Influences of season and age on maturation in vitro of rhesus monkey oocytes.
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Oocytes obtained from antral follicles of adult and adolescent rhesus monkeys during the annual breeding season extruded polar bodies in vitro at significantly higher rates (50--60%) than oocytes from animals of similar age during the non-breeding season ((20--30%) or from infant and prepubertal females at any time of the year (20--30%). The proportion of oocytes degenerating in culture was greatest in groups where maturation was highest. (+info)
Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus.
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Despite substantial differences between species in the organization and elaboration of the cortical dopamine innervation, little is known about the pharmacological response of cortical or striatal sites to antipsychotic medications in nonhuman primates. To examine this issue, rhesus monkeys were chronically implanted with guide cannulae directed at the principal sulcus, medial prefrontal cortex, premotor cortex, and caudate nucleus. Alterations in dopamine release in these discrete brain regions were measured in response to administration of clozapine or haloperidol. Clozapine produced significant and long-lasting increases in dopamine release in the principal sulcus, and to a lesser extent, in the caudate nucleus. Haloperidol did not produce a consistent effect on dopamine release in the principal sulcus, although it increased dopamine release in the caudate. Clozapine's preferential augmentation of dopamine release in the dorsolateral prefrontal cortex supports the idea that clozapine exerts its therapeutic effects in part by increasing cortical dopamine neurotransmission. (+info)
Differential tumor necrosis factor alpha production in simian immunodeficiency virus-infected rhesus macaques coinfected with Mycobacterium avium.
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Mycobacterium avium infections are the third most common opportunistic infection in patients with AIDS. Simian immunodeficiency virus (SIV)-infected rhesus macaques naturally acquire M. avium infections from the environment, and their clinical symptoms are similar to those observed in AIDS patients. We characterized concurrent infection with SIV and M. avium in monkeys on the basis of the growth of the bacteria in macrophages (Mphis) from rhesus macaques and the ability of M. avium to induce SIV replication and tumor necrosis factor alpha (TNF-alpha) production. The simian M. avium isolate grew significantly better than did an isolate from an AIDS patient or a chicken isolate (P = .001); it induced significantly more TNF-alpha production in Mphis from SIV-positive and SIV-negative monkeys than did the isolate from an AIDS patient (P = .013). No significant increase in SIV replication was seen in the M. avium isolates, and no correlation was found between increased SIV replication and increased TNF-alpha production. In addition, Mphis from monkeys infected with M. avium during late-stage SIV disease produced less TNF-alpha when stimulated with virulent M. avium. (+info)
High major histocompatibility complex-unrestricted lysis of simian immunodeficiency virus envelope-expressing cells predisposes macaques to rapid AIDS progression.
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Before the development of virus-specific immune responses, peripheral blood mononuclear cells (PBMC) from uninfected rhesus monkeys and human beings have the capacity to lyse target cells expressing simian immunodeficiency virus (SIV) or human immunodeficiency virus-1 (HIV) envelope (gp130 and gp120) antigens. Lysis by naive effector cells does not require major histocompatibility complex (MHC)-restricted antigen presentation, is equally effective for allogeneic and xenogeneic targets, and is designated MHC-unrestricted (UR) lysis. UR lysis is not sensitive to EGTA and does not require de novo RNA or protein synthesis. Several kinds of envelope-expressing targets, including cells that poorly express MHC class I antigens, can be lysed. CD4(+) effectors are responsible for most of the lytic activity. High lysis is correlated with high expression of HIV or SIV envelope, specifically, the central one-third of the gp130 molecule, and lysis is completely inhibited by a monoclonal antibody against envelope. Our work extends observations of human lymphocytes expressing HIV gp120 to the SIV/rhesus monkey model for AIDS. Additionally, we address the relevance of UR lysis in vivo. A survey of PBMC from 56 uninfected rhesus monkeys indicates that 59% of the individuals had peak UR lytic activity above 15% specific lysis. Eleven of these monkeys were subsequently infected with SIV. Animals with UR lytic activity above 15% specific lysis were predisposed to more rapid disease progression than animals with low UR lytic activity, suggesting a strong correlation between this form of innate immunity and disease progression to AIDS. (+info)
Gene therapy vectors based on adeno-associated virus type 1.
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The complete sequence of adeno-associated virus type 1 (AAV-1) was defined. Its genome of 4,718 nucleotides demonstrates high homology with those of other AAV serotypes, including AAV-6, which appears to have arisen from homologous recombination between AAV-1 and AAV-2. Analysis of sera from nonhuman and human primates for neutralizing antibodies (NAB) against AAV-1 and AAV-2 revealed the following. (i) NAB to AAV-1 are more common than NAB to AAV-2 in nonhuman primates, while the reverse is true in humans; and (ii) sera from 36% of nonhuman primates neutralized AAV-1 but not AAV-2, while sera from 8% of humans neutralized AAV-2 but not AAV-1. An infectious clone of AAV-1 was isolated from a replicated monomer form, and vectors were created with AAV-2 inverted terminal repeats and AAV-1 Rep and Cap functions. Both AAV-1- and AAV-2-based vectors transduced murine liver and muscle in vivo; AAV-1 was more efficient for muscle, while AAV-2 transduced liver more efficiently. Strong NAB responses were detected for each vector administered to murine skeletal muscle; these responses prevented readministration of the same serotype but did not substantially cross-neutralize the other serotype. Similar results were observed in the context of liver-directed gene transfer, except for a significant, but incomplete, neutralization of AAV-1 from a previous treatment with AAV-2. Vectors based on AAV-1 may be preferred in some applications of human gene therapy. (+info)
Protection of Macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies.
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The role of antibody in protection against human immunodeficiency virus (HIV-1) has been difficult to study in animal models because most primary HIV-1 strains do not infect nonhuman primates. Using a chimeric simian/human immunodeficiency virus (SHIV) based on the envelope of a primary isolate (HIV-89.6), we performed passive-transfer experiments in rhesus macaques to study the role of anti-envelope antibodies in protection. Based on prior in vitro data showing neutralization synergy by antibody combinations, we evaluated HIV immune globulin (HIVIG), and human monoclonal antibodies (MAbs) 2F5 and 2G12 given alone, compared with the double combination 2F5/2G12 and the triple combination HIVIG/2F5/2G12. Antibodies were administered 24 h prior to intravenous challenge with the pathogenic SHIV-89.6PD. Six control monkeys displayed high plasma viremia, rapid CD4(+)-cell decline, and clinical AIDS within 14 weeks. Of six animals given HIVIG/2F5/2G12, three were completely protected; the remaining three animals became SHIV infected but displayed reduced plasma viremia and near normal CD4(+)-cell counts. One of three monkeys given 2F5/2G12 exhibited only transient evidence of infection; the other two had marked reductions in viral load. All monkeys that received HIVIG, 2F5, or 2G12 alone became infected and developed high-level plasma viremia. However, compared to controls, monkeys that received HIVIG or MAb 2G12 displayed a less profound drop in CD4(+) T cells and a more benign clinical course. These data indicate a general correlation between in vitro neutralization and protection and suggest that a vaccine that elicits neutralizing antibody should have a protective effect against HIV-1 infection or disease. (+info)
Immunization with a live, attenuated simian immunodeficiency virus vaccine leads to restriction of viral diversity in Rhesus macaques not protected from pathogenic challenge.
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Rhesus macaques immunized with simian immunodeficiency virus SIVmac239Deltanef but not protected from SIVmac251 challenge were studied to determine the genetic and biological characteristics of the breakthrough viruses. Assessment of SIV genetic diversity (env V1-V2) revealed a reduction in the number of viral species in the immunized, unprotected macaques, compared to the number in nonimmunized controls. However, no evidence for selection of a specific V1-V2 genotype was observed, and biologically cloned isolates from the animals with breakthrough virus were similar with respect to replication kinetics and coreceptor use in vitro. (+info)
Type 1 CD4(+) T-cell help is required for induction of antipeptide multispecific cytotoxic T lymphocytes by a lipopeptidic vaccine in rhesus macaques.
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We have optimized the induction of antiviral cytotoxic T lymphocytes (CTL) in rhesus macaques by a lipopeptide vaccine containing seven peptides from simian immunodeficiency virus (SIV) Nef and Gag proteins and a strong T-helper peptide from tetanus toxoid (TT) that is promiscuous in humans (peptide TT 830-846). Two of the eight immunized macaques showed T-helper (Th) cell proliferation and a specific synthesis of gamma interferon in response to TT 830-846 peptide. They also showed multispecific cytotoxic activity against three to five of the immunizing SIV peptides. These results show the importance of a strong specific type 1 Th response for inducing a multispecific CTL response in vivo, which is essential for the development of an anti-human immunodeficiency virus vaccine. (+info)