TRIM5α Resistance Escape Mutations in the Capsid Are Transferable between Simian Immunodeficiency Virus Strains.

TRIM5α polymorphism limits and complicates the use of simian immunodeficiency virus (SIV) for evaluation of human immunodeficiency virus (HIV) vaccine strategies in rhesus macaques. We previously reported that the TRIM5α-sensitive SIV from sooty mangabeys (SIVsm) clone SIVsmE543-3 acquired amino acid substitutions in the capsid that overcame TRIM5α restriction when it was passaged in rhesus macaques expressing restrictive TRIM5α alleles. Here we generated TRIM5α-resistant clones of the related SIVsmE660 strain without animal passage by introducing the same amino acid capsid substitutions. We evaluated one of the variants in rhesus macaques expressing permissive and restrictive TRIM5α alleles. The SIVsmE660 variant infected and replicated in macaques with restrictive TRIM5α genotypes as efficiently as in macaques with permissive TRIM5α genotypes. These results demonstrated that mutations in the SIV capsid can confer SIV resistance to TRIM5α restriction without animal passage, suggesting an applicable method to generate more diverse SIV strains for HIV vaccine studies. IMPORTANCE: Many strains of SIV from sooty mangabey monkeys are susceptible to resistance by common rhesus macaque TRIM5α alleles and result in reduced virus acquisition and replication in macaques that express these restrictive alleles. We previously observed that spontaneous variations in the capsid gene were associated with improved replication in macaques, and the introduction of two amino acid changes in the capsid transfers this improved replication to the parent clone. In the present study, we introduced these mutations into a related but distinct strain of SIV that is commonly used for challenge studies for vaccine trials. These mutations also improved the replication of this strain in macaques with the restrictive TRIM5α genotype and thus will eliminate the confounding effects of TRIM5α in vaccine studies.

TRIM5 suppresses cross-species transmission of a primate immunodeficiency virus and selects for emergence of resistant variants in the new species.

Simian immunodeficiency viruses of sooty mangabeys (SIVsm) are the source of multiple, successful cross-species transmissions, having given rise to HIV-2 in humans, SIVmac in rhesus macaques, and SIVstm in stump-tailed macaques. Cellular assays and phylogenetic comparisons indirectly support a role for TRIM5alpha, the product of the TRIM5 gene, in suppressing interspecies transmission and emergence of retroviruses in nature. Here, we investigate the in vivo role of TRIM5 directly, focusing on transmission of primate immunodeficiency viruses between outbred primate hosts. Specifically, we retrospectively analyzed experimental cross-species transmission of SIVsm in two cohorts of rhesus macaques and found a significant effect of TRIM5 genotype on viral replication levels. The effect was especially pronounced in a cohort of animals infected with SIVsmE543-3, where TRIM5 genotype correlated with approximately 100-fold to 1,000-fold differences in viral replication levels. Surprisingly, transmission occurred even in individuals bearing restrictive TRIM5 genotypes, resulting in attenuation of replication rather than an outright block to infection. In cell-culture assays, the same TRIM5 alleles associated with viral suppression in vivo blocked infectivity of two SIVsm strains, but not the macaque-adapted strain SIVmac239. Adaptations appeared in the viral capsid in animals with restrictive TRIM5 genotypes, and similar adaptations coincide with emergence of SIVmac in captive macaques in the 1970s. Thus, host TRIM5 can suppress viral replication in vivo, exerting selective pressure during the initial stages of cross-species transmission.

Late preterm birth and risk of developing asthma.

OBJECTIVE: To evaluate the association between gestational age at birth (late preterm vs term) and risk for physician-diagnosed asthma. STUDY DESIGN: We conducted a retrospective cohort study using the Third National Health and Nutrition Examination Survey (1988-1994) linked natality files. The study included children age 2-83 months from singleton births, born late preterm (n=537) or term (n=5650). Using survival analysis, we modeled time to diagnosis of asthma; children with no asthma diagnosis were censored at the age of their survey interview. We used Cox proportional hazard regression to estimate hazard ratios and 95% confidence intervals for gestational age and asthma risk, adjusting for maternal age, maternal education, parental history of asthma/hay fever, maternal smoking history during pregnancy, race/ethnicity, and sex of the child. RESULTS: Adjusted analysis showed that physician-diagnosed asthma was modestly associated with late preterm birth (hazard ratio, 1.3; 95% confidence interval, 0.8-2.0), but this association was not statistically significant (P=.30). CONCLUSIONS: Our study found that late preterm birth was not associated with a diagnosis of asthma in early childhood.

Gestational diabetes mellitus: all Asians are not alike.

OBJECTIVE: To estimate the prevalence of gestational diabetes mellitus (GDM) prevalence estimates for subgroups of US Asian and Pacific Islander (API) women by using data from 2005 and 2006 birth certificates. METHODS: Using 2005-2006 natality files from states that implemented the revised 2003 US birth certificate, which differentiates between GDM and preexisting diabetes (2005: 12 states; 2006: 19 states), we calculated age-adjusted GDM prevalence estimates for API mothers who delivered singleton infants. RESULTS: Among 3,108,877 births, US APIs had a substantially higher age-adjusted prevalence of GDM (6.3%) than whites (3.8%), blacks (3.5%), or Hispanics (3.6%). Among API subgroups, age-adjusted GDM prevalence varied significantly, from 3.7% among women of Japanese descent to 8.6% among women of Asian Indian descent. Foreign-born APIs had significantly higher GDM rates than US-born APIs except among women of Japanese and Korean ancestry. CONCLUSION: Overall, US API women have the highest risk for GDM among all US racial/ethnic groups. However, APIs are a heterogeneous group by genetic background, culture, and diet and other lifestyle behaviors. Our findings imply that, whenever possible, API subgroups should be evaluated separately in health research.

Abortion surveillance - United States, 2007.

PROBLEM/CONDITION: Since 1969, CDC has conducted abortion surveillance to document the number and characteristics of women obtaining legal induced abortions in the United States. REPORTING PERIOD COVERED: 2007. DESCRIPTION OF SYSTEM: Each year, CDC requests abortion data from the central health agencies of 52 reporting areas (the 50 states, the District of Columbia, and New York City). This information is provided voluntarily. For 2007, data were received from 49 reporting areas. For the purpose of trend analysis, data were evaluated from the 45 areas that reported data every year during the preceding decade (1998-2007). Abortion rates (number of abortions per 1,000 women) and ratios (number of abortions per 1,000 live births) were calculated using census and natality data, respectively. RESULTS: A total of 827,609 abortions were reported to CDC for 2007. Among the 45 reporting areas that provided data every year during 1998-2007, a total of 810,582 abortions (97.9% of the total) were reported for 2007; the abortion rate was 16.0 abortions per 1,000 women aged 15-44 years, and the abortion ratio was 231 abortions per 1,000 live births. Compared with 2006, the total number and rate of reported abortions decreased 2%, and the abortion ratio decreased 3%. Reported abortion numbers, rates, and ratios were 6%, 7%, and 14% lower, respectively, in 2007 than in 1998. Women aged 20-29 years accounted for 56.9% of all abortions in 2007 and for the majority of abortions during the entire period of analysis (1998-2007). In 2007, women aged 20-29 years also had the highest abortion rates (29.4 abortions per 1,000 women aged 20-24 years and 21.4 abortions per 1,000 women aged 25-29 years). Adolescents aged 15-19 years accounted for 16.5% of all abortions in 2007 and had an abortion rate of 14.5 abortions per 1,000 adolescents aged 15-19 years; women aged ≥35 years accounted for a smaller percentage (12.0%) of abortions and had lower abortion rates (7.7 abortions per 1,000 women aged 35-39 years and 2.6 abortions per 1,000 women aged ≥40 years). During 1998-2007, the abortion rate increased among women aged ≥35 years but decreased among adolescents aged ≤19 years and among women aged 20-29 years. In contrast to the percentage distribution of abortions and abortion rates, abortion ratios were highest at the extremes of reproductive age, both in 2007 and throughout the entire period of analysis. During 1998-2007 abortion ratios decreased among women in all age groups except for those aged <15 years. In 2007, most (62.3%) abortions were performed at ≤8 weeks' gestation, and 91.5% were performed at ≤13 weeks' gestation. Few abortions (7.2%) were performed at 14-20 weeks' gestation, and 1.3% were performed at ≥21 weeks' gestation. During 1998-2007, the percentage of abortions performed at ≤13 weeks' gestation remained stable; however, abortions performed at ≥16 weeks' gestation decreased by 13%-14%, and among the abortions performed at ≤13 weeks' gestation, the percentage performed at ≤6 weeks' gestation increased 65%. In 2007, 78.1% of abortions were performed by curettage at ≤13 weeks' gestation, and 13.1% were performed by early medical abortion (a nonsurgical abortion at ≤8 weeks' gestation); 7.9% of abortions were performed by curettage at >13 weeks' gestation. Among the 62.3% of abortions that were performed at ≤8 weeks' gestation, and thus were eligible for early medical abortion, 20.3% were completed by this method. Deaths of women associated with complications from abortions for 2007 are being investigated under CDC's Pregnancy Mortality Surveillance System. In 2006, the most recent year for which data were available, six women were reported to have died as a result of complications from known legal induced abortions. No reported deaths were associated with known illegal induced abortions. INTERPRETATION: Among the 45 areas that reported data every year during 1998-2007, the total number, rate, and ratio of reported abortions decreased during 2006-2007. This decrease reversed the increase in reported abortion numbers and rates that occurred during 2005-2006; however, reported abortion numbers and rates for 2007 still were higher than they had been previously in 2005. In 2006, as in previous years, reported deaths related to abortion were rare. PUBLIC HEALTH ACTION: Abortion surveillance in the United States continues to provide the data needed to examine trends in the number and characteristics of women obtaining abortions. Policymakers and program planners can use these data to guide and evaluate efforts to prevent unintended pregnancies.

Abortion surveillance--United States, 2008.

PROBLEM/CONDITION: Since 1969, CDC has conducted abortion surveillance to document the number and characteristics of women obtaining legal induced abortions in the United States. REPORTING PERIOD COVERED: 1999-2008. DESCRIPTION OF SYSTEM: Each year, CDC requests abortion data from the central health agencies of 52 reporting areas (the 50 states, the District of Columbia, and New York City). This information is provided voluntarily. For 2008, data were received from 49 reporting areas. For the purpose of trend analysis, data were evaluated from the 45 areas that reported data every year during 1999-2008. Abortion rates (number of abortions per 1,000 women) and ratios (number of abortions per 1,000 live births) were calculated using census and natality data, respectively. RESULTS: A total of 825,564 abortions were reported to CDC for 2008. Of these, 808,528 abortions (97.9% of the total) were from the 45 reporting areas that provided data every year during 1999-2008. Among these same 45 reporting areas, the abortion rate for 2008 was 16.0 abortions per 1,000 women aged 15-44 years, and the abortion ratio was 234 abortions per 1,000 live births. Compared with 2007, the total number and rate of reported abortions for these 45 reporting areas essentially were unchanged, although the abortion ratio was 1% higher. Reported abortion numbers, rates, and ratios remained 3%, 4%, and 10% lower, respectively, in 2008 than they had been in 1999. Women aged 20-29 years accounted for 57.1% of all abortions reported in 2008 and for the majority of abortions during the entire period of analysis (1999-2008). In 2008, women aged 20-29 years also had the highest abortion rates (29.6 abortions per 1,000 women aged 20-24 years and 21.6 abortions per 1,000 women aged 25-29 years). Adolescents aged 15-19 years accounted for 16.2% of all abortions in 2008 and had an abortion rate of 14.3 abortions per 1,000 adolescents aged 15-19 years; women aged ≥35 years accounted for a smaller percentage (11.9%) of abortions and had lower abortion rates (7.8 abortions per 1,000 women aged 35-39 years and 2.7 abortions per 1,000 women aged ≥40 years). Throughout the period of analysis, abortion rates decreased among adolescents aged ≤19 years, whereas they increased among women aged ≥35 years. Among women aged 20-24 years abortion rates decreased during 1999-2003 and then leveled off during 2004-2008. In contrast to the percentage distribution of abortions and abortion rates by age, abortion ratios in 2008 and throughout the entire period of analysis were highest among adolescents aged ≤19 years and lowest among women aged 30-39 years. Abortion ratios decreased during 1999-2008 for women in all age groups except for those aged <15 years; however, the steady decrease was interrupted from 2007 to 2008 when abortion ratios increased among women in all age groups except for those aged ≥40 years. In 2008, most (62.8%) abortions were performed at ≤8 weeks' gestation, and 91.4% were performed at ≤13 weeks' gestation. Few abortions (7.3%) were performed at 14-20 weeks' gestation, and even fewer (1.3%) were performed at ≥21 weeks' gestation. During 1999-2008, the percentage of abortions performed at ≤13 weeks' gestation remained stable, whereas abortions performed at ≥16 weeks' gestation decreased 13%-17%. Moreover, among the abortions performed at ≤13 weeks' gestation, the distribution shifted toward earlier gestational ages, with the percentage of abortions performed at ≤6 weeks' gestation increasing 53%. In 2008, 75.9% of abortions were performed by curettage at ≤13 weeks' gestation, and 14.6% were performed by early medical abortion (a nonsurgical abortion at ≤8 weeks' gestation); 8.5% of abortions were performed by curettage at >13 weeks' gestation. Among the 62.8% of abortions that were performed at ≤8 weeks' gestation and thus were eligible for early medical abortion, 22.5% were completed by this method. The use of medical abortion increased 17% from 2007 to 2008. Deaths of women associated with complications from abortions for 2008 are being investigated under CDC's Pregnancy Mortality Surveillance System. In 2007, the most recent year for which data were available, six women were reported to have died as a result of complications from known legal induced abortions. No reported deaths were associated with known illegal induced abortions. INTERPRETATION: Among the 45 areas that reported data every year during 1999-2008, the total number and rate of reported abortions essentially did not change from 2007 to 2008. This finding is consistent with the recent leveling off from steady decreases that had been observed in the past. In contrast, the abortion ratio increased from 2007 to 2008 after having decreased steadily. In 2007, as in previous years, reported deaths related to abortion were rare. PUBLIC HEALTH ACTION: This report provides the data for examining trends in the number and characteristics of women obtaining abortions. This information is needed to better understand the reasons why efforts to reduced unintended pregnancy have stalled and can be used by policymakers and program planners to guide and evaluate efforts to prevent unintended pregnancy.

Flow cytometry based identification of simian immunodeficiency virus Env-specific B lymphocytes.

SIV infection of macaques is the most widely employed model for preclinical AIDS vaccine and pathogenesis research. In macaques, high-titer virus-specific antibodies are induced by infection, and antibody responses can drive evolution of viral escape variants. However, neutralizing antibodies (Nabs) induced in response to SIVmac239 and SIVmac251 infection or immunization are generally undetectable or of low titer, and the identification and cloning of potent Nabs from SIVmac-infected macaques remains elusive. Based on recent advances in labeling HIV-specific B lymphocytes [1-3], we have generated recombinant, secreted, soluble SIVmac envelope (Env) proteins (gp120 and gp140) for detection and quantification of SIVmac Env-specific B lymphocytes. In contrast to HIV-1, we found that soluble SIVmac239 gp140 retains the ability to form stable oligomers without the necessity for introducing additional, stabilizing modifications. Soluble oligomeric gp140 reacted with rhesus anti-SIV Env-specific monoclonal antibodies (MAbs), and was used to deplete Env-specific antibodies with SIV neutralization capability from plasma taken from a rhesus macaque immunized with live attenuated SIVmac239∆nef. Soluble gp120 and gp140 bound to SIV-specific immortalized B cells, and to SIV Env-specific B lymphocytes in peripheral blood of immunized animals. These reagents will be useful for analyzing development of Env-specific B cell responses in preclinical studies using SIV-infected or vaccinated rhesus macaques.