Predictors of participation in genetic testing for hereditary breast and ovarian cancer

Up to 10% of all breast and ovarian cancers are attributable to mutations in cancer susceptibility genes. Clinical genetic testing for deleterious gene mutations that predispose to hereditary breast and ovarian cancer (HBOC) syndrome is available. Mutation carriers may benefit from following high-risk guidelines for cancer prevention and early detection; however, few studies have reported the uptake of clinical genetic testing for HBOC. This study identified predictors of HBOC genetic testing uptake among a case series of 268 women who underwent genetic counseling at The University of Texas M. D. Anderson Cancer Center from October, 1996, through July, 2000. Women completed a baseline questionnaire that measured psychosocial and demographic variables. Additional medical characteristics were obtained from the medical charts. Logistic regression modeling identified predictors of participation in HBOC genetic testing. Psychological variables were hypothesized to be the strongest predictors of testing uptake—in particular, one's readiness (intention) to have testing. Testing uptake among all women in this study was 37% (n = 99). Contrary to the hypotheses, one's actual risk of carrying a BRCA1 or BRCA2 gene mutation was the strongest predictor of testing participation (OR = 15.37, CI = 5.15, 45.86). Other predictors included religious background, greater readiness to have testing, knowledge about HBOC and genetic testing, not having female children, and adherence to breast self-exam. Among the subgroup of women who were at ≥10% risk of carrying a mutation, 51% (n = 90) had genetic testing. Consistent with the hypotheses, predictors of testing participation in the high-risk subgroup included greater readiness to have testing, knowledge, and greater self-efficacy regarding one's ability to cope with test results. Women with CES-D scores ≥16, indicating the presence of depressive symptoms, were less likely to have genetic testing. Results indicate that among women with a wide range of risk for HBOC, actual risk of carrying an HBOC-predisposing mutation may be the strongest predictor of their decision to have genetic testing. Psychological variables (e.g., distress and self-efficacy) may influence testing participation only among women at highest risk of carrying a mutation, for whom genetic testing is most likely to be informative. ^

DNA incisions stimulate genetic instability of triplet repeat sequences related to human hereditary neurological diseases

The molecular mechanisms responsible for the expansion and deletion of trinucleotide repeat sequences (TRS) are the focus of our studies. Several hereditary neurological diseases including Huntington's disease, myotonic dystrophy, and fragile X syndrome are associated with the instability of TRS. Using the well defined and controllable model system of Escherichia coli, the influences of three types of DNA incisions on genetic instability of CTG•CAG repeats were studied: DNA double-strand breaks (DSB), single-strand nicks, and single-strand gaps. The DNA incisions were generated in pUC19 derivatives by in vitro cleavage with restriction endonucleases. The cleaved DNA was then transformed into E. coli parental and mutant strains. Double-strand breaks induced deletions throughout the TRS region in an orientation dependent manner relative to the origin of replication. The extent of instability was enhanced by the repeat length and sequence (CTG•CAG vs. CGG•CCG). Mutations in recA and recBC increased deletions, mutations in recF stabilized the TRS, whereas mutations in ruvA had no effect. DSB were repaired by intramolecular recombination, versus an intermolecular gene conversion or crossover mechanism. 30 nt gaps formed a distinct 30 nt deletion product, whereas single strand nicks and gaps of 15 nts did not induce expansions or deletions. Formation of this deletion product required the CTG•CAG repeats to be present in the single-stranded region and was stimulated by E. coli DNA ligase, but was not dependent upon the RecFOR pathway. Models are presented to explain the DSB induced instabilities and formation of the 30 nucleotide deletion product. In addition to the in vitro creation of DSBs, several attempts to generate this incision in vivo with the use of EcoR I restriction modification systems were conducted. ^

DNA nucleotide excision repair gene single nucleotide polymorphisms and hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease caused by germline mutations in DNA mismatch repair(MMR) genes. The nucleotide excision repair(NER) pathway plays a very important role in cancer development. We systematically studied interactions between NER and MMR genes to identify NER gene single nucleotide polymorphism (SNP) risk factors that modify the effect of MMR mutations on risk for cancer in HNPCC. We analyzed data from polymorphisms in 10 NER genes that had been genotyped in HNPCC patients that carry MSH2 and MLH1 gene mutations. The influence of the NER gene SNPs on time to onset of colorectal cancer (CRC) was assessed using survival analysis and a semiparametric proportional hazard model. We found the median age of onset for CRC among MMR mutation carriers with the ERCC1 mutation was 3.9 years earlier than patients with wildtype ERCC1(median 47.7 vs 51.6, log-rank test p=0.035). The influence of Rad23B A249V SNP on age of onset of HNPCC is age dependent (likelihood ratio test p=0.0056). Interestingly, using the likelihood ratio test, we also found evidence of genetic interactions between the MMR gene mutations and SNPs in ERCC1 gene(C8092A) and XPG/ERCC5 gene(D1104H) with p-values of 0.004 and 0.042, respectively. An assessment using tree structured survival analysis (TSSA) showed distinct gene interactions in MLH1 mutation carriers and MSH2 mutation carriers. ERCC1 SNP genotypes greatly modified the age onset of HNPCC in MSH2 mutation carriers, while no effect was detected in MLH1 mutation carriers. Given the NER genes in this study play different roles in NER pathway, they may have distinct influences on the development of HNPCC. The findings of this study are very important for elucidation of the molecular mechanism of colon cancer development and for understanding why some mutation carriers of the MSH2 and MLH1 gene develop CRC early and others never develop CRC. Overall, the findings also have important implications for the development of early detection strategies and prevention as well as understanding the mechanism of colorectal carcinogenesis in HNPCC. ^

Hypotensive resuscitation versus standard fluid resuscitation for the management of trauma patients in hemorrhagic shock: The safety phase of a randomized controlled trial

Trauma is a leading cause of death worldwide, and is thus a major public health concern. Improving current resuscitation strategies may help to reduce morbidity and mortality from trauma, and clinical research plays an important role in addressing these issues. This thesis is a secondary analysis of data that was collected for a randomized clinical trial being conducted at Ben Taub General Hospital. The trial is designed to compare a hypotensive resuscitation strategy to standard fluid resuscitation for the early treatment of trauma patients in hemorrhagic shock. This thesis examines the clinical outcomes from the first 90 subjects enrolled in the study, with the primary aim of assessing the safety of hypotensive resuscitation within the trauma population. ^ Patients in hemorrhagic shock who required emergent surgery were randomized to one of two arms of the study. Those in the experimental (LMAP) arm were managed with a hypotensive resuscitation strategy in which the target mean arterial pressure was 50mmHg. Those in the control (HMAP) arm were managed with standard fluid resuscitation to a target mean arterial pressure of 65mmHg. Patients were followed for 30 days. Mortality, post-operative complications, and other clinical data were prospectively gathered by the Ben Taub surgical staff and then secondarily analyzed for the purpose of this thesis.^ Subjects in the LMAP group had significantly lower early post-operative mortality compared to those in the HMAP group. 30-day mortality was also lower in the LMAP group, although this did not reach statistical significance. There were no statistically significant differences between the two groups with regards to development of ischemic, hematologic or infectious complications, length of hospitalization, length of ICU stay or duration of mechanical ventilation. ^ Based upon the data presented in this thesis, it appears that hypotensive resuscitation is a safe strategy for use in the trauma population. Specifically, hypotensive resuscitation reduced the risk of early post-operative death from coagulopathic bleeding and did not result in an increased risk of ischemic or other post-operative complications. The preliminary results described in this thesis provide convincing evidence support the continued investigation and use of hypotensive resuscitation in a trauma setting.^

Genome instability quantified in constitutive tissues as well as putatively stable tumor tissue in hereditary non -polyposis colon cancer patients by small pool PCR

Microsatellite instability (MSI) is a hallmark of the mutator phenotype associated with Hereditary Non-Polyposis Colon Cancer (HNPCC). The MSI-High (MSI-H) HNPCC population has been well characterized, but the microsatellite low and stable (MSI-L/MSS) HNPCC population is much less understood. We hypothesize there are significant levels of MSI in HNPCC DNA classified as MSI-L/MSS, but no single variant allele makes up a sufficient population in the tumor DNA to be detected by standard analysis. Finding variants would suggest there is a mutator phenotype for the MSI-L/MSS HNPCC population that is distinct from the MSI-H HNPCC populations. This study quantified and compared MSI in HNPCC patients previously shown to be MSI-H, MSI-L/MSS and an MSI-H older, sporadic colorectal cancer patient. Small-pool Polymerase Chain Reactions (SP-PCRs) were conducted where the DNAs from each sample and controls are diluted into multiple pools, each containing approximately single genome equivalents. At least 100 alleles/sample were studied at six microsatellite loci. Mutant fragments were identified, quantified, and compared using Poisson statistics. Most of the variants were small deletions or insertions, with more mutants being deletions, as has been previously described in yeast and transgenic mice. SP-PCR, where most of the pools contained only 3 or less fragments, enabled identification of variants too infrequent to be detected by large pool PCR. Mutant fragments in positive control MSI-H tumor samples ranged from 0.26 to 0.68 in at least 4 of the 6 loci tested and were consistent with their MSI-H status. In the so called MSS tumors and constitutive tissues (normal colon tissue, and PBLs) of all the HNPCC patients, low, but significant levels of MSI were seen in at least two of the loci studied. This phenomenon was not seen in the sporadic MSI constitutive tissues nor the normal controls and suggests haploinsufficiency, gain-of-function, or a dominant/negative basis of the instability in HNPCC patients carrying germline mutations for tumor suppressor genes. A different frequency and spectrum of mutant fragments suggests a different genetic basis (other than a major mutation in MLH1 or MSH2) for disease in MSI-L and MSS HNPCC patients. ^

Attitudes of Parents at risk of inheriting Li-Fraumeni Syndrome towards predictive genetic testing in their minor-aged children.

Li-Fraumeni Syndrome (LFS) is a hereditary cancer syndrome which predisposes individuals to cancer beginning in childhood. These risks are spread across a lifetime, from early childhood to adulthood. Mutations in the p53 tumor suppressor gene are known to cause the majority of cases of LFS. The risk for early onset cancer in individuals with Li-Fraumeni Syndrome is high. Studies have shown that individuals with LFS have a 90% lifetime cancer risk. Children under 18 have up to a 15% chance of cancer development. Effectiveness of cancer screening and management in individuals with Li-Fraumeni Syndrome is unclear. Screening for LFS-associated cancers has not been shown to reduce mortality. Due to the lack of effective screening techniques for childhood cancers, institutions vary with regard to their policies on testing children for LFS. There are currently no national guidelines regarding predictive testing of children who are at risk of inheriting LFS. No studies have looked at parental attitudes towards predictive p53 genetic testing in their children. This was a cross-sectional pilot study aimed at describing these attitudes. We identified individuals whose children were at risk for inheriting p53 genetic mutations. These individuals were provided with surveys which included validated measures addressing attitudes and beliefs towards genetic testing. The questionnaire included qualitative and quantitative measures. Six individuals completed and returned the questionnaire with a response rate of 28.57%. In general, respondents agreed that parents should have the opportunity to obtain p53 genetic testing for their child. Parents vary in regard to their attitudes towards who should be involved in the decision making process and at what time and under what considerations testing should occur. Testing motivations cited most important by respondents included family history, planning for the future and health management. Concern for insurance genetic discrimination was cited as the most important “con” to genetic testing. Although limited by a poor response rate, this study can give health care practitioners insight into testing attitudes and beliefs of families considering pediatric genetic testing.

An assessment of obesity and hyperphagia in individuals with Smith-Magenis syndrome

Smith-Magenis syndrome (SMS;OMIM# 182290) is a multiple congenital anomalies and mental retardation syndrome caused by a 3.7- Mb deletion on chromosome 17p11.2 or a mutation in the RAI1 gene. Although the majority of the SMS phenotype has been well described, limited studies are available describing growth patterns in SMS. There is some evidence that individuals with SMS develop obesity. Thus, this study aims to characterize the growth and potential influence of hyperphagia in a cohort of individuals with SMS. A retrospective chart review was conducted of 78 individuals with SMS through Baylor College of Medicine (BCM) at Texas Children¡¯s Hospital (TCH.) All documented height and weight measurements were abstracted and Z-scores (SD units) for height-for-age, length-for-age and BMI-for-age were calculated. Mail-out questionnaires were provided to the corresponding parents of the cohort to assess for the presence of hyperphagia through a validated hyperphagia questionnaire (HQ). Analysis of this data demonstrates that by the age ¡Ý 20 years males with SMS have mean BMI¡¯s in the 85th-90th percentile corresponding to an overweight BMI, and females with SMS had mean BMI¡¯s in the 95th -97th percentile corresponding to an obese BMI. Parents indicated that hyperphagia is present in individuals with SMS as 76% of parent¡¯s report having to lock food away from their child. Females¡¯ age ¡Ý 20 years of age had the highest mean behavior, drive and severity scores as well as the highest BMI. Thus, this study concludes that it appears overweight and obesity, as well as hyperphagia, are present in this cohort of SMS individuals. The results of this study will hopefully enable parents and caregivers of children with SMS to take preventative measures in order to control food related behaviors present in their children as well as to prevent overweight and obesity and the associated negative health consequences.

Regulation of survivin gene expression in the human endometrium and endometrial cancer

In the United States, endometrial cancer is the leading cancer of the female reproductive tract. There are 40,100 new cases and 7,470 deaths from endometrial cancer estimated for 2008 (47). The average five year survival rate for endometrial cancer is 84% however, this figure is substantially lower in patients diagnosed with late stage, advanced disease and much higher for patients diagnosed in early stage disease (47). Endometrial cancer (EC) has been associated with several risk factors including obesity, diabetes, hypertension, previously documented occurrence of hereditary non-polyposis colorectal cancer (HNPCC), and heightened exposure to estrogen (25). As of yet, there has not been a dependable molecular predictor of endometrial cancer occurrence in women with these predisposing factors. The goal of our lab is to identify genes that are aberrantly expressed in EC and may serve as molecular biomarkers of EC progression. One candidate protein that we are exploring as a biomarker of EC progression is the cell survival protein survivin.

Factors Associated with Early Versus Late Development of Breast and Ovarian Cancer in BRCA1 and BRCA2 Positive Women

Hereditary breast and ovarian cancer (HBOC) is caused by a mutation in the BRCA1 or BRCA2 genes. Women with a BRCA1/2 mutation are at increased risks for breast and ovarian cancer and often develop cancer at an earlier age than the general population. However, some women with a BRCA1/2 mutation do not develop breast or ovarian cancer under the age of 50 years. There have been no specific studies on BRCA positive women with no cancer prior to age 50, therefore this study sought to investigate factors within these women with no cancer under age 50 with respect to reproductive risk factors, BMI, tumor pathology, screening history, risk-reducing surgeries, and family history. 241 women were diagnosed with cancer prior to age 50, 92 with cancer at age 50 or older, and 20 women were over age 50 with no cancer. Data were stratified based on BRCA1 and BRCA2 mutation status. Within the cohorts we investigated differences between women who developed cancer prior to age 50 and those who developed cancer at age 50 or older. We also investigated the differences between women who developed cancer at age 50 or older and those who were age 50 or older with no cancer. Of the 92 women with a BRCA1/2 mutation who developed cancer at age 50 or older, 46 developed ovarian cancer first, 45 developed breast cancer, and one had breast and ovarian cancer diagnosed synchronously. BRCA2 carriers diagnosed age 50 or older were more likely to have ER/PR negative breast tumors when compared to BRCA2 carriers who were diagnosed before age 50. This is consistent with one other study that has been performed. Ashkenazi Jewish women with a BRCA1 mutation were more likely to be diagnosed age 50 or older than other ethnicities. Hispanic women with a BRCA2 mutation were more likely to be diagnosed prior to age 50 when compared to other ethnicities. No differences in reproductive factors or BMI were observed. Further characterization of BRCA positive women with no cancer prior to age 50 may aid in finding factors important in the development of breast or ovarian cancer.

Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1, and GSTP1 and susceptibility to colorectal cancer in Lynch syndrome.

Individuals with Lynch syndrome are predisposed to cancer due to an inherited DNA mismatch repair gene mutation. However, there is significant variability observed in disease expression likely due to the influence of other environmental, lifestyle, or genetic factors. Polymorphisms in genes encoding xenobiotic-metabolizing enzymes may modify cancer risk by influencing the metabolism and clearance of potential carcinogens from the body. In this retrospective analysis, we examined key candidate gene polymorphisms in CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 as modifiers of age at onset of colorectal cancer among 257 individuals with Lynch syndrome. We found that subjects heterozygous for CYP1A1 I462V (c.1384A>G) developed colorectal cancer 4 years earlier than those with the homozygous wild-type genotype (median ages, 39 and 43 years, respectively; log-rank test P = 0.018). Furthermore, being heterozygous for the CYP1A1 polymorphisms, I462V and Msp1 (g.6235T>C), was associated with an increased risk for developing colorectal cancer [adjusted hazard ratio for AG relative to AA, 1.78; 95% confidence interval, 1.16-2.74; P = 0.008; hazard ratio for TC relative to TT, 1.53; 95% confidence interval, 1.06-2.22; P = 0.02]. Because homozygous variants for both CYP1A1 polymorphisms were rare, risk estimates were imprecise. None of the other gene polymorphisms examined were associated with an earlier onset age for colorectal cancer. Our results suggest that the I462V and Msp1 polymorphisms in CYP1A1 may be an additional susceptibility factor for disease expression in Lynch syndrome because they modify the age of colorectal cancer onset by up to 4 years.

ATM Signaling to TSC2: Mechanisms and Implications for Cancer Therapy

Ataxia telangiectasia mutated (ATM) is a critical component of the cellular response to DNA damage, where it acts as a damage sensor, and signals to a large network of proteins which execute the important tasks involved in responding to the damage, namely inducing cell cycle checkpoints, inducing DNA repair, modulating transcriptional responses, and regulating cell death pathways if the damage cannot be repaired faithfully. We have now discovered that an additional novel component of this ATM-dependent damage response involves induction of autophagy in response to oxidative stress. In contrast to DNA damage-induced ATM activation however, oxidative stress induced ATM, occurs in the cytoplasm, and does not require nuclear-to-cytoplasmic shuttling of ATM. Using several cell culture systems including MCF7 breast carcinoma cells, SKOV3 ovarian cancer cells, and various lineages of mouse embryonic fibroblasts, we showed that once activated by reactive oxygen species (ROS), ATM signals to mTORC1 to induce autophagy via the LKB1-AMPK-TSC2 pathway. Targeting dysregulation of mTORC1 in Atm-deficient mice, which succumb to lymphomagenesis within 3-4 months of age with daily administration of rapamycin, could significantly extend survival and cause regression of tumors, suggesting that pharmacologically targeting this pathway has therapeutic implications in cancer. We also identified a second contrasting pathway for DNA damage-induced mTORC1 repression which does not require AMPK activation, but does require ATM and TSC2. Several potential mechanisms including mTOR localization and p53-mediated pathways were ruled out however we identified that TSC2 may be an additional cytoplasmic direct ATM substrate that is engaged in response to DNA damage specifically. Lastly, a study was performed to examine whether autophagy induced by ovarian cancer therapeutics (focusing on cisplatin, since paclitaxel does not induce autophagy in the SKOV3 cell line model we used) plays a role in resistance to therapy since autophagy can play both pro-survival mechanisms or be a mechanism of cell death. Using a genetic approach to knock-down Atg5 expression with shRNA in SKOV3 ovarian carcinoma cells, we compared the cytotoxicity of cisplatin in vector or Atg5 knock-down cells, and demonstrated that autophagy does not play any significant role in the response to cisplatin in this cell line.

Natural history study of arthrogryposis multiplex congenita, amyoplasia type

Arthrogryposis or Arthrogrypsosis Multiplex Congenita (AMC) are terms used to describe the clinical finding of multiple congenital contractures. There are more than 300 distinct disorders associated with arthrogryposis. Amyoplasia is the most common type of arthrogryposis and is often referred to as the “classic” type. There is no known cause of amyoplasia and no risk factors have been identified. Moreover, there is no established diagnostic criteria, which has led to inconsistency and confusion in the medical literature. The purpose of this study was to describe the natural history of amyoplasia, to determine if there are any identifiable risk factors and develop a list of diagnostic criteria. A retrospective chart review of 59 children with arthrogryposis ascertained at the Shriners Hospitals for Children in Houston, Texas was performed and included the following information: prenatal, birth, and family histories, and phenotypic descriptions. Forty-four children were identified with amyoplasia and 15 children with other multiple congenital contractures and other anomalies (MCC) were used as a comparison group. With the exception of abnormal amniotic fluid levels during pregnancy, there were no significant demographic or prenatal risk factors identified. However, we found common features that discriminate amyoplasia from other types of arthrogryposis and developed a diagnostic checklist. This checklist can be used as diagnostic criteria for discriminating amyoplasia from isolated and multiple contracture conditions.

Evaluation of Recurrence Risks for Left-Sided Cardiac Lesions

It is widely accepted that hypoplastic left heart syndrome (HLHS), aortic valve stenosis with or without bicuspid aortic valve (AS/BAV) and coarctation of the aorta (CoA) occur in families more commonly with each other than with any other congenital heart defect (CHD). Genetic counseling for CHDs is currently based on empiric risk estimates derived from data collected on all types of CHDs between 1968 and 1990. Additionally, for the specific group of defects described above, termed left-sided lesions, estimates are available for sibling recurrence. Utilizing family history data from 757 probands recruited between 1997 and 2007 from The Children’s Hospital of Philadelphia, this study reassessed the pre/recurrence risks for LSLs specifically. Sibling pre/recurrence risks for HLHS (5.5%, 95% CI: 3.1%-8.9%), CoA (4.0%, 95% CI: 2.1%-6.7%), and AS/BAV (6.0%, 95% CI: 3.3%-9.8%) were higher than currently quoted risks based on sibling data for individual LSLs. Additionally, the prevalence of BAV in 202, apparently unaffected, parents of 134 probands was assessed by echocardiography. BAV, which occurs at a frequency of 1% in the general population, was found to occur in approximately 10% of parents of LSL probands. Lastly, among affected first-degree relative pairs (i.e. siblings, parent-offspring), the majority (65%-70%) were both affected with a LSL. Defect specific concordance rates were highest for AS/BAV. Together, these findings suggest that over the past 20 years with changing diagnostic capabilities and environmental/maternal conditions (e.g. folic acid fortification, increased maternal diabetes and obesity) recurrence risks may have increased, as compared to current LSL specific risk estimates. Based on these risk estimate increases and prior studies, a protocol for screening first-degree relatives of LSL probands should be devised.

Upregulation of Reactive Oxygen Species During the Retrovirus Life Cycle and Their Roles in a Mutant of Moloney Murine Leukemia Virus, ts1-Mediated Neurodegeneration

Viral invasion of the central nervous system (CNS) and development of neurological symptoms is a characteristic of many retroviruses. The mechanism by which retrovirus infection causes neurological dysfunction has yet to be fully elucidated. Given the complexity of the retrovirus-mediated neuropathogenesis, studies using small animal models are extremely valuable. Our laboratory has used a mutant moloney murine leukemia retrovirus, ts1-mediated neurodegneration. We hypothesize that astrocytes play an important role in ts1-induced neurodegeneration since they are retroviral reservoirs and supporting cells for neurons. It has been shown that ts1 is able to infect astrocytes in vivo and in vitro. Astrocytes, the dominant cell population in the CNS, extend their end feet to endothelial cells and neuronal synapse to provide neuronal support. Signs of oxidative stress in the ts1-infected CNS have been well-documented from previous studies. After viral infection, retroviral DNA is generated from its RNA genome and integrated into the host genome. In this study, we identified the life cycle of ts1 in the infected astrocytes. During the infection, we observed reactive oxygen species (ROS) upregulations: one at low levels during the early infection phase and another at high levels during the late infection phase. Initially we hypothesized that p53 might play an important role in ts1-mediated astrocytic cell death. Subsequently, we found that p53 is unlikely to be involved in the ts1-mediated astrocytic cell death. Instead, p53 phosphorylation was increased by the early ROS upregulation via ATM, the protein encoded by the ataxia-telangiectasia (A-T) mutated gene. The early upregulation of p53 delayed viral gene expression by suppressing expression of the catalytic subunit of NADPH oxidase (NOX). We further demonstrated that the ROS upregulation induced by NOX activation plays an important role in establishing retroviral genome into the host. Inhibition of NOX decreased viral replication and delayed the onset of pathological symptoms in ts1-infected mice. These observations lead us to conclude that suppression of NOX not only prevents the establishment of the retrovirus but also decreases oxidative stress in the CNS. This study provides us with new perspectives on the retrovirus-host cell interaction and sheds light on retrovirus-induced neurodegeneration as a result of the astrocyte-neuron interaction.