC adjuvant produced a trend of lower levels of the beta-chemokine MIP-1 alpha compared with inactivated HIV-1 in IFA or saline. Dose and adjuvant play an important role in the type of immune response elicited to a whole-killed HIV vaccine. Low doses of inactivated HIV-1 antigen in Detox PC adjuvant are currently being studied in animal models in order to optimize cell-mediated immunity against HIV infection.
Vaccine 05/1998; 16(7):727-31. · 3.77 Impact Factor
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ABSTRACT: The nasal mucosa is the initial site in the upper airway of host defence against antigenic challenge in the form of airborne allergens, irritants, toxins and infectious agents, and yet little is known about nasal mucosal cytokine expression and function. We hypothesized that IL-2 might play a role in immunocompetence of the upper airway.
IL-2 immunoreactivity was measured by ELISA in nasal secretions and by Western blot. Immunohistochemistry and electron microscopy were performed on turbinated tissue. mRNA for IL-2 was evaluated by RTPCR and Southern hybridization.
IL-2 immunoreactivity was demonstrated by Western blot and quantitated by an enzyme immunoassay. Immunohistochemical and electron microscopy analysis of turbinate tissue revealed interstitial staining for IL-2. By RTPCR, IL-2 message was evident in 5/5 atopics and 5/5 non-atopics. IL-2 message was expressed in all subjects by Southern hybridization to an internal probe after PCR.
This study has demonstrated constitutive expression of IL-2 protein and mRNA in the upper airway of healthy individuals. The further characterization of cytokines in the upper airway could provide useful insights into immune regulation at the mucosal level.
Clinical & Experimental Allergy 05/1997; 27(4):406-12. · 5.03 Impact Factor
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R B Moss,
R J Trauger,
W K Giermakowska,
J L Turner,
M R Wallace,
F C Jensen,
S P Richieri,
F Ferre,
A E Daigle,
C Duffy,
G Theofan,
D J Carlo
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ABSTRACT: To measure beta-chemokine and cytokine production in HIV-1-infected subjects undergoing treatment with HIV-1 immunogen (REMUNE).
Open label treatment study.
beta-Chemokine and cytokine production in peripheral blood mononuclear cell (PBMC) culture.
Interferon-gamma production (p = 0.04) and lymphocyte proliferation (p = 0.001) to HIV-1 antigen-stimulated PBMCs increased after immunization with the HIV-1 immunogen. A correlation was demonstrated after immunization between HIV-1 antigen-stimulated lymphocyte proliferation and interferon-gamma levels (r = 0.53, p = 0.04). No significant change after immunization was seen for interleukin-4 production. A significant increase in mean levels of HIV-1 antigen-stimulated RANTES (i.e., regulated upon, activation normal T-cell expressed and secreted), was evident 1 month after immunization (p = 0.002) and remained elevated 3 months after immunization. RANTES production was decreased in CD8-depleted PBMC cultures. Mean serum HIV-1 RNA copy numbers and CD4 cell counts remained stable after immunization (p > 0.5). A correlation was demonstrated between HIV-1 antigen-stimulated interferon-gamma and RANTES production (r = 0.54, p = 0.002).
This report describes an augmentation of beta-chemokines and TH1-type cytokines from PBMCs after immunization with the HIV-1 immunogen.
Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 04/1997; 14(4):343-50.
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ABSTRACT: Background The nasal mucosa is the initial site in the upper airway of host defence against antigenic challenge in the form of airborne allergens, irritants, toxins and infectious agents, and yet little is known about nasal mucosal cytokine expression and function. We hypothesized that IL-2 might play a role in immunocompetence of the upper airway.Methods IL-2 immunoreactivity was measured by ELISA in nasal secretions and by Western blot. Immunohistochemistry and electron microscopy were performed on turbinated tissue. mRNA for IL-2 was evaluated by RTPCR and Southern hybridization.Results IL-2 immunoreactivity was demonstrated by Western blot and quantitated by an enzyme immunoassay. Immunohistochemical and electron microscopy analysis of turbinate tissue revealed interstitial staining for IL-2. By RTPCR, IL-2 message was evident in 5/5 atopies and 5/5 non-atopics. IL-2 message was expressed in all subjects by Southern hybridization to an internal probe after PCR.Conclusion This study has demonstrated constitutive expression of IL-2 protein and mRNA in the upper airway of heallhy individuals. The further characterization of cytokines in the upper airway could provide useful insights into immune regulation at the mucosal level.
Clinical & Experimental Allergy 03/1997; 27(4):406 - 412. · 5.03 Impact Factor
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ABSTRACT: Two cases of biopsy-proven Microsporidium-associated chronic sinusitis in HIV-seropositive patients are presented. Spores of Septata intestinalis were identified by light microscopy and confirmed by electron microscopy in each case. Both patients displayed severe deficiencies of nasal mucosa CD4-positive cells, demonstrated by immunohistochemical methods. Only two other cases of Septata intestinalis-associated sinusitis have been reported previously. Our observations agree with the theory that functional defects in local mucosal immunity may partially explain the acquisition of opportunistic mucosal infections in many HIV-seropositive patients.
Ear, nose, & throat journal 03/1997; 76(2):95-101. · 0.66 Impact Factor
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R.B. Moss,
S.P. Richieri,
F. Ferre,
A.E. Daigle,
R. Trauger,
G. Theofan,
W. Giermakowska,
P. Lanza,
S. Brostoff,
D.J. Carlo,
F.C. Jensen
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ABSTRACT: The impairment of lymphocytes to proliferate to HIV antigen is a relatively early functional defect of cell-mediated immunity found in HIV-infected individuals. The finding of strong proliferative responses in nonprogressive HIV disease as well as its inverse association with viral load and clinical manifestation of AIDS supports the further use of this marker as a surrogate of disease progression. The observation that HIV-specific lymphocyte proliferation is associated with the production of CD8-derived HIV suppressive factors such as the beta-chemokines further supports this conclusion. These functional immune measurements provide an additional marker to monitor disease progression in HIV-infected individuals, along with the current standards of CD4 counts and viral load. Copyright 1997 S. Karger AG, Basel
Journal of Biomedical Science 02/1997; 4(4):127-131. · 2.01 Impact Factor
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ABSTRACT: Lymphocyte proliferation responses to gp120-depleted HZ321 virus (clade A) antigen were compared to BAL human immunodeficiency virus (HIV) virus antigen (clade B) responses, clade E HIV virus antigen responses, and purified native p24 antigen responses in 15 human immunodeficiency virus type-1 (HIV-1) seropositive subjects immunized with a whole-killed inactivated gp120-depleted HIV-1 antigen in Incomplete Freund's adjuvant (HIV-1 immunogen, REMUNE). A significant increase in lymphocyte proliferation to HZ321 antigen was observed after immunization with the HIV-1 immunogen (p = 0.02). A strong association was demonstrated between the HIV-1 immunizing antigen, HZ321, and native p24 antigen responses (r = 0.80, p < 0.0001). Furthermore, a strong association in terms of proliferative responses was demonstrated between HZ321 virus (clade A) responses and BAL virus (clade B) (r = 0.95, p < 0.0001) and clade E virus antigen (r = 0.92, p < 0.0001). Proliferative responses to HIV antigens also correlated with baseline CD4 counts. Taken together, these results support the specificity of immune responses induced by REMUNE (HIV-1 immunogen). The development of cross-reactive immune responses between clades and to the more conserved epitopes of the virus have implications in the development of therapeutic and prophylactic HIV vaccines.
Viral Immunology 01/1997; 10(4):221-8. · 1.97 Impact Factor
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ABSTRACT: The deleterious effect of HIV on the immune system begins at the time of infection. At seroconversion the virologic and immunologic factors that ultimately will dictate the rate of disease progression are believed to be already in place. The concept developed in this paper implies that, to impact significantly on the progression of disease, anti-HIV therapies should be initiated as early as possible in asymptomatic individuals. Published results have shown that combination drug therapies are potent in reducing HIV-1 RNA load in plasma in asymptomatic individuals, and that some HIV-1 immune-based therapies have a positive impact on immunological markers of disease progression, including HIV-1 cell-mediated immunity (CMI) and CD4 percent. The strategy discussed is to test a combination of antiretroviral therapy with HIV-1 immune-based therapy, such as the inactivated HIV-1 immunogen preparation, in asymptomatic individuals. The goal of this combination approach is to overcome the limitations of each therapy alone. Preliminary data suggest that antiretroviral therapy and the HIV-1 Immunogen can be combined with no noticeable interference and/or added toxicity in a broad range of HIV-1-infected individuals. Combining both therapies may enhance and expand the impact on key surrogate markers of disease progression, although they likely achieve this impact through different mechanisms. Thus, the primary question remains: Can these effects be synergistic?
AIDS PATIENT CARE and STDs 01/1997; 10(6):357-61. · 2.41 Impact Factor
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R B Moss,
F Ferre,
A Levine,
J Turner,
F C Jensen,
A E Daigle,
S P Richieri,
A Truckenbrod,
R J Trauger,
D J Carlo,
J Salk
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ABSTRACT: Two trials of subjects inoculated with the inactivated, gp120-depleted HIV-1 Immunogen are reported. In one study, in which 19 subjects received ZDV and 8 subjects received ddI, treatment with the HIV-1 Immunogen did not affect the pharmacokinetic parameters of the antiviral drugs. In another study, 65 subjects who were previously immunized with the HIV-1 Immunogen over a mean period of 4.0 years (range, 1.2-5.4 years) received inoculations at 0 and 6 months. At some point during this 48-week study, 72% of the subjects (47/65) were receiving antiviral drug therapy. The HIV-1 DNA load in CD4 cells and CD4 percentage were found to be stable over the 48-week period. Delayed-type hypersensitivity to HIV-1 antigens increased after two inoculations with the HIV-1 Immunogen. In these two trials, no serious treatment-related adverse events were documented in the subjects. The two studies presented herein are the first to suggest that an immune-based therapy such as the HIV-1 Immunogen can be combined safely with antiviral drugs, supporting further study to evaluate the clinical utility of this approach.
Journal of Clinical Immunology 10/1996; 16(5):266-71. · 3.08 Impact Factor
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M R Wallace, R B Moss,
H J Beecham,
C J Grace,
E M Hersh,
E Peterson,
R Murphy,
D H Shepp,
F P Siegal,
J L Turner,
S Safrin,
D J Carlo,
A M Levine
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ABSTRACT: In a clinical trial involving asymptomatic, HIV-seropositive subjects treated with either the HIV-1 immunogen (an inactivated, gp120-depleted HIV-1 virus in incomplete Freund's adjuvant) or an adjuvant control, we examined the relationship between changes in the percentage of CD4 cells over time and early clinical markers of HIV disease progression. Subjects who had an early clinical event were more likely to have a greater decline in the percentage of CD4 cells than those subjects who did not have a clinical event (p = 0.054). The greatest decline in CD4 percentage occurred within 10 weeks prior to a clinical event (mean 11% decrease from baseline). Subjects from the quartile with the greatest decline in CD4 percentage had a fivefold greater risk of having a clinical event than subjects from the quartile with the second largest decline (p = 0.045). These results demonstrate a relationship between changes in the percentage of CD4 cells and early clinical events. Further validation of this association may be useful in clinical monitoring and in evaluating therapies to treat HIV infection.
Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 09/1996; 12(4):358-62.
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ABSTRACT: Recently, sinusitis has been recognized as a frequent clinical problem in human immunodeficiency virus (HIV-1)-infected individuals. We hypothesized that quantitative defects in immune cells in the nasal mucosa of HIV-positive subjects might mirror those in the peripheral blood and explain a predisposition to sinus disease in this population. Nasal mucosa biopsies were obtained from three different groups of patients-HIV-1 seropositive with sinusitis, HIV-1 seronegative with sinusitis, and HIV-1 seronegative without sinusitis (normal volunteer)-and phenotyped for cluster of differentiation antigen (CD) markers. In this study, we found patients with HIV-1 and sinus disease to have significantly lower numbers of both CD3 and CD4 nasal mucosa lymphocytes than seronegative controls in the nasal mucosa (P < 0.05, P < 0.01, respectively). A correlation between nasal mucosal CD4 cells and peripheral-blood CD4 cells was noted (R = 0.67, P < or = 0.01). No deficiency in the number of nasal mucosa T or TC type mast cells was noted for the HIV-1-positive sinusitis group. Further study is warranted to define more completely the pathophysiology and microbiology of, and therapy for, this important clinical problem.
Journal of Clinical Laboratory Analysis 01/1996; 10(6):418-22. · 1.38 Impact Factor
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ABSTRACT: During the symposium on surrogate markers of HIV, the Scientific Advisory Committee posed the following question: "Which surrogate markers currently deserve the greatest commitment of investigative resources to validate them in a clinical setting?" The Committee concluded that for antiretroviral drugs measurements of HIV RNA in plasma deserve the greatest priority, and for immune-based therapies assessing viral load still had the highest priority. But it was recognized that assessing viral load should not be restricted to plasma RNA because the primary mechanisms of action are different from antiretroviral drugs. Thus, the Committee voted that based on current knowledge, investigating the clinical relevance of changes in HIV-1 DNA and RNA copy number in peripheral blood mononuclear cells (PBMCs) with validated assays should be given equal focus for immune-based therapies. This article reviews the rationale for using HIV-1 DNA and RNA load in PBMCs for the monitoring of clinical trials and presents recent data that indicate that the postseroconversion level and the dissemination of proviral DNA in the blood cells have prognostic value, i.e., high levels correlate with disease progression. In addition, longitudinal studies show that an increase in proviral DNA and/or HIV mRNA load correlates with disease progression. We present evidence that these markers are relevant activity markers for anti-HIV therapies. Changes in both DNA and RNA load can be achieved using either antiretroviral drugs or immune-based therapies. These results suggest that these markers should be evaluated in clinical studies to firmly establish their value as surrogates of clinical progression.
Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 02/1995; 10 Suppl 2:S51-6.
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ABSTRACT: We report the safety and immunogenicity results of a double-blind adjuvant controlled trial of the human immunodeficiency virus type 1 (HIV-1) immunogen. Healthy, asymptomatic HIV-1-seropositive individuals received either three 100 microgram doses of the inactivated HIV-1 antigen in incomplete Freund's adjuvant (IFA) or three doses of IFA alone. The results of this study show that this HIV-1 immunogen is safe, with mild and transient adverse events. No difference in the number or type of adverse events was noted between the treatment groups. Rises in HIV-1-specific humoral and cell-mediated immune (CMI) responses were also noted, favoring the HIV-1 immunogen-treated group. The results of this study confirm and extend the safety and immunogenicity profile of this HIV-1 immunotherapeutic agent. The observation that this treatment can augment HIV-1-specific CMI is encouraging because this immunological marker may represent a key surrogate end point in HIV-1 infection and disease.
Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 02/1995; 10 Suppl 2:S74-82.
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ABSTRACT: A 1-year study measured the effect of administration of an inactivated human immunodeficiency virus type 1 (HIV-1) immunogen in incomplete Freund's adjuvant (IFA) on HIV-1-specific immunity and viral burden in asymptomatic HIV-1-infected patients. A total of 103 patients were enrolled in this double-blind, randomized study comparing immunogen in adjuvant with adjuvant alone. This study was conducted at nine medical centers throughout the United States. Significant differences in cell-mediated immune responses to HIV-1 and p24 core antigen were observed between the treated and control groups (P < .01). Compared with controls, treated patients as a group had a significantly lower rate of increase in viral DNA as determined by quantitative HIV-1 DNA-polymerase chain reaction (P = .016). Significant differences in the rate of percent CD4 cell decline were also observed between the 2 groups (P = .024). These data suggest that augmentation of HIV-1-specific immunity via immunotherapy may alter the rate of increase of HIV-1 DNA in peripheral blood mononuclear cells and stabilize the percent of CD4 cell decline in relatively healthy HIV-1-infected persons.
The Journal of Infectious Diseases 07/1994; 169(6):1256-64. · 6.41 Impact Factor
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ABSTRACT: The pursuit of valid markers of disease progression in human immunodeficiency virus type 1 (HIV-1) infection is especially relevant considering the potential treatment alternatives that presently are under evaluation. Because HIV-1 infection results in a virally induced immune suppression characterized by the loss of cell-mediated immunity (CMI), depletion of CD4+ cells, loss of core antibody, and an increase in viral burden, these markers seemed to be appropriate to monitor in a controlled study. We monitored a number of virologic, immunologic, and cytologic markers of disease progression in 103 subjects who were enrolled in a 12-month, double-blind, randomized, adjuvant-controlled study of the HIV-1 inactivated Immunogen. The markers included HIV-1 DNA, HIV-1 RNA, CD4 percent, p24 antibody, and lymphocyte proliferation. Analysis of HIV-1 DNA with a quantitatively polymerase chain reaction (PCR) assay indicated a treatment effect on viral burden in the HIV-1 Immunogen-treated group. Analysis of HIV-1 RNA revealed a similar trend favoring the Immunogen-treated group. In addition, a significant effect was shown on CD4 percent and CMI in the Immunogen-treated group. An analysis of CMI that used stimulation indices underrepresented the immunogenicity of the Immunogen. Further examination revealed that the lymphocytes of the HIV-1 Immunogen-treated patients were proliferating in vitro without exogenous antigen. Although the clinical significance of this phenomenon currently is unknown, it may be a relevant prognostic marker for assessment of HIV-1 therapy. The data presented here support the concept that immunotherapy with the HIV-1 Immunogen may slow disease progression.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of acquired immune deficiency syndromes 02/1994; 7 Suppl 1:S21-7.
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ABSTRACT: A novel PCR in situ protocol is described which can be implemented in one day. An initial amplification step with a single primer pair is followed by an amplification with an internal oligonucleotide probe with labeled nucleotides (dig-dUTP). Detection is then accomplished with an antidigoxigenin antibody and substrate solution. This rapid and sensitive method may be useful in diagnosing low copy DNA in tissue specimens and cells.
Journal of Clinical Laboratory Analysis 02/1994; 8(2):120-2. · 1.38 Impact Factor
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ABSTRACT: The chemokine receptors CXCR4 and CCR5 have been identified as the major coreceptors for HIV-1 on CD4+ cells and macrophages. The natural ligands for these receptors are SDF-1 and the beta-chemokines (MIP-1alpha, MIP-1beta, RANTES), respectively, and are the products of a variety of immune cells, including CD8+ T lymphocytes.
We hypothesized that the ability to stimulate the natural ligands for these receptors using an immune based therapy might influence in vivo chemokine receptor expression.
In vivo CXCR4 expression remained stable after treatment with an HIV-1 Immunogen (REMUNE), whereas CCR5 expression on CD4+ T cells decreased (p < .05). Furthermore, HIV-1 antigen-specific production of beta-chemokines in vitro was also augmented (P < .05).
These preliminary results suggest that this HIV-1-specific immune-based therapy can stimulate antigen-specific beta-chemokine production in vitro and downregulate CCR5 receptor expression on CD4 cells in vivo.
Journal of human virology 3(1):44-9.
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R B Moss,
L Li,
W K Giermakowska,
P Lanza,
J L Turner,
M R Wallace,
F C Jensen,
S P Richieri,
A E Daigle,
G Theofan,
D J Carlo
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ABSTRACT: We examined the relation between tumor necrosis factor-alpha (TNF-alpha) levels and human immunodeficiency virus type 1 (HIV-1)-specific functional immune responses, as measured by HIV-1 antigen-stimulated lymphocyte proliferation and beta-chemokine production after immunization with gp120-depleted, inactivated HIV-1 in incomplete Freund's adjuvant (i.e., HIV-1 Immunogen; REMUNE, The Immune Response Corporation, Carlsbad, CA, U.S.A.).
HIV-1-seropositive subjects who enrolled in an open-label study were immunized with REMUNE every 12 weeks and monitored for 60 weeks. HIV-1 antigen-stimulated lymphocyte proliferation and RANTES production were measured in peripheral blood mononuclear cells (PBMCs). TNF-alpha levels were measured in serum.
TNF-alpha (P = 0.0003) significantly decreased and HIV-1 antigen-stimulated RANTES production (P = 0.002) and lymphocyte proliferation (P = 0.07) increased after immunization with REMUNE. TNF-alpha levels negatively correlated with HIV-1 antigen-stimulated RANTES production (r = -0.71; P = 0.0002) and lymphocyte proliferation (r = -0.37; P = 0.09).
This study demonstrated decreased TNF-alpha levels with a concomitant augmentation of HIV-specific functional immunity in subjects immunized with REMUNE. Because TNF-alpha has been implicated in the induction of anergy in HIV-1 infection, the ability to decrease TNF-alpha may allow the immune system to respond to HIV and non-HIV antigens. Larger studies are being conducted to confirm the clinical utility of REMUNE in combination with potent antiviral drugs.
Journal of human virology 1(2):77-81.
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ABSTRACT: The safety and immunogenicity of REMUNE, an HIV-specific immune based therapy for HIV infection, was evaluated in a cohort of 30 HIV infected subjects in Thailand. This therapy utilizes a gp120 depleted inactivated virus (HZ321), which exhibits a high degree of conservation with the core antigens of both type B' and E strains of HIV, the predominant Thailand isolates. The treatment was well tolerated, with no serious adverse events reported over the course of the 4-month trial. Treatment in which four doses were administered with REMUNE appeared to boost HIV-specific immune responses, with approximately 75% of the treated subjects demonstrating an increase in either the repertoire or the intensity of the serological response to HIV as measured by Western blot. CD4%, viral load, and weight remained stable over the course of the 4-month study relative to baseline values. Viral subtyping of this cohort revealed a predominance of type 'E'. These data suggest that REMUNE is safe and immunogenic in seropositive Thai subjects and supports further study of the therapeutic potential of REMUNE to treat HIV-1 infection.
Vaccine 16(2-3):142-9. · 3.77 Impact Factor
