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Biomedical subjects

W R Morton

Publications and source records attributed to W R Morton.

At least 55 records · Page 3Linked to original sources
PubMed1994

T-cell proliferation to subinfectious SIV correlates with lack of infection after challenge of macaques.

OBJECTIVES: To analyze correlates of protection in macaques exposed to SIV. METHODS: Peripheral blood mononuclear cells (PBMC) from macaques inoculated intrarectally with various dilutions of SIV were examined for their in vitro proliferative response to SIV envelope peptides and generation of SIV-specific antibodies. Some macaques previously exposed intravenously to subinfectious doses of SIV were subsequently challenged 16 months later with an infectious intrarectal dose of SIV. RESULTS: The viral-specific immune responses of macaques exposed to infectious doses of SIV were characterized by generation of antibodies and weak or undetectable T-cell-mediated responses. In contrast, macaques inoculated with doses of SIV below the threshold required for seroconversion and recovery of virus exhibited T-cell proliferation in response to SIV envelope synthetic peptides. The macaques that had previously been exposed to SIV resisted the subsequent virus challenge, whereas the naive macaques (never exposed to SIV) all became infected. CONCLUSIONS: The inability to productively infect macaques previously exposed to subinfectious doses of SIV suggests that a T-cell-mediated response may confer long-term protection against infection, and that AIDS vaccines should be designed to optimize the cellular arm of the immune response.

Amino Acid Sequence↗
PubMed1994

Intrarectal inoculation of macaques by the simian immunodeficiency virus, SIVmne E11S: CD4+ depletion and AIDS.

Macaca nemestrina and Macaca fascicularis were inoculated with various doses of a single-cell clone of SIVmne-infected HuT 78 cells (E11S) by both the intravenous and intrarectal routes. Animals inoculated intravenously at each dose seroconverted and virus was isolated from peripheral blood mononuclear cells, but only the high-dose intrarectally exposed macaques became viremic and seroconverted. However, some seronegative, virus isolation negative intrarectally inoculated macaques showed evidence of infection and disease.

Animals↗
PubMed1994

Persistence of simian immunodeficiency virus Mne variants upon transmission.

In macaques infected with a clone of simian immunodeficiency virus (SIV) Mne, viral variants consistently evolve multiple new potential glycosylation sites in the first variable region (V1) prior to the development of AIDS. In the present study, we asked whether viruses with these glycosylation sites persist when they are transmitted to a naive macaque. Variants that evolved after transmission to a recipient macaque were compared with virus that evolved in the donor, which had been infected by cloned SIV Mne. Upon transmission, the specific serine/threonine-rich motifs potentially encoding novel O-linked glycosylation site(s) in V1 were conserved in virus isolated from lymph node, spleen, and liver tissue from the recipient. There was some accumulation of changes in V3 of envelope in virus from the recipient, whereas changes in this region were not observed in virus from the donor macaque. Some variants detected in the tissue of the recipient at necropsy were most closely related to viruses present in the donor inoculum even though these particular variants were not detected early after infection in the recipient's peripheral blood mononuclear cells. Overall, virus with the predominant V1 sequences associated with progression to disease are transmitted to and persist in the recipient animal.

Amino Acid Sequence↗
PubMed1993

Acute infection of Macaca nemestrina by human immunodeficiency virus type 1.

The pigtail macaque (Macaca nemestrina) has a marked sensitivity to infection by simian immunodeficiency virus and human immunodeficiency virus type 2 (HIV-2). On this basis, we previously studied this species' susceptibility to HIV-1 and demonstrated infection in six macaques inoculated with either cell-associated HIV-1 or cell-free virus alone. This report expands upon our initial in vitro and in vivo findings. Five laboratory-adapted and one primary clinical strain of HIV-1 replicated in vitro in human and M. nemestrina peripheral blood mononuclear cells (PBMCs). Replication was enhanced when CD4+ purified PBMCs were infected and inhibited when PBMC cultures were treated with zidovudine. All six macaques demonstrated HIV-1 infection of PBMCs from 2 to 8 weeks after inoculation but nearly all PBMC cultures were negative from weeks 10 to 40. Polymerase chain reaction showed HIV-1 gag DNA in the PBMCs of all infected macaques, including times when the macaques were culture negative. All macaques developed and maintained antibodies to gag and envelope HIV-1 proteins from week 4 after inoculation through the period of observation. Five macaques showed neutralizing antibody. These findings suggest that M. nemestrina can be infected by cell-free and cell-associated HIV-1. This model of acute HIV-1 infection may help in evaluating the pathogenesis of HIV-1 replication and candidate vaccines and therapies.

Acute Disease↗
PubMed1992

Infection of Macaca nemestrina by human immunodeficiency virus type-1.

After observations that Macaca nemestrina were exceptionally susceptible to simian immunodeficiency virus and human immunodeficiency virus type-2 (HIV-2), studies of HIV-1 replication were initiated. Several strains of HIV-1, including a recent patient isolate, replicated in vitro in peripheral blood mononuclear cells (PBMCs) and in CD4-positive M. nemestrina lymphocytes in a CD4-dependent fashion. Eight animals were subsequently inoculated with either cell-associated or cell-free suspensions of HIV-1. All animals had HIV-1 isolated by cocultivation, had HIV-1 DNA in their PBMCs as shown by polymerase chain reaction, and experienced sustained seroconversion to a broad spectrum of HIV-1 proteins. Macaca nemestrina is an animal model of HIV-1 infections that provides opportunities for evaluating the pathogenesis of acute HIV-1 replication and candidate vaccines and therapies.

Animals↗
PubMed1992

Protection of macaques against SIV infection by subunit vaccines of SIV envelope glycoprotein gp160.

Simian immunodeficiency virus (SIV) is a primate lentivirus related to human immunodeficiency viruses and is an etiologic agent for acquired immunodeficiency syndrome (AIDS)-like diseases in macaques. To date, only inactivated whole virus vaccines have been shown to protect macaques against SIV infection. Protective immunity was elicited by recombinant subunit vaccines. Four Macaca fascicularis were immunized with recombinant vaccinia virus expressing SIVmne gp160 and were boosted with gp160 produced in baculovirus-infected cells. All four animals were protected against an intravenous challenge of the homologous virus at one to nine animal-infectious doses. These results indicate that immunization with viral envelope antigens alone is sufficient to elicit protective immunity against a primate immunodeficiency virus. The combination immunization regimen, similar to one now being evaluated in humans as candidate human immunodeficiency virus (HIV)-1 vaccines, appears to be an effective way to elicit such immune responses.

Animals↗
PubMed1992

Alterations in the course of experimental syphilis associated with concurrent simian immunodeficiency virus infection.

Case reports suggest that the course of syphilis is altered in patients infected with human immunodeficiency virus (HIV). To investigate this issue, a model of syphilis in rhesus macaques with and without simian immunodeficiency virus (SIV) was developed. After intradermal inoculation with Treponema pallidum, 2 SIV-infected monkeys had persistent ulcerative primary lesions and 1 developed secondary syphilis. Two SIV-uninfected controls developed transient nonulcerative primary lesions. Only the controls showed consistent VDRL antibody responses. In contrast, reciprocal antibody titers to T. pallidum detected by microhemagglutination were higher in SIV-infected animals (greater than or equal to 20,480) than controls (greater than or equal to 1280). All 4 animals developed a full range of T. pallidum antigen-specific antibodies shown by immunoblot and had similar peak lymphocyte proliferative responses to T. pallidum antigens. These results support the contention that retrovirus-induced immunodeficiency delays clearance of T. pallidum from sites of infection and may impair the humoral immune response to syphilis.

Animals↗
PubMed1992

Transmission of SIVMne from female to male Macaca nemestrina.

Three SIVMne-infected female pigtailed macaques (Macaca nemestrina) were mated with two SIV-negative males. The females exhibited signs of SAIDS and SIVMne was readily isolated from peripheral blood mononuclear cells (PBMC). Both males became infected with SIVMne, developed SAIDS, and died. This is the first documented case of the transmission of SIVMne between adult macaques housed together. Although transmission through scratching or biting cannot be ruled out, heterosexual transmission appears the most likely mode of SIVMne transmission in this study.

Animals↗
PubMed1991

Variation in simian immunodeficiency virus env is confined to V1 and V4 during progression to simian AIDS.

We have monitored changes in the simian immunodeficiency virus (SIV) envelope (env) gene in two macaques which developed AIDS after inoculation with a molecular clone of SIV. As the animals progressed to AIDS, selection occurred for viruses with variation in two discrete regions (V1 and V4) but not for viruses with changes in the region of SIV env that corresponds to the immunodominant, V3 loop of human immunodeficiency virus. Within the highly variable domains, the vast majority of nucleotide changes encoded an amino acid change (98%), suggesting that these envelope variants had evolved as a result of phenotypic selection. Analysis of the biological properties of these variants, which have been selected for in the host, may be useful in defining the mechanisms underlying viral persistence and progression to simian AIDS.

Amino Acid Sequence↗
PubMed1991

Maternal-fetal transmission of SIV in macaques: disseminated adenovirus infection in an offspring with congenital SIV infection.

To develop a nonhuman primate model for maternal-fetal transmission of HIV infection, we have inoculated pregnant Macaca nemestrina with uncloned SIVMne. Three animals inoculated during the third trimester delivered healthy infants. One of the three infants, a male born 31 days after the mother was inoculated with SIV, became virus-positive but failed to produce SIV-specific antibody and died with overt simian immunodeficiency and disseminated adenovirus (SV20) infection at age six and one-half months. SIV and adenovirus antigen could be demonstrated by immunohistochemical methods in multiple organ systems.

Adenoviridae Infections↗
PubMed1990

Experimental cryptosporidiosis in a primate model.

Cryptosporidium causes a disease in infant macaques that is clinically, histologically, and microbiologically indistinguishable from that seen in young children. A reproducible experimental model of cryptosporidiosis has been developed in pigtailed macaques (Macaca nemestrina) and used to studied the infectious dose of oocysts and the effect of inoculum size on severity of disease. Inoculation with either 2 x 10(5) or 10 oocysts via nasogastric tube resulted in clinical enteritis and the fecal passage of large numbers of cryptosporidial oocysts in all four primates studied. The size of the inoculum had no apparent effect on the severity or duration of disease. Rechallenge 2 weeks after resolution of the primary infection demonstrated partial acquired immunity. The small inoculum size coupled with the passage of large numbers of oocysts contributes to the highly contagious nature of cryptosporidiosis among captive primates and may be relevant to the epidemiology and control of cryptosporidiosis in humans.

Animals↗
PubMed1990

CD4 and CD8 T cells from SIV-infected macaques have defective signaling responses after perturbation of either CD3 or CD2 receptors.

Single-cell clones, designated E11S, C11R, and A1S, were obtained from the HuT-78 T cell line persistently infected with an isolate of Simian immunodeficiency virus (SIV), SIV/Mne. The infected clones, unlike uncloned uninfected HuT-78 cells, no longer expressed the CD4 marker and, after their CD3 receptors were cross-linked, had dramatically reduced intracellular free calcium ([Ca2+]i) responses. In one clone, E11S, the unresponsiveness was not limited to the inositol phospholipid pathway of signaling since a reduction in CD3-mediated activation of protein tyrosine kinase-dependent phosphorylation also was evident in this SIV-infected clone. These results led us to test whether T lymphocytes from animals infected with SIV had defective [Ca2+]i responses prior to detectable changes in CD4 levels or lymphadenopathy. The [Ca2+]i responses to both CD3 mAb and CD2 mAb were 10-50% less in T cells from Walter Reed stage 2 animals than in healthy controls. This anergy was more pronounced in chronically infected animals progressing to Walter Reed stage 3/4. The responses of these animals could not be augmented even when combinations of CD3 and CD4 mAb were used. Both CD4+CD44lo T cells, which are not infected with SIV, and the CD4+CD44hi T cell subset, previously shown to be the reservoir of SIV infection in blood, had pronounced defective responses to CD3 mAb. Similarly, both CD4+ and CD8+ T cells were consistently unresponsive in chronically infected animals, again implying that an indirect mechanism, rather than SIV infection per se, may be responsible for this immune dysfunction.

Animals↗
PubMed1990

Experimental infection of pig-tailed macaques (Macaca nemestrina) with Campylobacter cinaedi and Campylobacter fennelliae.

Campylobacter cinaedi and C. fennelliae have been associated with proctocolitis, bacteremia, and asymptomatic rectal infection, primarily in homosexual men. To more directly assess the pathogenic role of these organisms, we studied their disease-producing potential in 12- to 25-day-old pig-tailed macaques (Macaca nemestrina). Four infant monkeys were challenged with 10(8) to 10(9) C. cinaedi, three were challenged with C. fennelliae, two were challenged with C. jejuni, and one received no microorganisms. Watery or loose stools without associated fever or fecal leukocytes developed 3 to 7 days postinoculation in all of the animals given C. cinaedi, C. fennelliae, and C. jejuni, but not in the control animal. Stool cultures were simultaneously positive and remained so in the animals challenged with C. cinaedi or C. fennelliae for 3 weeks after inoculation despite the resolution of clinical illness. All of the animals challenged with C. cinaedi and C. fennelliae became bacteremic, and three had clinical evidence of septicemia. Histopathologic evaluation of rectal biopsies (five animals) and necropsy (one animal) showed no evidence of mucosal disruption. Specific immunoglobulin M and immunoglobulin G antibody responses occurred in all of the animals challenged with C. cinaedi and C. fennelliae, as determined by enzyme-linked immunosorbent assay and immunoblotting. We conclude that C. cinaedi and C. fennelliae consistently produce a diarrheal illness accompanied by bacteremia and followed by prolonged gastrointestinal colonization in M. nemestrina.

Animals↗
PubMed1990

Clinical and parasitologic aspects of cryptosporidiosis in nonhuman primates.

Eighty-one cases of acute cryptosporidiosis were diagnosed among 157 (52%) infant primates, predominantly Macaca nemestrina, housed in the nursery unit of the Washington Regional Primate Research Center. The mean age at onset of oocyst passage was 38 +/- 25 days. The outbreak was confined to the nursery and no cases were detected among juvenile or adult primates housed in other rooms within the colony. All but one animal manifested symptoms of enteric infection, including severe diarrhea and dehydration. Infected animals excreted oocysts for a mean of 36 days (range 7-78 days). No reinfections occurred. Cryptosporidium was the second most common enteric pathogen detected in the population, after Campylobacter jejuni. The risk of infection was related to the length of time the animal was housed in the nursery and to social interaction with other monkeys. These findings are relevant to the understanding of the epidemiology of cryptosporidiosis among human infants and children in environments with close social interactions and minimal learned personal hygiene practices.

Animals↗
PubMed1990

Maternal transmission of type D simian retrovirus (SRV-2) in pigtailed macaques.

Pregnant macaques were used as a natural model for maternal-infant transmission of SRV-2 retrovirus. Fifty-one pregnant females were placed into one of four virus/antibody groups. Nonviremic mothers produced 100% virus-negative offspring at birth. In contrast, viremic mothers produced offspring which were 17% virus-negative and 83% virus-positive at birth. SRV-2 infection occurred principally in utero by the transplacental route. Infants born to viremic mothers exhibited low birth weight, prematurity, high perinatal death, and increased incidence of SAIDS.

Animals↗
PubMed1990

Inoculation of Macaca fascicularis with simian immunodeficiency virus, SIVmne immunologic, serologic, and pathologic changes.

Previous studies had tested the susceptibility of two macaque species, Macaca nemestrina and M. mulatta, to infection with the primate lymphotropic lentivirus SIVmne. In this report we describe the results obtained after infecting eleven M. fascicularis with SIVmne. Six of the animals had previously been immunized with a recombinant vaccinia virus expressing the envelope gene of HIV-1. All eleven animals became seropositive. To date ten animals have died 43 to 155 weeks post infection of an AIDS-like disease.

Animals↗