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PubMed2001

Resistance to neutralizing antibody and expanded coreceptor usage are associated with human immunodeficiency virus type 1 isolates derived from chimpanzees with pathogenic infections.

Immunologic and biologic factors associated with the progression to AIDS in HIV-1-infected chimpanzees were investigated. Chimpanzee C499 was euthanized in 1996 as a result of the development of AIDS approximately 11 years after infection with HIV-1. At the time of initial disease development (September 1995), blood from this animal was transfused to an uninfected chimpanzee, C455, resulting in a rapid loss of CD4(+) T cells. Virus isolates were derived from both animals and termed HIV-1(JC) (derived from C499 at the time of disease development; JC isolate) and HIV-1(NC) (derived from C455 1 month posttransfusion; NC isolate). In vitro studies demonstrate that the parental viruses used to inoculate C499 were susceptible to neutralization by serum from that animal. In contrast, serum from C499 at any time was unable to neutralize the JC or NC isolates. Similarly, the JC and NC isolates were highly resistant to neutralization by serum from C455. However, serum from C455 was also unable to neutralize either of the parental viruses or any of the normally neutralization sensitive isolates tested. Serum samples from the two additional chimpanzees that were inoculated with the NC isolate were also unable to neutralize these isolates. Coreceptor usage of the uncloned JC and NC isolates was somewhat expanded when compared with that of LAV1b and SF2. However, molecular clones derived from the JC and NC isolates (JC16 and NC7) displayed only a limited coreceptor repertoire despite having unique V3 loop sequences. The results suggest that the JC and NC isolates are neutralization escape mutants and display a different phenotype than the parental strains LAV1b and SF2.

Animals↗
PubMed1999

The relative resistance of HIV type 1-infected chimpanzees to AIDS correlates with the maintenance of follicular architecture and the absence of infiltration by CD8+ cytotoxic T lymphocytes.

Lymphoid tissues are the focus of critical events in HIV pathogenesis. Persistent and high levels of virus production, extensive trapping of virus particles in germinal centers, and progressive degenerative changes in lymph node architecture are characteristics of progressive HIV-1 infection. Infiltrates of granzyme B- and TIA-expressing CD8+ "cytotoxic" T lymphocytes (CTLs) precede involution of germinal centers in humans who develop AIDS. Similar to humans, HIV-1 infection in chimpanzees is active and persistent. However, in contrast to humans, they remain relatively resistant to AIDS. Lymph node biopsies from chimpanzees infected with HIV-1 or a related chimpanzee lentivirus were studied for the level and pattern of virus expression, changes in lymphoid architecture, CD8+ T cell infiltrates and the presence or absence of CTL markers. In stark contrast to HIV-1-infected humans, lymph nodes from infected chimpanzees had little virus deposition in germinal centers and a paucity of virus-expressing cells. Although some of the lymph nodes examined from infected animals had moderate follicular hyperplasia with infiltrating CD8+ T cells, none had evidence of follicular fragmentation. Most importantly, in marked contrast to infected humans, CD8+ T cells infiltrating the germinal center were negative for the CTL marker granzyme B. This evidence suggests that the infiltration of CD8+ CTLs into the germinal centers of lymph nodes may be a key determinant in AIDS pathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Stages in the progression of HIV infection in chimpanzees.

Circulating HIV antigens and HIV specific antibodies in sera of experimentally infected chimpanzees were monitored by ELISA immunoassay, Western blot, and radioimmunoprecipitation procedures. Three of three chimpanzees given plasma from patients with AIDS or ARC tested positive for HIV antigens beginning six to ten weeks after transfusion. Antigen production rose sharply but was of short duration. Despite their proven infectivity and the presence of anti-HIV antibody, all donors to these chimpanzees tested negative for the HIV antigen. Of the three animals that developed HIV antigen one animal did not produce any HIV antibodies or evidence of disease. A second produced antibodies to only the p24 and p18 antigens and remained clinically well. The third produced antibodies beginning with anti-p24, to all the major HIV proteins except gp120, and then developed marked lymphadenopathy which persisted for 32 weeks. Antibody persistence after the disappearance of clinical disease was variable and was greatest for gp41 and least for p24. These data may be of value in the interpretation of human serological testing for HIV and in further studies of the sequence of events leading to the pathological effects of HIV infection. A significant value of the chimpanzee model is the capacity of this animal to respond in a variety of ways to HIV infection, suggesting the existence of successive or alternate states of early HIV infection, and may have implications in the design of early interventions.

AIDS-Related Complex↗
PubMed1989

Long-term observation of baboons, rhesus monkeys, and chimpanzees inoculated with HIV and given periodic immunosuppressive treatment.

Baboons, rhesus monkeys, and chimpanzees were injected with the human immunodeficiency virus (HIV) and monitored for up to 4 years. Various immunosuppressive regimens were used during this time in attempts to induce development of the acquired immune deficiency syndrome (AIDS). No infectious virus was recovered or anti-HIV antibodies detected in the baboons and rhesus monkeys. Virus has been recovered from lymphocyte cultures of all five of the chimpanzees at intermittent periods following inoculation. The chimpanzees developed anti-HIV antibodies from 1 to 5 months after virus inoculation and had circulating antibodies that neutralized HIV. All the infected animals were capable of in vitro lymphocyte blastogenic responses to recombinant envelope and core HIV antigens. Despite immunosuppressive therapies and evidence of some immunologic abnormalities, none of the five chimpanzees has yet developed AIDS or a related disorder.

Animals↗
PubMed1993

CD3, CD8 double-positive cells from HIV-1-infected chimpanzees show group-specific inhibition of HIV-1 replication.

The CD8-positive (CD8+) lymphocyte population in the chimpanzee is composed of two major subsets, a CD3-positive, CD8-positive (CD3+CD8+) and a CD3-negative, CD8-positive (CD3-CD8+) population. The aim of this study was to delineate the function of CD3+CD8+ T cells with respect to inhibition of HIV-1 replication. It could be shown that this cell population had the capacity to control the growth of HIV-1 in exogenously infected CD4-positive (CD4+) lymphocytes. This effect was observed only with cells from HIV-1-infected chimpanzees, was operative only in an autologous and not in a homologous situation, and was not due to cytotoxicity. CD3+CD8+ lymphocyte-mediated inhibition of HIV-1 replication was group-specific in that CD3+CD8+ cells of HIV-1 (IIIB)-infected chimpanzees were capable of inhibiting replication of HIV-1 strains IIIB, MN, and RF. The effect observed was operational during the early stages of HIV-1 replication only; the effector cells had to be added to CD4+ cells within 3 days after HIV-1 infection in order to suppress growth of the virus. The presence of CD3+CD8+ lymphocytes with anti-HIV-1 activity in the circulation of HIV-1-infected chimpanzees might contribute to the lack of progression toward AIDS observed in this species.

Animals↗
PubMed2005

Chimpanzee DC-SIGN alleles predict the existence of A and B isoforms, but do not support a role for resistance to HIV infection.

We report here the gene sequence for DC-SIGN (CD209) from chimpanzees. DC-SIGN is a C-type lectin expressed by dendritic cells. It is involved in DC-T cell interactions as well as in HIV-1 and SIV transmission. We have cloned two new alleles for chimpanzee DC-SIGN. The coding sequences are highly homologous to the two previously described chimpanzee alleles. We confirm the existence of a polymorphism within the repeat region of DC-SIGN. In humans polymorphisms in the repeat region have been associated with resistance to HIV infection. However, we have not been able to correlate the number of repeats with susceptibility of chimpanzees to HIV infection. The actual impact of DC-SIGN variability in HIV infection therefore remains to be determined.

Alleles↗
PubMed1998

A synthetic peptide from the first conserved region in the envelope protein gp160 is a strong T-cell epitope in HIV-infected chimpanzees and humans.

We reported earlier that synthetic peptides corresponding to highly conserved regions in the envelope protein gp160 of the human immunodeficiency virus type 1 (HIV-1), in particular an 11-amino acid sequence (peptide 104) from the first conserved region at the amino-terminus, were capable of inducing strong HIV-specific T-cell proliferative responses in several inbred mouse strains as well as in outbred Rhesus monkeys. We have now obtained evidence of the presence of significant levels of proliferative response to peptide 104 in 7 of 9 chimpanzees chronically infected with HIV-1 (p < or = 0.05) and 8 of 17 HIV+ individuals (p < or = 0.001). Further, four other conserved HIV envelope-derived peptides, identified previously in our murine and Rhesus monkey model systems, were widely recognized as T-cell epitopes in both chimpanzees and humans infected with HIV-1. In none of the infected subjects did peripheral blood mononuclear cells show proliferative responses to unrelated control peptides. Also, neither the control normal chimpanzees nor HIV-seronegative individuals showed proliferative responses to the conserved peptides. With respect to the humoral responses, serum samples from none of the chimpanzees showed reactivity with any of the conserved peptides, and only low levels of antibody responses against peptide 104 were observed in 3 of the 17 patients (p > 0.05). Importantly, three of the conserved envelope-derived peptides, including peptide 104, overlap with sequences that were reported in the literature to be epitopes for virus-induced cytotoxic T lymphocytes in asymptomatic HIV+ individuals. These observations, together with our results in multiple animal models and humans, establish that these conserved HIV envelope-derived peptides, particularly peptide 104, are significant T-cell epitopes with potential usefulness for induction of HIV-specific cell-mediated immune responses in humans.

Amino Acid Sequence↗
PubMed1996

Analysis of CAG repeat of the Machado-Joseph gene in human, chimpanzee and monkey populations: a variant nucleotide is associated with the number of CAG repeats.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder associated with an unstable and expanded CAG repeat. We analyzed this locus from various sources including MJD families, Acadian, African American, Caucasian, Greenland Inuit and Thai populations. The range of the CAG repeat size was 14-40 in the normal alleles while the MJD alleles contained 73-78 repeats in our studies. We found 25 different alleles on normal chromosomes with a heterozygosity of 0.86 in combined populations. The most common alleles were 23 (22.9%) and 14 (25.5%) repeats. We also examined 16 chimpanzees and various Old World monkeys: a pigtail macaque, a mangabey and 12 rhesus macaques. The DNA sequences surrounding the CAG repeat did not vary among species. The range of the number of the CAG repeats is 13-14 in macaques, 16 in mangabey and 14-20 in chimpanzees. Variant CAA or AAG triplets in the CAG repeat tracts were found in all 268 human, 28 monkey and 32 chimpanzee chromosomes. As reported in a previous study [Kawaguchi et al. (1994) Nature Genet. 8, 221-228] the common variant positions were the third (CAA), fourth (AAG) and sixth (CAA) positions. However, we found three human chromosomes containing CAG at the sixth position and the mangabey had AAG at the ninth position. In addition, we found CAG at the fourth position and AAG at the sixth position in all macaque chromosomes. The nucleotide following the CAG repeat tract was usually G in all species studied. However, we sometimes found C at this position in human and chimpanzee chromosomes. Interestingly, this variant C was found in all expanded chromosomes and in 54.5% of chromosomes with 27-40 CAG repeats but it was not found in any chromosomes with less than 20 CAG repeats. We hypothesize that the variant C may be associated with CAG repeat instability.

Animals↗
PubMed1979

Simultaneous acute infections with hepatitis A and hepatitis B viruses in a chimpanzee.

The unexpected occurrence of a hepatitis B virus (HBV) infection in a chimpanzee experimentally inoculated with hepatitis A virus (HAV) provided an opportunity to examine the course of simultaneous acute infections with both agents. A chimpanzee inoculated intravenously with HAV developed elevated levels of aminotransferases in serum, detectable excretion of hepatitis A antigen in feces, and a marked antibody response to HAV. During the acute phase of this experimentally induced infection with HAV, the chimpanzee simultaneously developed an HBV infection. The latter was characterized by jaundice, a second increase in levels of aminotransferases in serum, and the appearance in serum of hepatitis B surface antigen (HBsAg), hepatitis B e antigen, antibody to hepatitis B core antigen, and, later, antibody to HBsAg. During the acute phase of both HAV and HBV infections, marked histopathologic inflammatory changes were observed in serial liver biopsy specimens. In this chimpanzee, the concurrent acute infection with both HAV and HBV occurred in association with marked liver damage.

Acute Disease↗
PubMed1986

Urogenital challenge of primate species with Mycoplasma genitalium and characteristics of infection induced in chimpanzees.

Eighteen male and eight female primates, representing five subhuman species, were inoculated urogenitally with Mycoplasma genitalium, a microorganism recovered from men with nongonococcal urethritis. Male rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys apparently were resistant. Female squirrel monkeys (Saimiri sciureus) and female tamarins (Saguinus mystax) exhibited low-level, genital-tract infections. Male chimpanzees (Pan troglodytes) developed an obvious genital-tract infection, with some shedding organisms for 21 weeks. M. genitalium was recovered from the blood of two of the male chimpanzees, usually when large numbers of organisms were in the urethra. Female chimpanzees generally shed organisms for 12-15 weeks. Most chimpanzees colonized with the organism exhibited increased numbers of polymorphonuclear leukocytes in the genital tract and developed a significant antibody response. The results offer substantial evidence for the pathogenicity of M. genitalium for the urogenital tract of higher primates and suggest the microorganism may have a role in human genital-tract infections.

Animals↗
PubMed1987

Titration of the infectivity of hepatitis D virus in chimpanzees.

The infectivity of hepatitis D virus (HDV) was evaluated by intravenous inoculation of chimpanzees. HDV was present in the inoculum at a titer of 10(11) chimpanzee infectious doses (CID). In contrast, the titer of hepatitis B virus (HBV) in the same inoculum was 10(6) CID. All HBV-infected chimpanzees inoculated with less than or equal to 10(-11) dilutions of the HDV-positive plasma were superinfected; an animal receiving a 10(-12) dilution did not develop markers of HDV replication in serum or liver. All HDV-infected chimpanzees had marked elevations of serum alanine aminotransferase activities. The incubation period from exposure to development of hepatitis was inversely related to the dose of HDV inoculum, although the severity and duration of hepatitis were independent of it. All animals recovered and rapidly developed antibody to hepatitis D antigen.

Alanine Transaminase↗
PubMed1989

Reappearance of hepatitis D virus (HDV) replication in chronic hepatitis B virus carrier chimpanzees rechallenged with HDV.

Four chronic hepatitis B virus (HBV) carrier chimpanzees, which had apparently cleared hepatitis D virus (HDV) after a first experimental challenge with HDV, were reinoculated with a homologous strain of HDV. All animals had reappearance of low levels of serum HDV RNA and transient, mild alanine aminotransferase (ALT) elevations, which in two cases correlated with HDV RNA positivity. Plasmas obtained from two chimpanzees after rechallenge were inoculated into two other chronic HBV carrier animals that had recovered from a previous HDV infection. A similar reappearance of HDV RNA in serum (without ALT elevation) was noticed. These same plasmas, however, when inoculated into a chronic HBV carrier chimpanzee never exposed to HDV caused a severe acute hepatitis D. Rechallenge with HDV in chimpanzees apparently recovered from a first HDV infection resulted in the reappearance of HDV replication, sometimes associated with hepatitis. This can be interpreted as reinfection with HDV, but other explanations are possible. Although the serum level of HDV RNA observed after rechallenge with HDV is low, its transmission to individuals susceptible to HDV infection can result in severe acute hepatitis D.

Alanine Transaminase↗
PubMed1992

The natural history of infection with hepatitis C virus (HCV) in chimpanzees: comparison of serologic responses measured with first- and second-generation assays and relationship to HCV viremia.

The sensitivity of first- and second-generation tests for antibody to hepatitis C virus (HCV) and the relationship among the patterns of antibody response and HCV viremia were examined in serial serum samples from 6 chimpanzees experimentally infected with HCV and followed less than or equal to 3 years. HCV infection was transient in 4 chimpanzees and became chronic in 2. All chimpanzees developed antibodies to HCV detectable by second-generation assays, while only 5 of the 6 became positive by first-generation assay. Second-generation were consistently more sensitive than first-generation assays for the early diagnosis of primary HCV infection. The pattern observed with second-generation assays was not influenced by the outcome of HCV infection, since antibodies remained persistently detectable throughout follow-up regardless of whether viremia was transient or persistent. In contrast, the first-generation antibody response was variable: It usually disappeared after loss of viremia, whereas its presence paralleled HCV viremia in chimpanzees with chronic infection.

Animals↗
PubMed1993

A cold-adapted mutant of parainfluenza virus type 3 is attenuated and protective in chimpanzees.

A live attenuated cold-adapted parainfluenza virus type 3 (PIV-3) vaccine is being developed to prevent the serious lower respiratory tract disease caused by this virus in infants and young children. This cold-passaged mutant (cp45) was evaluated in seronegative chimpanzees and found to be highly attenuated in both the upper and lower respiratory tracts compared to its wild-type parent. Animals immunized with cp45 were also highly resistant to wild-type PIV-3 challenge. Stability of the attenuation phenotype was demonstrated by the administration to 2 additional chimpanzees of an isolate of cp45 obtained after 10 days of replication in a chimpanzee. It was attenuated in both the upper and lower respiratory tracts. The cp45 virus present in the respiratory tract secretions of chimpanzees retained the temperature-sensitive (ts) phenotype, but some loss of ts property was observed in the isolates. These results provide a basis on which to proceed to clinical trials in seronegative human infants and children.

Adaptation, Physiological↗
PubMed1995

Phenotypic and functional parameters of cellular immunity in a chimpanzee with a naturally acquired simian immunodeficiency virus infection.

The cellular immunologic and virologic status of a chimpanzee, naturally infected with a human immunodeficiency virus type 1 (HIV-1)-like lentivirus (SIVcpz-ant), was compared longitudinally with those of 3 HIV-1-infected and 5 uninfected chimpanzees for a period of 49 months. Evidence of immune deficiency was not observed in the HIV-1-infected chimpanzees, nor could virus be isolated from plasma. Virus could be isolated from plasma of the SIVcpz-ant-infected chimpanzee, but clinical signs of immune deficiency were never observed. Absolute CD4+ cell counts remained relatively stable, but NK cells fluctuated significantly over time and tended to correlate inversely with the virus titer in peripheral blood. Although only CD8+ T cells were directly demonstrated to exert a suppressive effect on viral replication in vitro, the observed fluctuation of NK cells suggests that these cells may also be involved in the interaction with lentivirus infection in this species.

Animals↗
PubMedDate not supplied

Gene diversity of chimpanzee ABO blood group genes elucidated from intron 6 sequences.

The human and nonhuman primate ABO blood group gene shows relatively large numbers of nucleotide differences around the exon 7 region. In this study we determined intron 6 sequences for 9 alleles of common chimpanzee and for 3 alleles of bonobo to estimate nucleotide diversities among them. Sequence length polymorphisms are observed in this region as a repeat appears one to five times. From a phylogenetic network of intron 6 sequences of ABO blood group genes for humans, common chimpanzee, and bonobo, parallel substitutions and/or some kinds of convergent events are predicted in the chimpanzee lineage. We also estimated nucleotide diversities for common chimpanzee and bonobo ABO blood group genes; these values were 0.219% and 0.208%, respectively.

ABO Blood-Group System↗
PubMed2003

Gene diversity patterns at 10 X-chromosomal loci in humans and chimpanzees.

We have investigated the pattern and extent of nucleotide diversity in 10 X-chromosomal genes where mutations are known to cause mental retardation in humans. For each gene, we sequenced the entire coding region from cDNA in humans, chimpanzees, and orangutans, as well as about 3 kb of genomic DNA in 20 humans sampled worldwide and in 10 chimpanzees representing two "subspecies." Overall nucleotide diversity in these genes is about twofold lower in humans than in chimpanzees, and nucleotide diversity within and between species is low, suggesting that a high level of functional constraint acts on these genes. Strikingly, we find that a summary of the allele frequency spectrum is significantly correlated in humans and chimpanzees, perhaps reflecting very similar levels of constraint at these genes in the two species. A possible exception is FMR2, which shows a higher number of nonsynonymous than synonymous substitutions on the human lineage, suggesting the action of positive selection.

Animals↗
PubMed2006

A comparative analysis of numt evolution in human and chimpanzee.

Mitochondrial DNA sequences are frequently transferred into the nuclear genome, giving rise to numts (nuclear DNA sequences of mitochondrial origin). So far, the evolutionary history of numts has largely been studied by using single genomes. Here, we present the first attempt to study numt evolution in a comparative manner by using a pairwise genomic alignment. The total number of numts was estimated to be 452 in human and 469 in chimpanzee. numts that were found in both genomes at identical loci were deemed to be orthologous; 391 numts (>80%) were classified as such. The preponderance of orthologous numts is due to the very short divergence time between the 2 hominoids. The rest of numts were deemed to be nonorthologous. Nonorthologous numts were subdivided into 1) ancestral numts that have lost an ortholog in one species through deletion (12 in human and 11 in chimpanzee), 2) new numts acquired by the insertion of a mitochondrial sequence after the divergence of the 2 species (34 in human and 46 in chimpanzee), and 3) paralogous numts created by the tandem duplication of a preexisting numt (2 in human). This approach also enabled us to reconstruct the numt repertoire in the common ancestor of humans and chimpanzees (409 numts). Our comparative approach is also useful in identifying the exact boundaries of numts.

Animals↗