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Biomedical subjects

M B Gardner

Publications and source records attributed to M B Gardner.

At least 73 records · Page 4Linked to original sources

Cellular immune response of SIV-infected rhesus macaques.

Optimal conditions for the assessment of T cell proliferation and cytolytic T lymphocyte (CTL) responses specific for primate lentivirus were established. CTL and T cell proliferative responses were demonstrated as early as two weeks post-infection. Although the majority of CTL were CD8+, MHC class I-restricted, this study demonstrated CD4+, MHC class II-restricted CTL. Experiments also demonstrated that CTL were CD16 negative. Target cell generation could be blocked with CD4 mAb specific for the SIV binding site.

Animals↗

Feline immunodeficiency virus and feline leukemia virus infections and their relationships to lymphoid malignancies in cats: a retrospective study (1968-1988).

Sera from 353 cats with naturally occurring feline leukemia virus (FeLV) infection were collected in Boston, Los Angeles, New York City, and Seattle between 1968 and 1988. These sera were retrospectively assayed by enzyme-linked immunosorbent assay for antibodies to feline immunodeficiency virus (FIV). Fifty-one (14.4%) of the FeLV-positive sera had antibodies to FIV, indicating dual oncovirus and lentivirus infections. FIV infections were confirmed by Western blot analysis, antibodies against the 15 and 27 kDa proteins being used as definitive markers. FIV infection was diagnosed in one cat sampled in 1968 and in eight other cats sampled before 1975 in New York City. Illnesses exhibited by coinfected cats were similar to those of cats infected with FeLV only. Two unrelated cats with multicentric fibrosarcomas were found to be simultaneously infected with FIV, FeLV, and feline sarcoma virus. FIV was less contagious than FeLV in 73 cats residing in an exposure household between 1977 and 1980 as determined by evaluation of sera collected sequentially. In this household, 15 resident cats became FeLV infected whereas no cats contracted FIV infection. Comparison of serologic results from 53 cats with leukemia/lymphoma and matched controls confirmed a strong correlation between FeLV viremia and leukemia/lymphoma. A significant correlation between FIV infection and lymphoproliferative malignancies was also found independent of FeLV infection.

Animals↗

Immunohistochemical localization of type D retrovirus serotype 1 in the digestive tract of rhesus monkeys with simian AIDS.

Type D retrovirus infection of rhesus macaques (Macaca mulatta) shares many features with AIDS in man including gastrointestinal signs such as chronic diarrhea and wasting. In some humans and macaques afflicted with these signs and symptoms no etiology can be established. In this study immunohistochemistry was employed to localize D/1/California in the digestive tract of ten animals with simian AIDS. This revealed that both epithelial and lymphoid cells of the digestive tract are commonly infected by this immunosuppressive type D retrovirus.

Animals↗

SIV infection of macaques: a model for AIDS vaccine development.

The SIV macaque model is an excellent surrogate for SIV infection of humans. Genital mucosal transmission of SIV presents the opportunity for testing the effectiveness of spermicides, pharmacologic agents and vaccines in preventing the heterosexual transmission of HIV. Because the incubation period is usually shorter and the disease tempo more rapid than seen with HIV infection, the endpoint for therapeutic, prophylaxis and vaccine trials can be reached sooner in the monkey model. Initial vaccine experiments using inactivated whole SIV mac did not protect rhesus macaques against IV or genital mucosal challenge with a moderately high dose of homologous live virus but did appear to delay disease in the IV challenge group. Similarly, a modified live SIVmac immunogen also failed to protect rhesus monkeys against IV challenge with live virus but did delay disease. It appears, therefore, that a strong immediate immune response to SIVmac, whether naturally or artificially induced can reduce the level of viremia and delay the onset of clinical SAIDS. We believe that these inactivated whole virus and modified live virus approaches are worth pursuing further and they may guide us towards an eventual effective vaccine for AIDS.

Acquired Immunodeficiency Syndrome↗

Animal models of AIDS.

Animal models of AIDS are essential for understanding the pathogenesis of retrovirus-induced immune deficiency and encephalopathy and for development and testing of new therapies and vaccines. AIDS and related disorders are etiologically linked to members of the lentivirus subfamily of retroviruses; these lymphocytopathic lentiviruses are designated human immuno-deficiency virus type 1 (HIV-1) and human immuno-deficiency virus type 2 (HIV-2). The only animals susceptible to experimental HIV-1 infection are the chimpanzee, gibbon ape, and rabbit but AIDS-like disease has not yet been reported in these species. Macaques can be persistently infected with some strains of HIV-2 but no AIDS-like disease has resulted. It is not yet clear how suitable HIV-infected SCID-hu mice will be as a model for AIDS. Several subfamilies of naturally occurring cytopathic retroviruses cause immune suppression, including fatal immunodeficiency syndromes in chickens, mice, cats, and monkeys. Domestic cats suffer immunosuppression from both an onco-virus, feline leukemia virus, and a member of the lentivirus subfamily, feline immunodeficiency virus (FIV). Asian macaques are susceptible to fatal simian AIDS from a type D retrovirus, indigenous in macaques, and from a lentivirus, simian immunodeficiency virus (SIV), which is indigenous to healthy African monkeys. SIV is the animal lentivirus most closely related to HIV. Of these animal models, the lentivirus infections of cats (FIV) and macaques (SIV) appear to bear the closest similarity in their pathogenesis to HIV infection and AIDS. This review will summarize these various animal model systems for AIDS and illustrate their usefulness for antiviral therapy and vaccinology.

Acquired Immunodeficiency Syndrome↗

Characterization of simian immunodeficiency virus-specific T-cell-mediated cytotoxic response of infected rhesus macaques.

Four juvenile rhesus macaques were infected with simian immunodeficiency virus (SIV)MAC-Freshly isolated peripheral blood mononuclear cells (PBMC) from these SIVMAC-infected and from uninfected control macaques were assessed for cytotoxic T-lymphocyte (CTL) activity monthly for 7 consecutive months, beginning 2 months after infection. Target cells consisted of major histocompatibility complex (MHC) haploidentical parental PBMC which were stimulated with mitogen and then pulsed with heat-killed SIVMAC. CTL activity was demonstrated on all four infected animals. The effector cells are T cells which mediate cytotoxicity against SIVMAC-pulsed target cells in an MHC-restricted manner. Furthermore, the cytotoxicity is virus specific and predominantly, if not exclusively, mediated by CD8+ T cells; it is also MHC class-I restricted. Incubation of target cells with leupeptin prior to the cytotoxic assay inhibited target cell generation, suggesting that viral antigens are processed via an endocytic pathway.

Animals↗

Asymptomatic infection of the central nervous system by the macaque immunosuppressive type D retrovirus, SRV-1.

The aetiological agent of spontaneously occurring simian acquired immune deficiency syndrome (SAIDS) in rhesus monkeys (Macaca mulatta) at the California Primate Research Center is a type D retrovirus designated SAIDS retrovirus serotype 1 (SRV-1). SRV-1 DNA and RNA have previously been detected in the brains of rhesus monkeys with SAIDS in the absence of viral antigen or neuropathological lesions. In this study we further define the relationship between SRV-1 and the central nervous system (CNS) in rhesus monkeys by examining the CNS for infectious SRV-1, viral antigen and anti-SRV-1 antibodies. In addition, cerebrospinal fluid (CSF) was assayed for alterations in IgG and albumin levels, IgG/albumin ratios and cell count in comparison to uninfected control animals. No differences in CSF parameters were detected between infected and uninfected animals except for the presence of infectious SRV-1 which was isolated from the CSF from 13 out of 19 (68%) viraemic rhesus monkeys. The probable source of this virus was the choroid plexus, where approximately 1 in 1000 surface epithelial cells were found to contain viral antigen by immunohistochemistry. Antibodies against SRV-1 were not detected in the CSF even when present in the serum. Neither infectious virus nor viral antigen were found in the brain parenchyma of any animal examined. Thus infection of the CNS by SRV-1 appears to be subclinical without an intrathecal immune response. This may be related to the apparent restriction of productive infection in the CNS to cells of the choroid plexus.

Albumins↗

Mucosal epithelial cells and Langerhans cells are targets for infection by the immunosuppressive type D retrovirus simian AIDS retrovirus serotype 1.

Simian acquired immune deficiency syndrome (SAIDS) caused by the type D retrovirus SRV-1 results in opportunistic infections and a spectrum of oral lesions similar to those seen in humans with AIDS. To better understand the pathogenesis of these oral lesions we have retrospectively examined the oral mucosa from ten rhesus monkeys that died with SAIDS and prospectively examined the oral mucosa of ten additional animals inoculated with SRV-1 to determine at what time, and in what cells SRV-1 infection of the oral mucosa occurs. Using single and double label immunohistologic techniques, and electron microscopy we detected SRV-1 in clusters of oral epithelial cells and rare Langerhans cells as early as 1 month postinoculation.

Animals↗

Rhesus macaques inoculated with molecularly cloned simian immunodeficiency virus.

We have isolated a biologically active molecular clone of simian immunodeficiency virus (SIV), SIVmac 1A11, originally obtained from a rhesus macaque at the New England Regional Primate Research Center. Virus derived from cells transfected with this clone is cytopathic for rhesus peripheral blood mononuclear cells, replicates in cultures of rhesus macrophages, and infects rhesus macaques when inoculated intravenously. Six macaques inoculated with SIVmac 1A11 all became infected and produced antibodies to viral envelope glycoproteins that neutralized virus. Antibodies to viral core proteins were detected in only one animal. No clinical signs of disease were observed throughout 7 months postinoculation.

Animals↗

Postexposure immunotherapy of simian immunodeficiency virus (SIV) infected rhesus with an SIV immunogen.

An inactivated whole simian immunodeficiency virus (SIV) immunogen given to healthy, seropositive rhesus macaques 4 months after infection had no effect on the humoral immune response to SIV, the presence of antigenemia, cell-associated viremia, or disease course. Further immunotherapeutic trials in this highly susceptible animal model should be carried out sooner after exposure, before significant loss of CD4 cells has occurred. The SIV infected macaque model will continue to serve an essential role in development and testing of anti-AIDS drugs and immunogens.

Animals↗

Preliminary molecular characterization of a human immunodeficiency virus (HIV-I) associated with neuropathology.

A human immunodeficiency virus (HIV-I) was isolated from the brain of a patient with progressive dementia but no obvious immunosuppression. This isolate, designated as HIV-IBR, was molecularly cloned and sequenced, and its long terminal repeat (LTR) and envelope sequences were compared with those of other HIV isolates not uniquely associated with dementia. The HIV-IBR LTR showed marked homology with the LTR sequences of the other HIV-I isolates. The predicted amino acid sequence of the external glycoprotein (gp120) of HIV-IBR revealed a pattern of conserved and variable regions similar to that of other HIV isolates. The sequence of the transmembrane portion of envelope, gp 41, was highly homologous to the counterpart region of other isolates. Further analysis is required to determine whether specific sequence variation can account for neurological manifestations of HIV-IBR infection.

Acquired Immunodeficiency Syndrome↗

Neurotropic retroviruses of wild mice and macaques.

A neurotropic retrovirus causes a naturally occurring lower-limb paralysis in wild mice, characterized by a noninflammatory spongiform change located primarily in the lower spinal cord. The causative agent is an ecotropic murine leukemia virus, unique to certain wild mice in southern California. The disease is readily transmitted to newborn susceptible laboratory mice. The paralytogenic property is attributed to direct viral injury to motor neurons and glial cells and is associated with unique amino acids in the murine leukemia virus envelope gp70. This murine model may have relevance to both human T-lymphotropic virus type I, and human immunodeficiency virus infection of human brain. It presents a practical model for testing antiviral agents aimed at retrovirus infection of the mammalian central nervous system. Simian acquired immunodeficiency syndrome type D retrovirus causes a silent infection of the brain in infected macaques. Viral nucleic acids are detected in the brain parenchyma in the absence of viral antigen, neurological symptoms, and neuropathology. Infected choroid plexus epithelial cells are the source of cell-free virus in the cerebrospinal fluid of viremic monkeys. This model adds yet another example of retroviral infection of the central nervous system and points to the choroid plexus as a potential source of infectious virus.

Animals↗

Simian retrovirus D serogroup 1 has a broad cellular tropism for lymphoid and nonlymphoid cells.

Simian acquired immunodeficiency syndrome is a fatal immunosuppressive disease caused by type D retroviruses such as simian acquired immunodeficiency syndrome retrovirus type 1 (SRV-1). The disease is characterized by generalized lymphadenopathy, opportunistic infections, and lymphoid depletion with defects in both humoral and cell-mediated immunity. To understand how SRV-1 infection relates to the immune defect, we studied in vivo-infected lymphocytes from SRV-1-positive macaques with and without clinical signs of immunosuppressive disease. B and T helper/inducer and T suppressor/cytotoxic lymphocytes were purified by panning or by flow cytometry. Neutrophils were purified by dextran sedimentation, and platelets were purified by low-speed centrifugation. In vitro infection studies were also done with HUT78, H9, K562, rhesus lung fibroblast, rhesus monkey kidney, and bat lung cells. SRV-1 in lymphocytes or culture supernatants was detected by the induction of syncytia in cocultivated Raji cells and was confirmed by immunofluorescence, electron microscopy, or reverse transcriptase assay. We found that B and T helper/inducer lymphocytes were infected in all animals tested. The number of infected T suppressor/cytotoxic cells was generally lower than that of the other cell subsets, and not all animals in this subset had SRV-1 infections. All other cells exposed in vitro to SRV-1, except bat lung cells, were able to be infected. These findings show that SRV-1 has a broad cell tropism for lymphoid and nonlymphoid cell types.

Acquired Immunodeficiency Syndrome↗

Distribution of a macaque immunosuppressive type D retrovirus in neural, lymphoid, and salivary tissues.

Simian acquired immune deficiency syndrome (SAIDS) in rhesus macaques (Macaca mulatta) at the California Primate Research Center is caused by a type D retrovirus designated SAIDS retrovirus serotype 1 (SRV-1). This syndrome is characterized by profound immunosuppression and death associated with opportunistic infections. Neurologic signs and lesions have not been described as part of this syndrome. The distribution of SRV-1 in the salivary glands, lymph nodes, spleens, thymuses, and brains of eight virus-infected rhesus macaques was examined by immunohistochemistry. Electron microscopy, in situ RNA hybridization, and Southern blot hybridization were also performed on selected tissues to detect viral particles, RNA, and DNA, respectively. In seven of eight SRV-1-infected animals, the transmembrane envelope glycoprotein (gp20) of SRV-1 was present in three or more tissues, but never in the brain. In the remaining animal, no viral antigen was detected in any tissue. In this same group of animals, viral nucleic acid was detected in the lymph nodes of six of six animals by Southern blot hybridization, in the salivary glands of two of five animals by both Southern blot and in situ hybridizations, and, surprisingly, in the brains of three of three animals by Southern blot and of three of five animals by in situ hybridization, including the one animal in which viral gp20 was undetectable. None of these animals had neurologic signs or lesions. The detection of viral nucleic acid in the absence of viral antigen in the brain suggests latent SRV-1 infection of the central nervous system.

Acquired Immunodeficiency Syndrome↗