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D H O'Connor

Publications and source records attributed to D H O'Connor.

12 recordsLinked to original sources
PubMed2001

Simultaneous positive and purifying selection on overlapping reading frames of the tat and vpr genes of simian immunodeficiency virus.

Tat-specific cytotoxic T cells have previously been shown to exert positive Darwinian selection favoring amino acid replacements of an epitope of simian immunodeficiency virus (SIV). The region of the tat gene encoding this epitope falls within a region of overlap between the tat and vpr reading frames, and nonsynonymous nucleotide substitutions in the tat reading frame were found to occur disproportionately in such a way as to cause synonymous changes in the vpr reading frame. Comparison of published complete SIV genomes showed Tat to be the least conserved at the amino acid level of nine proteins encoded by the virus, while Vpr was one of the most conserved. Numerous parallel amino acid changes occurred within the Tat epitope independently in different monkeys, and purifying selection on the vpr reading frame, by limiting acceptable nonsynonymous substitutions in the tat reading frame, evidently has enhanced the probability of parallel evolution.

Animals↗
PubMed2001

CD8(+) lymphocytes from simian immunodeficiency virus-infected rhesus macaques recognize 14 different epitopes bound by the major histocompatibility complex class I molecule mamu-A*01: implications for vaccine design and testing.

It is becoming increasingly clear that any human immunodeficiency virus (HIV) vaccine should induce a strong CD8(+) response. Additional desirable elements are multispecificity and a focus on conserved epitopes. The use of multiple conserved epitopes arranged in an artificial gene (or EpiGene) is a potential means to achieve these goals. To test this concept in a relevant disease model we sought to identify multiple simian immunodeficiency virus (SIV)-derived CD8(+) epitopes bound by a single nonhuman primate major histocompatibility complex (MHC) class I molecule. We had previously identified the peptide binding motif of Mamu-A*01(2), a common rhesus macaque MHC class I molecule that presents the immunodominant SIV gag-derived cytotoxic T lymphocyte (CTL) epitope Gag_CM9 (CTPYDINQM). Herein, we scanned SIV proteins for the presence of Mamu-A*01 motifs. The binding capacity of 221 motif-positive peptides was determined using purified Mamu-A*01 molecules. Thirty-seven peptides bound with apparent K(d) values of 500 nM or lower, with 21 peptides binding better than the Gag_CM9 peptide. Peripheral blood mononuclear cells from SIV-infected Mamu-A*01(+) macaques recognized 14 of these peptides in ELISPOT, CTL, or tetramer analyses. This study reveals an unprecedented complexity and diversity of anti-SIV CTL responses. Furthermore, it represents an important step toward the design of a multiepitope vaccine for SIV and HIV.

AIDS Vaccines↗
PubMed2000

Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia.

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viraemia that decline as strong cellular immune responses develop. Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection, the data have been controversial. Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development.

AIDS Vaccines↗
PubMed2000

Definition of five new simian immunodeficiency virus cytotoxic T-lymphocyte epitopes and their restricting major histocompatibility complex class I molecules: evidence for an influence on disease progression.

Simian immunodeficiency virus (SIV) infection of the rhesus macaque is currently the best animal model for AIDS vaccine development. One limitation of this model, however, has been the small number of cytotoxic T-lymphocyte (CTL) epitopes and restricting major histocompatibility complex (MHC) class I molecules available for investigating virus-specific CTL responses. To identify new MHC class I-restricted CTL epitopes, we infected five members of a family of MHC-defined rhesus macaques intravenously with SIV. Five new CTL epitopes bound by four different MHC class I molecules were defined. These included two Env epitopes bound by Mamu-A*11 and -B*03 and three Nef epitopes bound by Mamu-B*03, -B*04, and -B*17. All four restricting MHC class I molecules were encoded on only two haplotypes (b or c). Interestingly, resistance to disease progression within this family appeared to be associated with the inheritance of one or both of these MHC class I haplotypes. Two individuals that inherited haplotypes b and c separately survived for 299 and 511 days, respectively, while another individual that inherited both haplotypes survived for 889 days. In contrast, two MHC class I-identical individuals that did not inherit either haplotype rapidly progressed to disease (survived <80 days). Since all five offspring were identical at their Mamu-DRB loci, MHC class II differences are unlikely to account for their patterns of disease progression. These results double the number of SIV CTL epitopes defined in rhesus macaques and provide evidence that allelic differences at the MHC class I loci may influence rates of disease progression among AIDS virus-infected individuals.

Amino Acid Sequence↗
PubMed1999

Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef.

Cytotoxic T-lymphocyte (CTL) responses to human immunodeficiency virus arise early after infection, but ultimately fail to prevent progression to AIDS. Human immunodeficiency virus may evade the CTL response by accumulating amino-acid replacements within CTL epitopes. We studied 10 CTL epitopes during the course of simian immunodeficiency virus disease progression in three related macaques. All 10 of these CTL epitopes accumulated amino-acid replacements and showed evidence of positive selection by the time the macaques died. Many of the amino-acid replacements in these epitopes reduced or eliminated major histocompatibility complex class I binding and/or CTL recognition. These findings strongly support the CTL 'escape' hypothesis.

Amino Acid Sequence↗
PubMed1999

Major histocompatibility complex class I genes in primates: co-evolution with pathogens.

The major histocompatibility complex (MHC) is the most polymorphic genetic system known, playing a central role in the cellular immune response to pathogens. The relationship between the MHC of humans and non-human primates has increased our understanding of MHC evolution and how polymorphism of this gene family may have been generated. We will review MHC class I evolution in great apes and Old World and New World primates and discuss new data from the simian immunodeficiency virus/rhesus monkey animal model that demonstrate the role of MHC class I alleles in selecting for new populations of viruses. This suggests that certain pathogens co-evolve with the MHC class I molecules they encounter in a population.

Amino Acid Sequence↗
PubMed1989

Influence of the type of dietary fat on developmental growth of the mammary gland in immature and mature female BALB/c mice.

The purpose of this study was to determine whether or not the type of dietary fat can affect mammary gland growth processes in the immature and mature female BALB/c mouse. Groups of immature and mature mice were fed one of the following purified semisynthetic diets containing different types of fat, i.e., five vegetable oil diets (5% corn oil, 20% corn oil, 20% olive oil, 20% linseed oil, 19% coconut oil-1% corn oil); two animal fat diets (20% lard, 19% beef tallow-1% corn oil); and one fish oil diet (19% Menhaden oil-1% corn oil). In addition, fish-corn oil diets (20%) containing three different levels of corn oil (15%, 10%, 4.5%) and fish oil (5%, 10%, 15.5%) were also examined in these studies. Immature mice were fed these diets from 21 to 45 days of age, ovariectomized at 35 days of age, given injections daily of 17 beta-estradiol (1 microgram) and progesterone (1 mg) on Days 42 to 44, and sacrificed on Day 45. Mammary ductal expansion through the mammary fat-pad (mm, nipple to farthest end bud) was determined on the inguinal (No. 4) mammary glands. Mature mice were fed these diets from 28 to 128 days of age. Half of these mice were sacrificed between 118 and 128 days of age during the stage of estrus of the estrous cycle. The remaining half were given injections daily of 17 beta-estradiol (1 microgram) and progesterone (1 mg) from 118 to 127 days of age and sacrificed on Day 128. Mammary developmental growth was assessed on inguinal mammary glands by ascription of development scores, determination of epithelial area (mm2), and determination of total DNA levels. In both immature mice and mammotrophic hormone-treated mature mice fed the fish oil diet (19% Menhaden oil-1% corn oil, 15.5% Menhaden oil-4.5% corn oil), significantly (P less than 0.05) reduced developmental growth of the mammary gland was observed when compared to mice fed the 19 to 20% vegetable oil or animal fat diets. No significant difference in mammary gland developmental growth was observed among the groups of mice fed the 19 to 20% vegetable oil or animal fat diets. In immature mice and mammotrophic hormone-treated mature mice, significantly (P less than 0.05) reduced mammary gland developmental growth was observed in mice fed the 5% corn oil diet compared with mice fed the 20% corn oil diet. In mature mice not treated with exogenous mammotrophic hormones, no significant effect of diet on mammae development was observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1988

Influence of caffeine and/or coffee consumption on the initiation and promotion phases of 7,12-dimethylbenz(a)anthracene-induced rat mammary gland tumorigenesis.

The effect of caffeine and/or coffee consumption (via the drinking water) during the initiation phase and promotion phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats fed a commercial laboratory animal chow was examined. In the initiation studies, DMBA was administered once at 53-55 days of age; caffeine (100-860 mg/liter of drinking water) and/or coffee (moderate or high dose, sole source of drinking water) treatments were for 32 consecutive days, commencing 29 days prior to DMBA treatment and terminating 3 days after DMBA treatment. In the promotion studies, DMBA was administered once at 54-55 days of age; caffeine and/or coffee treatments were daily from 57-58 days of age to termination of experiments (12-21 weeks after carcinogen treatment). In the initiation studies, either moderate (100-400 mg) or high (860 mg) dose levels of caffeine or moderate to high dose levels of caffeinated coffee significantly (P less than 0.05) reduced mammary carcinoma multiplicity (number of tumors/rat). Consumption of high or moderate dose levels of decaffeinated coffee did not significantly alter mammary carcinoma multiplicity. The addition of caffeine to the moderate dose level of decaffeinated coffee resulted in a significant (P less than 0.05) reduction in mammary carcinoma multiplicity. In the promotion studies, prolonged consumption of moderated dose levels of caffeine or moderate or high dose levels of caffeinated coffee or decaffeinated coffee did not significantly effect mammary carcinoma multiplicity. In the early stages of promotion, however, a significant (p less than 0.05) stimulatory effect of caffeine on mammary carcinoma multiplicity was observed; an effect that was temperate and transitory. In both the initiation and promotion studies caffeine and/or coffee consumption did not significantly affect the incidence of mammary carcinomas (percentage of rats bearing mammary carcinomas) or the mean latency period of mammary tumor appearance. These results provide evidence that caffeine and/or caffeinated coffee consumption can significantly influence mammary carcinoma multiplicity in female rats treated with DMBA, an effect that is dependent upon the dose level, duration, and time-span of caffeine administration.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Influence of caffeine consumption on carcinomatous and normal mammary gland development in mice.

The influence of caffeine consumption on the development of 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas in BD2F1 female mice and spontaneous mammary carcinomas in nulliparous C3H mice was examined. Caffeine (250 and 500 mg/liter of drinking water) was administered to BD2F1 mice commencing 1 week after a series of 6 weekly 7,12-dimethylbenz(a)anthracene intubations, until experiment termination. Caffeine was administered to C3H mice (via drinking water) commencing at 8 weeks of age to experiment termination. In BD2F1 mice receiving 250 and 500 mg of caffeine, mammary carcinoma multiplicity (number of mammary carcinomas/mouse) was increased by 20 and 40%, respectively. In C3H mice receiving 250 and 500 mg caffeine, mammary carcinoma multiplicity was increased by 13 and 117%, respectively. In both BD2F1 and C3H mice, the higher dose level of caffeine resulted in a significant (P less than 0.05) increase in mammary carcinoma multiplicity. Caffeine consumption did not significantly effect the percentage of mice bearing mammary carcinomas or the mean latency period of mammary tumor appearance. In a second series of studies, the influence of caffeine consumption on mammary gland development in female BALB/c mice was assessed in vivo and in vitro (organ culture). In mice consuming caffeine (500 mg/liter of drinking water), mammary gland development was significantly (P less than 0.05) increased compared to control mice; this difference in mammae development was more conspicuous in mice treated with mammotropic hormones. In the organ culture studies, mammary glands derived from caffeine (500 mg/liter of drinking water) consuming BALB/c mice were more responsive in vitro to a mammotropic hormonal developmental growth stimulus than were mammae derived from control mice (P less than 0.05). These results provide evidence that caffeine consumption can enhance mammary tumorigenesis in C3H and carcinogen-treated BD2F1 female mice and, in addition, enhance developmental growth of the normal female mouse (BALB/c) mammary gland.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Normal but not carcinomatous primary rat mammary epithelium: readily transplanted to and maintained in the athymic nude mouse.

Transplantation success rates of primary 7,12-dimethylbenz(a)anthracene [(DMBA) CAS: 57-97-6]-induced rat mammary carcinomas and normal rat mammary glandular epithelium into female athymic mice were compared. The rat mammary carcinomas obtained from female Sprague-Dawley rats were transplanted into host athymic mice (6-8 wk of age) as 1 x 1-cm slices xenografted sc (2 slices/mouse) or as enzymatically dissociated cells inoculated into the gland-free mammary fat pad. Normal rat mammary glands (No. 4 glands and 3- to 5-mo-old virgin rats) were transplanted into host athymic mice as whole, intact mammary glands sc (1 gland/mouse) or as enzymatically dissociated cells inoculated into the gland-free mammary fat pad. All (100%) of the normal rat mammary glands were readily accepted and maintained in the athymic mice when transplanted either sc as whole glands or as dispersed cells inoculated into the gland-free fat pad. In contrast, only 13-14% of the DMBA-induced rat mammary carcinomas were accepted and maintained in the athymic mice (transplanted as slices sc or as dispersed cells inoculated into the gland-free fat pad). Treatment of host athymic nude mice with an intense mammotropic hormonal stimulus (prolactin and/or ovarian steroids) markedly enhanced the developmental growth of the transplanted normal rat mammae (subcutaneous slices and fat-pad inoculates); such a hormonal stimulus did not influence the transplantation success rate of the DMBA-induced rat mammary carcinomas. Thus female athymic nude mice can readily accept and maintain transplants of normal rat mammae but not carcinogen-induced carcinomatous rat mammae; the meager acceptance rate of the carcinomatous rat mammae by the athymic nude mouse was not enhanced by providing the host mice with a potent mammotropic hormonal growth stimulant.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Influence of dietary fat levels on development and hormone responsiveness of the mouse mammary gland.

Twenty-one-day-old female BALB/c mice were divided into three groups and fed a diet containing 0, 5, and 20% fat (corn oil). Ten days prior to sacrifice, one-half of the mice were given injections daily with saline (0.9% NaCl solution), and the remaining half, with 17 beta-estradiol (1 microgram) and progesterone (1 mg). After 3 mo on diet and 10 days of saline or estradiol:progesterone treatments, all mice were sacrificed, and mammary glands were excised and prepared for whole-mount evaluation (No. 4 glands), [3H]thymidine-autoradiographic analysis (No. 2 glands), and organ culture analysis (No. 2 glands). Whole-mount evaluation involved a rating for ductal and alveolar development on a scale of 1 to 6. [3H]Thymidine-autoradiographic analysis consisted of determining the total number of labeled epithelial cells per anterior 3 mm of gland. Organ culture analysis consisted of placing one gland of each gland pair in basal tissue culture medium, and the contralateral gland was placed in basal medium plus mammogenic hormones. These glands were cultured for 6 days and then analyzed for development by whole-mount evaluation (scale, 1 to 6) and for epithelial area (mm2) (via computer image analysis). In saline- and estradiol:progesterone-treated mice, there was a significant linear increase in the number of [3H]thymidine-labeled mammary epithelial cells as the fat content of the diet increased from 0 to 5 to 20% (P less than 0.05). In saline- and estradiol:progesterone-treated mice, mammary gland development (assessed by whole-mount evaluation) was increased as the fat content of the diet increased from 0 to 5% (P less than 0.05). In saline-treated mice, no significant difference in mammae development was observed between mice fed 5 or 20% fat diets; in estradiol:progesterone-treated mice, mammae development was marginally increased in mice fed the 20% fat diet compared to mice fed the 5% fat diet (P approximately 0.07).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗