Major histocompatibility complex class II (HLA-DRB and -DQB) allele frequencies in Botswana: association with human immunodeficiency virus type 1 infection

Southern Africa is facing an unprecedented public health crisis due to the high prevalence of human immunodeficiency virus type 1 (HIV-1). Vaccine development and testing efforts, mainly based on elicitation of HIV-specific T cells, are under way. To understand the role of human leukocyte antigen (HLA) class II alleles in HIV pathogenesis and to facilitate HLA-based HIV-1 vaccine design, we analyzed the frequencies of HLA class II alleles within the southern African country of Botswana. Common HLA class II alleles were identified within the Botswana population through the molecular genotyping of DRB and DQB1 loci. The DRB1 allele groups DRB1*01, DRB1*02/15, DRB1*03, DRB1*11, and DRB1*13 were encountered at frequencies above 20%. Within the DQB1 locus, DQB1*06 (47.7%) was the most common allele group, followed by DQB1*03 (39.2%) and DQB1*04 (25.8%). We found that DRB1*01 was more common in HIV-negative than in HIV-positive individuals and that those who expressed DRB1*08 had lower median viral loads. We demonstrate that the frequencies of certain HLA class II alleles in this Botswana population differ substantially from those in North American populations, including African-Americans. Common allele groups within Botswana cover large percentages of other African populations and could be targeted in regional vaccine designs.     

The role of thiols and disulfides in platelet function

Disulfide bonds formed in newly synthesized proteins in the endoplasmic reticulum of cells are important for protein structure and stability. Recent research, however, emphasizes a role for thiol-disulfide reactions with disulfide bond rearrangement as a dynamic process in cell and protein function, and in platelet function in particular. Protein disulfide isomerase was found on the platelet surface where it appears to play an important role in the platelet responses of aggregation and secretion, as well as activation of the platelet fibrinogen receptor, the alphaIIbbeta3 integrin. Additionally, sulfhydryl groups in alphaIIbbeta3 have been implicated in the activation of this integrin. Physiologic concentrations of reduced glutathione generate sulfhydryls in alphaIIbbeta3 and potentiate sulfhydryl-dependent reactions in alphaIIbbeta3. Sulfhydryl labeling in alphaIIbbeta3 is inhibited by phenylarsine oxide, a reagent that binds to vicinal thiols. As vicinal thiols are in equilibrium with disulfide bonds, they provide redox-sensitive sites in alphaIIbbeta3 able to respond to external or cytoplasmic reducing equivalents. Furthermore, protein disulfide isomerase and sulfhydryls are now implicated in platelet adhesion by a second platelet integrin, the alpha2beta1 collagen receptor. Most recently, extracellular sulfhydryls in the P2Y12 ADP receptor were found to be required for platelet activation by this receptor. We here provide an overview of this field with a focus on recent developments, and conclude with a working model.     

Pregnancy rates and birth outcomes among women on efavirenz-containing highly active antiretroviral therapy in Botswana

BACKGROUND: Millions of HIV-infected women in developing countries are in need of safe and highly effective antiretroviral therapy. Pregnancy rates are usually high in developing countries, and efavirenz (EFV) use in women of childbearing age is of concern because of its potential teratogenicity. METHODS: As part of a prospective study comparing 6 initial highly active antiretroviral therapy (HAART) regimens, 3 of which contained EFV, pregnancy and birth outcomes were evaluated among female participants enrolled in a randomized clinical trial in Botswana. Before enrollment, all female participants indicated a willingness to avoid pregnancy for the 3-year duration of the study. Monthly urine pregnancy testing and regular contraceptive education and counseling were given to all women on study. RESULTS: Four hundred fifty-one (69.4%) of 650 enrolled study participants were female and experienced 71 pregnancies, for a rate of 7.9 per 100 person-years during the study. The mean time from HAART initiation to time of first pregnancy was 385 days. The median birth weight of babies was 2950 g (interquartile range: 2700-3250 g); the gender of babies (24 female and 15 male) and occurrence of early pregnancy loss (42%) and stillbirths (3%) did not differ between EFV- and non-EFV-exposed pregnancies (P=0.7). First-trimester EFV exposure occurred in 38 (53.5%) of the 71 pregnancies; 22 (57.9%) of these 38 pregnancies resulted in live births. One infant (4.5%) of the 22 EFV-exposed live births had a congenital abnormality with right limb shortening that was assessed to be unrelated to EFV exposure. CONCLUSIONS: The restoration of health and longevity in many HAART-treated women is often accompanied by childbearing, as evidenced by the large fraction of women in our cohort who became pregnant despite their initial statements of intent to avoid pregnancy. Of 22 first-trimester EFV-exposed live births, 1 neonate was found to have a major congenital abnormality; however, this defect was unrelated to EFV exposure. The small sample size is insufficient to estimate accurately the underlying risk of congenital malformation after exposure to EFV in early pregnancy, underscoring the importance of reporting to the existing international Antiretroviral Pregnancy Registry. In addition to accessing safe and effective HAART regimens, HIV-infected women require access to comprehensive family planning services, including contraception and procreation counseling.     

Prevalence of human papillomavirus genotypes and associated cervical squamous intraepithelial lesions in HIV-infected women in Botswana

Human papillomaviruses (HPV) constitute one of the most prevalent sexually transmitted infections and are the etiological agents for invasive cervical cancer, the predominant cancer among women in Botswana. However, the prevalence of HPV genotypes in Botswana has yet to be reported. One hundred thirty‐nine endocervical swabs were taken at baseline from HIV‐1 infected, HSV‐2 seropositive women enrolled in a longitudinal cohort study designed to assess the influence of herpes simplex virus‐2 (HSV‐2) infection on genital tract shedding of HIV‐1. Extracted DNA was evaluated for the presence of low‐risk and high‐risk HPV using the Roche Linear Array. Genotyping identified HPV in 95 of 139 women of which 61/95 were infected with high‐risk HPV and 56/95 with low‐risk HPV. The median number of genotypes was 2 (IQR: 1–4). The most prevalent HPV genotype in HIV‐infected women was HPV 58. Abnormal cervical cytology was detected in 87/127 women and was associated with contemporaneous HPV infection (RR = 1.43, 95% CI: 1.05–1.93; P = 0.02). HPV prevalence was high among HIV‐infected women with infection by multiple genotypes being widespread. The associations attributed to specific oncogenic HPV subtypes and cervical squamous intraepithelial lesions presented here provide critical information to inform future vaccine policy within Botswana. J. Med. Virol. 83:1689–1695, 2011. © 2011 Wiley‐Liss, Inc.     

Risk factors for very preterm delivery and delivery of very-small-for-gestational-age infants among HIV-exposed and HIV-unexposed infants in Botswana

Objective

To evaluate risk factors for very preterm delivery (VPTD) and very-small-for-gestational-age (VSGA) births in a country with a high HIV prevalence.

Methods

Obstetric records at 6 hospitals across Botswana were reviewed at delivery; VPTD was defined as birth before 32 weeks of pregnancy and VSGA as birth weight below the 3rd percentile for Botswana-specific norms.

Results

Of 16 219 live births born after 26 weeks of pregnancy, 701 (4.3%) were delivered very preterm and 607 (3.7%) were VSGA; 4347 (28.4%) were documented as HIV-exposed. In a multivariable analysis, HIV infection and hypertension during pregnancy were associated with a VPTD (adjusted odds ratio [AOR]: HIV 1.65, hypertension 1.75) and a VSGA birth (AOR: HIV infection 1.90, hypertension 3.44). Among HIV-infected women, the continuation of highly active antiretroviral therapy (HAART) from before conception was associated with a VSGA birth (AOR 1.75) but not with a VPTD (AOR 0.78). In a secondary analysis, HAART continuation was associated with hypertension during pregnancy (AOR 1.34).

Conclusion

Hypertension and HIV infection were risk factors for a VPTD and a VSGA birth. Continuation of HAART from before conception was associated with a VSGA birth but not with a VPTD.     

Genetic linkage of the tricho-dento-osseous syndrome to chromosome 17q21

Tricho-dento-osseous syndrome (TDO), MIM# 190320, is transmitted as a highly penetrant autosomal dominant trait that is characterized by variable clinical expression. The principal clinical features include kinky/curly hair in infancy, enamel hypoplasia, taurodontism, as well as increased thickness and density of cranial bones. Possible genetic linkage has been reported for TDO with the ABO blood group locus, but the gene defect remains unknown. We have identified four multiplex families (n = 63, 39 affected, 24 unaffected) from North Carolina segregating TDO. We previously have excluded a major locus for TDO in the ABO region for these families. Utilizing a genome-wide search strategy, we obtained conclusive evidence for linkage of the TDO syndrome locus to markers on chromosome 17q21 (D17S791, Z max = 10.54, Theta = 0.00) with no indication of genetic heterogeneity. Multipoint analysis suggests the TDO locus is located in a 7 cM chromosomal segment flanked by D17S932 and D17S941. This finding represents the first step towards isolation and cloning of the TDO gene. Identification of this gene has important implications for understanding normal and abnormal craniofacial development of hair, teeth and bone.      

Retrovirus-encoded transformation-specific polyproteins: expression coordinated with malignant phenotype in cells from different germ layers

A transformation-associated polyprotein designated "gag-x" was previously shown to be induced by the feline sarcoma virus (FeSV) after the nonproductive transformation of rat or mink cells. We found that this protein was also expressed in cells derived from the native species (cat) with or without the production of feline leukemia helper virus (FeLV) and that cats could mount a humoral antibody response to the transformation-specific (x) portion of the molecule. Such antisera also reacted with the feline oncornavirus-associated cell membrane antigen (FOCMA) by membrane immunofluorescence. Expression of the gag-x protein was coordinated with malignant phenotype in that both transformed cat fibroblasts and cultured cells from a FeSV-induced melanoma expressed antigenically indistinguishable proteins of the same size. These cells are derived from different embryonic germ layers, suggesting that such transformation-related proteins may function in a pleiotropic manner when introduced by a virus.     

Multiphasic examinations of the stomach: efficacy of individual techniques and combinations of techniques in detecting 153 lesions

Multiphasic examinations of 153 gastric abnormalities observed radiologically and endoscopically were reviewed to determine the efficacy of four radiologic techniques and of several common combinations of these techniques for examining the stomach. There were 68 gastric ulcers, 12 ulcer scars, 44 cases of gastritis including 27 with erosions, 24 benign neoplasms, and five malignancies. Double-contrast, compression, mucosal relief, and full-column techniques detected 82%, 65%, 62%, and 51%, respectively, of all lesions diagnosed with the complete multiphasic examinations. Results indicate that the greater the number of techniques employed, the more accurate the examination, with biphasic and multiphasic examinations detecting 9%-18% more lesions overall than simple single- or double-contrast studies.