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PubMed1999

Ebola virus outbreak among wild chimpanzees living in a rain forest of Côte d'Ivoire.

An outbreak of Ebola in nature is described for the first time. During a few weeks in November 1994, approximately 25% of 43 members of a wild chimpanzee community disappeared or were found dead in the Taï National Park, Côte d'Ivoire. A retrospective cohort study was done on the chimpanzee community. Laboratory procedures included histology, immunohistochemistry, bacteriology, and serology. Ebola-specific immunohistochemical staining was positive for autopsy tissue sections from 1 chimpanzee. Demographic, epidemiologic, and ecologic investigations were compatible with a point-source epidemic. Contact activities associated with a case (e.g., touching dead bodies or grooming) did not constitute significant risk factors, whereas consumption of meat did. The relative risk of meat consumption was 5.2 (95% confidence interval, 1.3-21.1). A similar outbreak occurred in November 1992 among the same community. A high mortality rate among apes tends to indicate that they are not the reservoir for the disease causing the illness. These points will have to be investigated by additional studies.

Animals↗
PubMed2004

Characterization of a family of chimpanzee adenoviruses and development of molecular clones for gene transfer vectors.

The high prevalence of preexisting immunity to the commonly used adenoviral vectors, as well as the requirement for readministration of vector for multiple therapeutic applications, necessitates the development of a panel of immunologically distinct adenoviral vectors against which neutralizing antibodies are rare in human populations. We have completely sequenced three chimpanzee-derived adenoviruses, Pan 5, Pan 6, and Pan 7, and have molecularly cloned E1-deleted vector genomes from each as bacterial plasmids. All the E1-deleted vectors were grown to high titer in HEK 293 cells. Neutralizing antibodies to the chimpanzee adenoviral vectors were not detected in serum samples from human subjects. In vitro cross-neutralization using rabbit antisera and in vivo readministration experiments in mice demonstrated that antibodies against Pan 5, Pan 7, or Pan 9 cross-neutralize one another but do not neutralize Pan 6. These results indicate that chimpanzee adenoviral vectors may be useful as vaccines or gene therapy vectors in human populations and should allow applications that require multiple vector administrations.

Adenoviridae↗
PubMed1989

Cell-mediated immune proliferative responses to HIV-1 of chimpanzees vaccinated with different vaccinia recombinant viruses.

The only animal that can be reproducibly infected with HIV, and that thus provides an experimental system for testing the effectiveness of prototype vaccines, is the chimpanzee. We compared proliferative responses to HIV and to vaccinia virus (VV) antigens of lymphocytes taken at various times from chimpanzees vaccinated with recombinant VV expressing different HIV genes. Animals were immunized with the original VV strain, as control, or with constructs expressing gp160 (VV160) given exclusively or in combination with one or two other constructs producing p25 (VV25), F/3'-orf (VVF), or the human interleukin-2 (IL-2) gene, which was included in an attempt to amplify immune responses. Irrespective of the HIV gene utilized, lymphocyte proliferation to HIV was usually weak and rapidly decreased after each inoculation, contrasting with strong and sustained responses to VV. Lack of adequate recall reactivity after challenge with fixed autologous lymphocytes expressing VV-produced HIV antigens indicated that vaccination resulted only in low levels of HIV-specific memory cell priming. The use of IL-2-producing VV did not lead to increased responsiveness. Reactivity to soluble purified gp160, but not to p25, could be detected in PBL from animals that had received both VV160 and VV25, while immunization with VVF resulted in a significant response to this protein in one of two animals. The transient nature of T cell reactivity to HIV might explain why, in similar studies, chimpanzees were not protected from infection with live HIV.

Animals↗
PubMed1993

Long-term observations of human immunodeficiency virus-infected chimpanzees.

Twenty-seven chimpanzees inoculated with material presumed to contain human immunodeficiency virus (HIV) between June 1983 and February 1985 were studied. The animals were examined on four to six occasions between 1989 and 1992 for serologic, virologic, hematologic, immunophenotypic, as well as clinical signs of HIV infection and compared to five uninfected control animals. The 19 animals that had seroconverted within 244 days of inoculation remained antibody positive, whereas those that did not seroconvert within 244 days of inoculation remained antibody negative 6 to 8 years later. HIV antigen was demonstrated at least once in lymphocyte cultures from 12 of the 19 antibody positive chimpanzees during this period. Nested polymerase chain reaction amplified proviral DNA in lymphocytes from 14 of the 19 animals. No proviral DNA was detected in antibody-negative animals. Antibody titers were generally higher in animals from which virus was recovered in lymphocyte cultures [granulocyte-macrophage (GM) titer, 1:8427] compared to virus-negative animals (GM titer, 1:3608). Mean total white blood cell and lymphocyte subtype counts were similar in the HIV-infected animals and uninfected controls. The high antibody levels and Western blot profiles, over periods as long as 9 years in these chimpanzees, suggest continuous stimulation of the immune system by HIV antigen although virus was detected only sporadically in the peripheral blood. No illness suggestive of immunodeficiency was seen.

Animals↗
PubMed1993

Immunogenicity of recombinant human adenovirus-human immunodeficiency virus vaccines in chimpanzees.

Recombinant human adenovirus (Ad) type 4-, 5-, and 7-vectored vaccines expressing either the HIV env or gag-protease genes were tested for immunogenicity in three chimpanzees. The first phase of the vaccination protocol consisted of a primary and two booster immunizations with Ad-HIVs by the oral route of administration, followed by a single booster immunization with Gag and/or Env subunit vaccines. The second phase of the vaccination protocol consisted of intranasal administration of Ad-HIVs previously administered by the oral route. Following the first phase adenovirus was shed into stools for only 1-7 days and modest type-specific anti-adenovirus neutralizing antibody titers were induced. Strong anti-Env binding antibody responses were detected in all three animals following the second oral booster immunization. One chimpanzee responded with a low-titered type-specific neutralizing antibody response to HIV. Cell-mediated immune responses to Env were not detected after the primary vaccination, but were detected following all booster immunizations. Administration of the Gag subunit vaccine boosted both humoral and cell-mediated immune responses to Gag antigens. In contrast, the Env subunit vaccine boosted cellular but not humoral immune responses. In the second phase of the vaccination protocol, both virus shedding and anti-adenovirus responses were enhanced. All three chimpanzees responded to the intranasal administration of Ad7-HIVs with boosted anti-HIV serum responses, including low-titered type-specific neutralizing antibodies, elicited anti-HIV antibodies at secretory sites, and stimulated cell-mediated immune responses to both Gag and Env antigens.

AIDS Vaccines↗
PubMed1994

Immunogenicity of recombinant adenovirus-human immunodeficiency virus vaccines in chimpanzees following intranasal administration.

Recombinant adenovirus (Ad)-human immunodeficiency virus (HIV) vaccines expressing HIVIIIB Env and Gag proteins were evaluated for immunogenicity in chimpanzees following intranasal administration. When Ad7-, Ad4-, and Ad5-vectored vaccines were administered sequentially at 0, 24, and 52 weeks, respectively, to three chimpanzees, the inoculations resulted in limited virus replication in the nasopharynx, but extensive Ad-HIV replication occurred in the intestine. High-titered IgG serum antibody responses to Env and Gag that were nonneutralizing were induced following booster administration of Ad4-HIV recombinant viruses. Following the Ad5-HIV booster, low levels of neutralizing antibodies as well as V3 loop antibodies were induced in all three chimpanzees that persisted for several months. Administration of a gp160 subunit vaccine (baculovirus derived) in SAF-m 24 weeks later boosted broadly neutralizing serum antibodies that peaked within 1 month of the injection. Two additional subunit boosters 19 and 37 weeks later were progressively less effective at stimulating serum neutralizing antibody responses. Substantial local immune responses were induced in nasal, vaginal, and salivary secretions following the third Ad-HIV intranasal immunization. These responses were further boosted with the gp160 subunit vaccine, which also stimulated production of rectal antibodies. The predominant responses in all secretions tested were of the IgG isotype, although some IgA responses were also detected. Strong blastogenic responses to HIV recombinant Env and Gag proteins were induced after each immunization.

AIDS Vaccines↗
PubMed1996

Titration of a vaccine stock preparation of human immunodeficiency virus type 1SF2 in cultured lymphocytes and in chimpanzees.

A large stock preparation of the HIV-1SF2 isolate has been derived after serial passage in human peripheral blood mononuclear cells (PBMCs). This viral stock has a titer of 10(4.9) TCID50 in human PBMCs and 10(4.2) TCID50 in chimpanzee PBMCs. By inoculation into animals the 50% chimpanzee infectious dose titer was found to be about 10(2.3). Virus isolation from animals was achieved on most occasions within 1-4 weeks after inoculation and then became transient. Viral RNA and DNA PCR analyses confirmed the virus infection of the chimpanzees. Anti-HIV antibody levels in the inoculated animals ranged from 1:400 to 1:6400 as measured by ELISA. About 680 vials of this stock preparation, frozen at -190 degrees C, are available for future studies of vaccines and antiviral therapies.

AIDS Vaccines↗
PubMed1994

Experimentally induced septic arthritis in chimpanzees infected with Mycoplasma hominis, Mycoplasma pneumoniae, and Ureaplasma urealyticum.

Mycoplasma hominis was isolated in pure culture from septic synovial aspirates from an individual (patient A) during 16 different bouts of exacerbation over a 70-month period of observation. Two isolates, 10(7) and also 10(6) color-changing units (CCU) of the 1620 isolate and 5 x 10(4) CCU of the 1628 isolate, caused inflammation in chimpanzees inoculated intraarticularly. Inflammation was also induced with 10(7) CCU of the 2010B isolate, serovar VII of Ureaplasma urealyticum, recovered from an agammaglobulinemic individual (patient B) with septic polyarthritis and with 3 x 10(6) CCU of the PI-1428 isolate of Mycoplasma pneumoniae. Inflammation persisted for up to 36 days and was self-limiting. The aspirates contained up to 220,000 white blood cells/mm3 and up to 10(7) CCU/mL. There was good correlation between the severity of inflammation and the numbers of organisms, but antibody was not detected in aspirates during the peak severity of disease. As the numbers of organisms, decreased, detectable levels of antibody increased, thus suggesting that antibody may have been bound to antigen. Chimpanzees previously infected with either the 1628 isolate of M. hominis or the 2010B isolate of U. urealyticum were protected on challenge with > 100 times the minimal dose causing arthritis. Chimpanzees showed little or no inflammation when inoculated intraarticularly with 5 x 10(8) CCU of the type strain PG-21 of M. hominis or with the type strain CO of U. urealyticum or when inoculated intravenously with 3 x 10(8) CCU of the arthrogenic 1620 isolate of M. hominis.

Animals↗
PubMed1998

Departure from neutrality at the mitochondrial NADH dehydrogenase subunit 2 gene in humans, but not in chimpanzees.

To test whether patterns of mitochondrial DNA (mtDNA) variation are consistent with a neutral model of molecular evolution, nucleotide sequences were determined for the 1041 bp of the NADH dehydrogenase subunit 2 (ND2) gene in 20 geographically diverse humans and 20 common chimpanzees. Contingency tests of neutrality were performed using four mutational categories for the ND2 molecule: synonymous and nonsynonymous mutations in the transmembrane regions, and synonymous and nonsynonymous mutations in the surface regions. The following three topological mutational categories were also used: intraspecific tips, intraspecific interiors, and interspecific fixed differences. The analyses reveal a significantly greater number of nonsynonymous polymorphisms within human transmembrane regions than expected based on interspecific comparisons, and they are inconsistent with a neutral equilibrium model. This pattern of excess nonsynonymous polymorphism is not seen within chimpanzees. Statistical tests of neutrality, such as TAJIMA's D test, and the D and F tests proposed by FU and LI, indicate an excess of low frequency polymorphisms in the human data, but not in the chimpanzee data. This is consistent with recent directional selection, a population bottleneck or background selection of slightly deleterious mutations in human mtDNA samples. The analyses further support the idea that mitochondrial genome evolution is governed by selective forces that have the potential to affect its use as a "neutral" marker in evolutionary and population genetic studies.

Animals↗
PubMed1998

Ascertainment bias cannot entirely account for human microsatellites being longer than their chimpanzee homologues.

A large majority of human microsatellite markers are longer than their homologues in chimpanzees, suggesting that more expansion mutations have occurred in the lineage leading to humans. However, such a length difference has also been explained as arising from the selection of unusually long microsatellites as genetic markers. In order to resolve this controversy and to establish the true source of the observed length differences, we have now conducted the necessary reciprocal study. We have compared the lengths of size-selected markers cloned from chimpanzees between this species and humans. We find that of 19 markers which were informative and polymorphic in both species, 13 are longer in humans. This result is incompatible with ascertainment bias being the sole explanation for the inter-specific length differences. We estimate that dinucleotide repeat microsatellites are an average of 3.2 repeat units longer in humans than in chimpanzees, implying a mutational bias in favour of microsatellite expansions and a higher average genome-wide microsatellite mutation rate in the human lineage.

Animals↗
PubMed2001

Perspectives on hepatitis B studies with chimpanzees.

Chimpanzees have been shown to be exquisitely susceptible to human hepatitis viruses, without themselves developing clinical illness, thus providing an important model for studies on these agents. Chimpanzees have contributed substantially to human welfare by making possible the development of hepatitis B vaccines, which now prevent development of cirrhosis and hepatocellular carcinoma in millions of people. They have provided a means to evaluate the efficacy of virus inactivation strategies, which have made blood derivatives formerly contaminated with blood-borne viruses (hepatitis B, C, and human immunodeficiency viruses) safe with respect to their transmission. In exchange for these contributions, humans owe chimpanzees lifelong retirement in sanctuaries that offer socialization and environmental enrichment.

Animal Welfare↗
PubMed1979

Acquired immunity to human non-A, non-B hepatitis: cross-challenge of chimpanzees with three infectious human sera.

Chimpanzees that had recovered from non-A, non-B hepatitis transmitted by inoculation of serum from each of three chronically infected humans were challenged by inoculation with a second of the three infectious sera to determine whether recovery from infection caused by one serum afforded protection against later infection by another. None of the challenge inoculations caused recognizable non-A, non-B hepatitis in any of the chimpanzees, a finding suggesting that either one agent or several agents sharing a common or similar antigen were responsible for the original non-A, non-B hepatitis in fections in these chimpanzees. Although circumstantial evidence in the literature suggests the existence of more than one agent of non-A, non-B hepatitis, the fact that the three inocula were obtained from humans residing in different geographic areas of the eastern United States suggests that one agent or a group of related agents may be the cause of many cases of non-A, non-B hepatitis in the United States.

Alanine Transaminase↗
PubMed1990

Expression of infectious viral particles by primary chimpanzee hepatocytes isolated during the acute phase of non-A, non-B hepatitis.

Liver wedge biopsies were obtained from chimpanzees during the acute phase of experimental non-A, non-B hepatitis infections. Primary chimpanzee hepatocytes were maintained for over 4 weeks in vitro with a serum-free medium supplemented with growth factors and hormones. The de novo synthesis and secretion of plasma proteins characteristic for differentiated primate hepatocytes were sustained under these culture conditions. Immunocytochemical staining for a non-A, non-B hepatitis-associated antigen revealed expression of this cytoplasmic marker during the culture period, indicating a persistence of the infection in vitro. Tissue culture medium derived from the hepatocyte cultures was used to inoculate a nonimmune chimpanzee. The animal subsequently displayed an increase in the serum levels of alanine aminotransferase, the development of histopathologic alterations indicative of viral hepatitis, and the appearance of liver cell cytoplasmic tubules diagnostic for non-A, non-B hepatitis. Concentrated tissue culture medium examined by electron microscopy contained virus-like particles with an average diameter of 39-46 nm, which exhibited an envelope and inner 37-nm core structure.

Acute Disease↗
PubMed1991

Prolonged CD4+ lymphocytopenia and thrombocytopenia in a chimpanzee persistently infected with human immunodeficiency virus type 1.

The immunologic and virologic status of a chimpanzee inoculated with multiple isolates of the human immunodeficiency virus type 1 (HIV-1) were assessed over 57 months to determine whether prolonged thrombocytopenia and CD4+ lymphocytopenia observed in the animal might be associated with long-term HIV infection. Although the chimpanzee showed no signs of disease, it lost both CD4+ (as low as 134 cells/microliter) and CD8+ lymphocytes approximately 30 months after initial infection, followed by thrombocytopenia that has persisted for greater than 2 years. Lymphopenia and thrombocytopenia were preceded by or coincided with the appearance of antibodies cross-reactive with histone H2B and decreased levels of complement component C4; an eightfold decrease in HIV-specific antibody titers; the inability of CD8+ lymphocytes to suppress virus replication; impaired proliferative responses to T cell mitogens; and the isolation of cell-free HIV from plasma. These data suggest that, given sufficient time, HIV-infected chimpanzees may develop disease.

Animals↗
PubMed1993

Lack of T cell dysfunction and programmed cell death in human immunodeficiency virus type 1-infected chimpanzees correlates with absence of monocytotropic variants.

In asymptomatic human immunodeficiency virus (HIV) infection in humans, disturbed T cell functions such as anergy and programmed cell death, thought to result from inappropriate signaling by antigen-presenting cells due to HIV infection, precede increase in virus load, decline in CD4+ T cell numbers, and subsequent disease progression. Here, in 3 long-term HIV-1-infected asymptomatic chimpanzees, antigen-presenting cell function was intact and T cells had normal proliferative capacity with no evidence of HIV-1-associated programmed cell death. Polymerase chain reaction analysis demonstrated low frequencies of cells harboring proviral DNA. Primary virus isolation from the infected animals demonstrated the absence of monocytotropic HIV-1 variants, in concordance with complete insusceptibility of chimpanzee monocytes for HIV-1 infection. Possibly, because of the incapacity of HIV-1 to infect monocytes, systemic immune dysfunction will not occur, contributing to controlled viral replication and maintenance of the asymptomatic state in HIV-infected chimpanzees.

Amino Acid Sequence↗
PubMed1997

Infectivity and pathogenicity in chimpanzees of a surface gene mutant of hepatitis B virus that emerged in a vaccinated infant.

Hepatitis B virus (HBV) variants with amino acid mutations in the a epitope of the major surface protein have been identified, and questions have been raised regarding their biologic properties. Dilutions of serum that contained the first such described HBV mutant, with an Arg-for-Gly substitution at codon 145 of the S gene, were inoculated into 6 seronegative chimpanzees. Five of the animals developed serologic and/or biochemical evidence of hepatitis B. A polymerase chain reaction-based assay that discriminated between the wild type and mutant viral genomes revealed that a pure population of the mutant genome was present in the 10(-6) and 10(-7) dilutions of the index serum, resulting in infection of the chimpanzees receiving these dilutions only with the mutant virus. A clone of the mutant virus replicated normally following transfection in vitro. Thus, this HBV surface gene mutant is viable, infectious, and pathogenic in chimpanzees.

Animals↗
PubMedDate not supplied

Genomic divergence between human and chimpanzee estimated from large-scale alignments of genomic sequences.

To study the genomic divergence between human and chimpanzee, large-scale genomic sequence alignments were performed. The genomic sequences of human and chimpanzee were first masked with the RepeatMasker and the repeats were excluded before alignments. The repeats were then reinserted into the alignments of nonrepetitive segments and entire sequences were aligned again. A total of 2.3 million base pairs (Mb) of genomic sequences, including repeats, were aligned and the average nucleotide divergence was estimated to be 1.22%. The Jukes-Cantor (JC) distances (nucleotide divergences) in nonrepetitive (1.44 Mb) and repetitive sequences (0.86 Mb) are 1.14% and 1.34%, respectively, suggesting a slightly higher average rate in repetitive sequences. Annotated coding and noncoding regions of homologous chimpanzee genes were also retrieved from GenBank and compared. The average synonymous and nonsynonymous divergences in 88 coding genes are 1.48% and 0.55%, respectively. The JC distances in intron, 5' flanking, 3' flanking, promoter, and pseudogene regions are 1.47%, 1.41%, 1.68%, 0.75%, and 1.39%, respectively. It is not clear why the genetic distances in most of these regions are somewhat higher than those in genomic sequences. One possible explanation is that some of the genes may be located in regions with higher mutation rates.

Animals↗
PubMed1988

Digestion and passage kinetics of chimpanzees fed high and low fiber diets and comparison with human data.

To investigate the digestive kinetics and fiber digestion of great apes, we conducted digestion trials on chimpanzees (Pan troglodytes) with diets of two fiber levels, one containing 34% neutral detergent fiber (NDF) and the other 14% NDF. Chimpanzees exhibited a response to fiber similar to that of humans. First, increases in the fiber concentration of the diet decreased mean transit time (MTT), hindgut turnover time (T) and the digestibility of fiber. Second, differences in MTT and T between the treatments and animals explained most of the variability in the digestibility of fiber components. Third, consistent with human data, the fiber marker passed more slowly than the liquid marker only when the high fiber diet was consumed. Fourth, individual variability, as in humans, was a significant factor affecting digestion and passage. Fifth, the MTT of chimpanzees was longer than that of humans. This result may be due to the apes' larger hindgut. In comparison with other hominoids, humans have smaller volumes in the gastrointestinal tract and hindgut. The gut proportions of modern humans, in combination with evidence from the fossil record, indicate that during its evolution the human lineage was able to overcome nutritional constraints imposed on body size increases in the great apes. We suggest that this advance was achieved through technological and social innovations that permitted early humans to achieve larger body size without lowering dietary quality.

Animals↗