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1.
Nat Med ; 3(6): 651-8, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9176492

ABSTRACT

A combination AIDS vaccine approach consisting of priming with adenovirus-HIV-1MN gp160 recombinants followed by boosting with HIV-1SF2 gp120 was evaluated in chimpanzees. Long-lasting protection, requiring only three immunizations, was achieved against a low-dose challenge with the SF2 strain of HIV-1 and a subsequent high-dose SF2 challenge administered 1 year later without an intervening boost. Notably, neutralizing antibody responses against both clinical and laboratory isolates developed in three chimpanzees and persisted until the time of high-dose challenge. The possibility that cytotoxic T-lymphocytes contribute to low-dose protection of a chimpanzee lacking neutralizing antibodies is suggested. Our results validate the live vector priming/subunit booster approach and should stimulate interest in assessing this combination vaccine approach in humans.


Subject(s)
Adenoviridae/immunology , HIV Envelope Protein gp120/immunology , HIV Envelope Protein gp160/immunology , HIV-1/pathogenicity , Recombinant Fusion Proteins/immunology , Vaccination/methods , Animals , Female , HIV Infections/immunology , HIV Infections/prevention & control , Pan troglodytes , Recombinant Fusion Proteins/administration & dosage , T-Lymphocytes, Cytotoxic/physiology , Vaccines/administration & dosage
2.
J Virol ; 70(7): 4361-9, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8676459

ABSTRACT

To test whether the protective effects of attenuated simian immunodeficiency virus vaccines in macaques were applicable to the human immunodeficiency virus type 1 (HIV-1)-chimpanzee system, two groups of animals, previously infected with HIV-1(IIIB) or HIV-1(SF2) were each challenged with a heterologous clade B virus, HIV-1(DH12). Following challenge, the parameters measured included virus isolation (from plasma, peripheral blood mononuclear cells, and lymph node tissue); quantitative DNA PCR using primers capable of distinguishing HIV-1(IIIB), HIV-1(SF2), and HIV-1(DH12) from one another; and serologic assays to monitor changes in binding and neutralizing antibodies. In contrast to an HIV-1-naive chimpanzee that rapidly became infected following the inoculation of HIV-1(DH12), the two chimpanzees previously infected with HIV-1(IIIB) resisted repeated and escalating inoculations of HIV-1(DH12), as monitored by virus isolation and PCR. The two animals previously infected with HIV-1(SF2) became infected with HIV-1(DH12) but in contrast to the case with the HIV-1-naive chimpanzee, no cell-free viral RNA was detected in the plasma by the branched DNA procedure and levels of peripheral blood mononuclear cell-associated viral DNA were reduced 35- to 50-fold.


Subject(s)
AIDS Vaccines/immunology , HIV Infections/immunology , HIV-1/immunology , Animals , Base Sequence , DNA, Viral/blood , HIV Antibodies/blood , HIV Infections/prevention & control , HIV-1/genetics , HIV-1/isolation & purification , Humans , Immunity, Innate , Molecular Sequence Data , Neutralization Tests , Pan troglodytes , RNA, Viral/blood , Tumor Cells, Cultured , Vaccines, Attenuated/immunology , Viral Interference
3.
J Virol ; 69(4): 2443-50, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7884892

ABSTRACT

We have isolated seven single-cell clones from an H9 culture infected with human immunodeficiency virus type 1 strain MN so that a stable producer of virus could be obtained. DNAs from these clones were examined by Southern blot analysis and found to contain between one and four proviruses per clone. One of these cell lines, Clone 4, produced high levels of replication-competent virus and contained two proviruses. Southern blot analysis of DNAs from Clone 4 revealed that, after extended culture, some of the cells had acquired additional proviruses, presumably by superinfection. Analysis of Clone 4 single-cell subclones isolated from a late-passage culture found that 14 out of 20 (70%) subclones were reinfected and that 8 out of 20 (40%) were reinfected more than once. Fluorescence-activated cell sorter analysis showed that surface CD4 levels on Clone 4 cells were appropriately down-regulated. Our results indicate that while there is significant interference to superinfection in the Clone 4 culture, it is not absolute and that superinfected cells accumulate in the culture over time in the presence of high virus exposure and extensive cell-to-cell contact. Given our data, it seems likely that superinfection can occur in vivo within the lymphoid reservoirs that harbor human immunodeficiency virus type 1 during the clinically latent period and may contribute to disease progression.


Subject(s)
HIV-1/physiology , Proviruses/physiology , CD4 Antigens/metabolism , Cell Line , Clone Cells , Down-Regulation , Humans , Superinfection , Virion/physiology , Virus Replication
4.
J Med Primatol ; 23(8): 432-41, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7602579

ABSTRACT

Using a panel of human T-cell receptor (TCR) variable region beta chain (V beta) polymerase chain reaction (PCR) primers, we performed cross-sectional and longitudinal analyses of the TCR V beta repertoire in naive and HIV-1 infected chimpanzees. We demonstrate that our TCR PCR primer panel will support amplification of chimpanzee cDNA from most of the TCR V beta families. However, no differences in TCR V beta expression were found between the naive and HIV-1 infected chimpanzees, unlike the TCR V beta repertoire perturbation found in HIV-1 infected human subjects. This finding suggests that a complete TCR repertoire in HIV-1 infected chimpanzees is associated with the maintenance CD4+ T-cell numbers and lack of progression to AIDS.


Subject(s)
Disease Models, Animal , HIV Infections/immunology , HIV-1 , Pan troglodytes/immunology , Receptors, Antigen, T-Cell, alpha-beta/genetics , Animals , Base Sequence , Cross-Sectional Studies , Female , HIV Infections/genetics , Humans , Longitudinal Studies , Male , Molecular Sequence Data , Polymerase Chain Reaction , Receptors, Antigen, T-Cell, alpha-beta/analysis
5.
J Acquir Immune Defic Syndr (1988) ; 7(4): 325-31, 1994 Apr.
Article in English | MEDLINE | ID: mdl-8133445

ABSTRACT

Despite its shortcomings as a disease model, the chimpanzee is still the most relevant animal model for human immunodeficiency virus type 1 (HIV-1) infection. Previous studies have revealed qualitative differences between human and chimpanzee anti-HIV-1 responses. In this study, the development of specific anti-HIV-1 antibody-dependent cellular cytotoxic (ADCC) reactivities was evaluated in chronically infected chimpanzees and compared to the human response, because anti-HIV-1 ADCC represents a major component of anti-envelope cytolytic response found in infected patients. Ten HIV-1-infected chimpanzees up to 5 years after the infection were investigated. Anti-HIV-1 ADCC-directing antibodies were detectable in only three of 10 infected chimpanzees, and in these animals, activity was apparent only several months after the HIV infection. In some of the infected animals, ADCC reactivity against infected cells preceded reactivity against gp120-coated targets. When anti-gp120 ADCC-directing antibodies were apparent, they exhibited the same broad reactivity described in humans against different HIV isolates. The pattern of ADCC reactivities in infected chimpanzees is completely different from the well-characterized anti-gp120 cytotoxic reactivities present in HIV-1-infected patients. It is a relatively rare and late-occurring event that may have an important bearing on the lack of virus-induced pathogenesis in the chimpanzee model.


Subject(s)
Antibody-Dependent Cell Cytotoxicity , Disease Models, Animal , HIV Infections/immunology , HIV-1/immunology , Pan troglodytes , Animals , Cell Line , HIV Antibodies/blood , HIV Envelope Protein gp120/immunology , HIV Envelope Protein gp41/immunology , Humans , Immune Sera/immunology , Pan troglodytes/immunology , Pan troglodytes/microbiology , T-Lymphocytes/immunology
6.
AIDS Res Hum Retroviruses ; 9(7): 647-56, 1993 Jul.
Article in English | MEDLINE | ID: mdl-8369169

ABSTRACT

As a means of assessing the immunological impact of HIV infection in the chimpanzee, as well as the participation of the cellular components in the control of HIV infection in these animals, various aspects of cellular immunity were investigated in chronically HIV-infected chimpanzees. Eight HIV-1-infected chimpanzees were included in this study; two of them were infected for more than 5 years and six for nearly 3 years at the time of study. All of the chimpanzees received either 40 or 100 TCID50 of HTLV-IIIB. Circulating peripheral blood lymphocytes were studied by flow cytofluorimetric analysis in order to reveal possible alterations in the CD4:CD8 ratio, as well as in specific CD4+ and CD8+ cell subpopulations. Chronically infected chimpanzees did not present significant alterations in the percentage of CD4+ or CD8+ lymphocyte subsets. Interestingly, the CD8+/CD57+ cell subset was not detectable. The expression of markers for activation on circulating lymphocytes, usually higher in the HIV-infected patients, was not altered in infected animals. The functional aspects of specific anti-HIV-1 non-MHC and MHC-restricted cellular cytotoxic reactivities were also investigated. The results were compared with the findings in normal uninfected chimpanzees and in HIV-infected humans. Only one chimpanzee (881) developed a detectable, specific non-MHC-restricted anti-HIV-1- reactivity. Compared to that seen in humans, the ontogeny of this activity is delayed. Among the other infected chimpanzees, no specific anti-HIV cellular reactivities were detectable in the peripheral blood. In chimpanzees, HIV-1 infection evidently does not elicit the same strong cellular reactivity as that detected in infected patients. The absence of chronic cellular activation, despite continued viral replication, may highlight a key determinant in HIV-1-induced pathogenesis that is likewise absent in infected chimpanzees.


Subject(s)
Cytotoxicity, Immunologic , HIV Infections/immunology , HIV-1/immunology , T-Lymphocyte Subsets/immunology , Animals , Antibody-Dependent Cell Cytotoxicity , CD4-CD8 Ratio , HIV Antibodies/immunology , HIV Envelope Protein gp120/immunology , Humans , Killer Cells, Lymphokine-Activated/immunology , Killer Cells, Natural/immunology , Pan troglodytes , Phenotype , T-Lymphocytes, Cytotoxic/immunology
7.
J Virol ; 64(7): 3207-11, 1990 Jul.
Article in English | MEDLINE | ID: mdl-2191147

ABSTRACT

All retroviruses contain, in the nucleocapsid domain of the Gag protein, one or two copies of the sequence Cys-X2-Cys-X4-His-X4-Cys. We have generated a series of mutants in the two copies of this motif present in human immunodeficiency virus type 1. These mutants encoded virus particles that were apparently composed of the normal complement of viral proteins but contained only 2 to 20% of the normal level of genomic RNA. No infectivity could be detected in the mutant particles, while 10(5) infectious U were present in an equivalent amount of wild-type particles. Thus, the mutants have another defect in addition to the inefficiency with which they encapsidate genomic RNA. Our results show that both copies of the motif are required for normal RNA packaging and for infectivity. Mutants of this type may have important applications, including nonhazardous materials for research, immunogens in vaccine and immunotherapy studies, and diagnostic reagents.


Subject(s)
HIV-1/genetics , RNA, Viral/genetics , Virus Replication , Amino Acid Sequence , Capsid/genetics , Cysteine , DNA Mutational Analysis , Gene Products, gag/genetics , HIV-1/growth & development , HeLa Cells , Molecular Sequence Data , Morphogenesis , Mutation , Viral Core Proteins/genetics
8.
Vaccine ; 7(5): 465-73, 1989 Oct.
Article in English | MEDLINE | ID: mdl-2554608

ABSTRACT

In mice, immunostimulatory complexes (ISCOMs) prepared from HIV-1 B external envelope glycoprotein (gp120) induced 10-fold higher antibody titres than gp120 emulsified in depot adjuvant, as measured by enzyme-linked immunosorbent assay (ELISA). Rhesus monkeys immunized with gp120 ISCOMs produced precipitating and virus neutralizing antibody titres equivalent to those seen in HIV-infected chimpanzees and humans. After multiple immunizations with HIV-1 B gp120 ISCOMs, a rhesus monkey developed a neutralizing response to the HIV-1 isolates RF and MN, but not to the CC isolate. Antisera from ISCOM-immunized rhesus monkeys recognized gp120 on the membranes of HIV-1 B-infected H9 cells, indicating the preservation of epitope structure in the ISCOMs matrix.


Subject(s)
Adjuvants, Immunologic , HIV Antibodies/biosynthesis , HIV Envelope Protein gp120/immunology , HIV-1/immunology , Animals , Blotting, Western , Centrifugation, Density Gradient , Chromatography, Affinity , Electrophoresis, Polyacrylamide Gel , Enzyme-Linked Immunosorbent Assay , Macaca mulatta , Mice , Mice, Inbred BALB C , Microscopy, Electron , Neutralization Tests , Rabbits , Radioimmunoassay
9.
Sex Transm Dis ; 14(1): 41-3, 1987.
Article in English | MEDLINE | ID: mdl-3031834

ABSTRACT

Primary oral and genital infections caused by herpes simplex virus type 2 were diagnosed in an 18-year-old female. A history of sexual practices was critical in determining the anatomic sites of infection. Restriction endonuclease analysis of viral DNAs helped to identify the male sexual partner from whom the virus had been acquired. He had been infected recently by a previous sexual partner but had not yet developed lesions. Clinicians should obtain a history of sexual practices from patients with newly acquired genital herpes and should advise patients with genital herpes that transmission of virus to sexual partners can occur in the absence of overt lesions.


Subject(s)
Herpes Genitalis/complications , Stomatitis, Herpetic/complications , Adolescent , Adult , Antibodies, Viral/analysis , Female , Herpes Genitalis/transmission , Humans , Male , Risk , Sexual Behavior , Simplexvirus/immunology , Simplexvirus/isolation & purification , Stomatitis, Herpetic/transmission
10.
Invest Ophthalmol Vis Sci ; 27(6): 909-14, 1986 Jun.
Article in English | MEDLINE | ID: mdl-3011703

ABSTRACT

Herpes simplex virus type 1 (HSV)-host cell interactions were studied in fibroblasts from inbred mice by measuring virus replication, virus adsorption, infectious center formation, and single-cell virus production. BALB/c mouse embryo fibroblasts (MEF) produced more intracellular and extracellular virus than C57BL/6 MEF, with differences in virus production first appearing at 16 hr after inoculation. Virus yield in C57BL/6 cells peaked earlier (16 hr) and at a lower level than in BALB/c cells (20 hr). These results were explained by a difference in single-cell virus replication, rather than less efficient adsorption or the presence of cells that could not be infected. Host-related variation in the ability of infected cells to support HSV replication may account, in part, for differences in the severity of HSV ocular disease.


Subject(s)
Fibroblasts/microbiology , Herpesviridae/physiology , Mice, Inbred BALB C/genetics , Mice, Inbred C57BL/genetics , Virus Replication , Adsorption , Animals , Cell Separation , Cornea/cytology , Cornea/physiology , Disease Susceptibility , Herpesviridae Infections , Kidney/cytology , Kidney/physiology , Kinetics , Mice/embryology
11.
Invest Ophthalmol Vis Sci ; 27(1): 77-82, 1986 Jan.
Article in English | MEDLINE | ID: mdl-3000975

ABSTRACT

The spread of herpes simplex virus (HSV) through neural tissues was studied in three inbred mouse strains that differ in susceptibility to HSV stromal keratitis. The left eyes of BALB/c, C57BL/6, and DBA/2 mice were inoculated topically with HSV type 1. The optic and trigeminal nerves, trigeminal ganglia, and eyes were assayed for infectious virus on days 1, 2, 3, 4, 7, 9, 11 and 14 after inoculation. At 2-4 months post-inoculation, eyes and trigeminal ganglia were assayed for latent virus. Up to 7 days post-inoculation, infectious virus was present at a similar frequency in the inoculated eyes of mice from all three strains. The quantity of virus recovered, however, was mouse strain-dependent: DBA mice yielded the most virus; C57BL/6, the least. The frequency of virus recovery and the quantity of virus recovered from trigeminal nerves and ganglia also varied according to mouse strain. Infectious virus was recovered from the uninoculated right eye of some DBA and C57BL/6 mice 1 wk after inoculation. The overall incidence of latency differed among inbred mouse strains. However, in mice that developed ocular disease (blepharitis, dendritic keratitis, or stromal keratitis), there was no host strain-related difference in the incidence of latency. These results support the hypothesis that host genetic factors play a role in controlling HSV replication and the spread of virus to neural tissues after ocular HSV inoculation. This control may influence the development and severity of disease. However, once infection occurs, latency is established in both susceptible and resistant mouse strains.


Subject(s)
Herpes Simplex , Keratitis/etiology , Mice, Inbred Strains/immunology , Virus Activation , Animals , Chlorocebus aethiops , Disease Susceptibility , Eye/microbiology , Herpes Simplex/transmission , Humans , Keratitis/microbiology , Mice , Nerve Tissue/microbiology , Rabbits , Simplexvirus/isolation & purification
12.
Cancer Genet Cytogenet ; 3(2): 101-8, 1981 Mar.
Article in English | MEDLINE | ID: mdl-6268289

ABSTRACT

The G-banded karyotypes of both normal lymphocytes and Epstein-Barr virus (EBV)-transformed lymphocytes of cotton-topped marmosets (Saguinus oedipus) were examined. The marmoset lymphocytes and EBV-transformed lymphoblastoid cells had normal diploid chromosomes (2n = 46) with no specific cytogenic change associated with transformation in vitro. EBV-transformed marmoset lymphocytes expressed the cell surface markers of B lymphocytes and EB viral antigens.


Subject(s)
Antigens, Surface/analysis , Antigens, Viral/analysis , Cell Transformation, Viral , Chromosomes/analysis , Herpesvirus 4, Human/genetics , Animals , Callitrichinae , Cell Line , Female , Karyotyping , Lymphocytes , Male , Rosette Formation
13.
Lab Anim Sci ; 29(1): 53-60, 1979 Feb.
Article in English | MEDLINE | ID: mdl-220464

ABSTRACT

Minced salivary glands from seven white-lipped marmosets (Saguinus fuscicollis and Saguinus nigricollis) and one cotton-topped marmoset (Saguinus oedipus) were cocultivated with marmoset cell cultures. A viral agent, designated SSG, was isolated from two Saguinus fuscicollis. Slowly progressing foci of rounded, vacuolated, refractile cells were first observed at 40-43 days incubation. Electron microscopy revealed intranuclear herpesvirus nucleocapsids and intracytoplasmic and extracellular enveloped particles. Infected cells stained with hematoxylin and eosin contained eosinophilic intranuclear and cytoplasmic inclusion bodies. SSG could be passaged in cell cultures only using viable whole cells; infectious cell-free virus was not detected in either culture supernatants or cell lysates. SSG replicated in marmoset fibroblastic but not in marmoset epithelioid or human fibroblastic cell cultures. Plasma antibodies to SSG were detected by indirect immunofluorescence assays in 16 of 56 (28.6%) adult wild-caught marmosets but were absent in 40 colony-born, hand-reared marmosets. Antigenic cross-reactivity of SSG with a rhesus monkey (Macaca mulatta) cytomegalovirus (bidirectional) and with a human cytomegalovirus (unidirectional) was also demonstrated by indirect immunofluorescence assays. SSG was identified as a herpesvirus by morphology and was classified as a cytomegalovirus by its site of isolation, biologic properties in vitro, and antigenic characteristics.


Subject(s)
Callitrichinae/microbiology , Cytomegalovirus/isolation & purification , Salivary Glands/microbiology , Animals , Antibodies, Viral/analysis , Cytomegalovirus/growth & development , Cytomegalovirus/immunology , Female , Haplorhini , Lung/microbiology , Lung/ultrastructure , Macaca mulatta , Male
14.
J Infect Dis ; 132(5): 582-6, 1975 Nov.
Article in English | MEDLINE | ID: mdl-171324

ABSTRACT

Two adult and two neonatal cotton-topped marmosets and two neonatal white-lipped marmosets (Saguinus species) were inoculated with 10(7) plaque-forming units of cytomegalovirus (Colburn strain). No overt clinical disease developed in four marmosets during observation for eight months; one adult and one neonatal cotton-topped marmoset died from nonspecific causes 63 and 259 days after inoculation, respectively. By days 7-16 after inoculation, all marmosets developed plasma antibodies, which were detectable by neutralization and immunofluorescence assays (peak titers, 1:128-1:256 and 1:64-1:256, respectively). Attempts to isolate virus from whole blood, peripheral lymphocytes, oropharyngeal swabs, or vaginal swabs by cocultivation with permissive cell cultures were unsuccessful. Virus was recovered, however, by cocultivation from the kidney tissues of the adult marmoset that died. Immunosuppressive treatment with azathioprine resulted in a fourfold increase in antibody levels in plasma of two of three marmosets.


Subject(s)
Antibody Formation , Callitrichinae/immunology , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , Disease Models, Animal , Animals , Animals, Newborn/immunology , Antibody Formation/drug effects , Azathioprine/pharmacology , Cells, Cultured , Cytomegalovirus/isolation & purification , Cytomegalovirus Infections/microbiology , Haplorhini , Humans , Immunosuppression Therapy , In Vitro Techniques , Male , Species Specificity
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