Christine Mant

High prevalence of human papillomavirus type 16 infection among children

Infection with high‐risk human papillomaviruses (HPV), is the most significant risk factor for cervical cancer and it may be possible to prevent this malignancy by immunisation. Before immunisation programmes can be designed, however, it is necessary to know the age of acquisition and all routes of infection for these viruses. Sexual transmission is well documented and vertical transmission has also been demonstrated, although the frequency of transmission remains controversial. We previously showed that vertical transmission frequently results in persistent infection, and now present data on the prevalence of HPV‐16 DNA (the most prevalent high‐risk HPV type) in healthy children. Buccal samples from 267 healthy children aged 3–11 years were tested for HPV DNA by generic PCR (MY09/MY11), and a HPV‐16 specific nested PCR. Reverse transcriptase (RT)‐PCR was used to determine the prevalence of transcriptionally active HPV‐16 infection in a subset of children. HPV‐16 DNA was detected by nested PCR in 138 of 267 (51.7%) samples, whereas HPV DNA was detected in only 45 (16.8%) specimens by generic PCR, that has a lower analytical sensitivity. There were no significant differences in prevalence according to age or sex. Early region mRNA was detected by RT‐PCR in six (11.3%) of 53 HPV‐16 E5 DNA positive samples. HPV‐16 E5 DNA sequences from 10 children confirmed the identity of the sequences detected and identified 13 HPV‐16 variants. J. Med. Virol. 61:70–75, 2000.

Cervical lesions are associated with human papillomavirus type 16 intratypic variants that have high transcriptional activity and increased usage of common mammalian codons.

Human papillomavirus type 16 (HPV-16) is a major cause of cervical neoplasia, but only a minority of HPV-16 infections result in cancer. Whether particular HPV-16 variants are associated with cervical disease has not yet been clearly established. An investigation of whether cervical neoplasia is associated with infection with HPV-16 intratypic variants was undertaken by using RFLP analyses in a study of 100 HPV-16 DNA-positive women with or without neoplasia. RFLP variant 2 was positively associated [odds ratio (OR)=2.57] and variant 5 was negatively associated with disease (OR=0.2). Variant 1, which resembles the reference isolate of HPV-16, was found at a similar prevalence among those with and without neoplasia. Variants 1 and 2 were also more likely to be associated with detectable viral mRNA than variant 5 (respectively P=0.03 and P=0.00). When HPV-16 E5 ORFs in 50 clones from 36 clinical samples were sequenced, 19 variant HPV-16 E5 DNA sequences were identified. Twelve of these DNA sequences encoded variant E5 amino acid sequences, 10 of which were novel. Whilst the associations between HPV-16 E5 RFLP variants and neoplasia could not be attributed to differences in amino acid sequences, correlation was observed in codon usage. DNA sequences of RFLP variant 2 (associated with greatest OR for neoplasia) had a significantly greater usage of common mammalian codons compared with RFLP pattern 1 variants.

A Viral Aetiology for Breast Cancer: Time to Re-Examine the Postulate

Despite decades of research, no aetiologic factor(s) for human breast cancer has been identified and the search for a causal agent has all but been abandoned during the past thirty years. Over 60 years ago, it was demonstrated that breast tumours in mice are caused by an oncornavirus, murine mammary tumour virus (MMTV). Whilst many at that time postulated a similar virus might be the causative agent of human breast cancer, genetic evidence was difficult to obtain primarily because of the occurrence of endogenous human retrovirus (HER) sequences within the human genome that share extensive regions of nucleotide homology with MMTV. Recently, there has been a resurgence of interest in the possibility that a significant proportion of human breast cancers may be caused by viral infections. Two candidate viruses have been proposed, a human retroviral analogue of MMTV (which differs significantly in sequence and characteristics from HERs) and, the Epstein-Barr virus (γ-herpes virus). These two viruses have been reported to occur in up to 37 and 50% of breast cancer cases, respectively. Here we present the background to the infectious hypothesis for the aetiology of breast cancer and review recent findings.

Effects on vitamin D, bone and the kidney of switching from fixed-dose tenofovir disoproxil fumarate/emtricitabine/efavirenz to darunavir/ritonavir monotherapy: a randomized, controlled trial (MIDAS).

BACKGROUND Efavirenz (EFV) has been associated with reductions in vitamin D (25[OH]D) and tenofovir (TDF) with increased bone turnover, reductions in bone mineral density (BMD) and renal tubular dysfunction. We hypothesized that switching from fixed-dose TDF/emtricitabine (FTC)/EFV to darunavir/ritonavir monotherapy (DRV/r) might increase 25(OH)D and BMD, and improve renal tubular function. METHODS Subjects with HIV RNA <50 copies/ml on TDF/FTC/EFV for ≥6 months were randomized 1:1 to ongoing TDF/FTC/EFV or DRV/r (800/100 mg once daily) for 48 weeks. The primary end point was change from baseline in 25(OH)D at week 48. Secondary end points included changes in BMD, bone turnover markers and renal tubular function. RESULTS A total of 64 subjects (86% male, 66% white, mean [sd] CD4(+) T-cell count 537.3 [191.5]/mm(3)) were analysed. After adjustment for baseline 25(OH)D and demographics, at week 48 DRV/r monotherapy was associated with a +3.6 (95% CI 0.6, 6.6) ng/ml increase in 25(OH)D compared to TDF/FTC/EFV (P=0.02). DRV/r monotherapy was associated with an increase in BMD (+2.9% versus -0.003% at the neck of femur and +2.6% versus +0.008% at the lumbar spine for DRV/r versus TDF/FTC/EFV; P<0.05 for all) and reductions in bone biomarkers compared with those remaining on TDF/FTC/EFV. No significant difference in renal tubular function was observed. Reasons for discontinuation in the DRV/r arm included side effects (n=4) and viral load rebound (n=3), all of which resolved with DRV/r discontinuation or regimen intensification. CONCLUSIONS Switching from TDF/FTC/EFV to DRV/r in patients with suppressed HIV RNA resulted in significant improvements in 25(OH)D and bone biomarkers, and a 2-3% increase in BMD.

Human tissue biobanks: the balance between consent and the common good

Biobanks are currently archiving human materials for medical research at a hitherto unprecedented rate. These valuable resources will be essential for developing ‘personalized’ medicines and for a better understanding of disease susceptibilities. However, for such scientific advances to benefit everyone, it is crucial that biobanks recruit donations from all sections of the community. Unfortunately, other initiatives, such as transplant programmes, have clearly demonstrated that ethnic minorities are under-represented. Here we suggest that this issue deserves serious consideration to avoid biobanks evolving into ethnically biased archives which unwittingly promote race-specific research. Specifically, this necessitates research ethics committees engaging in a re-assessment of the relative merits of individual personal sovereignty and the common good.

Bridging the financial gap through providing contract services: a model for publicly funded clinical biobanks.

Biobanks offer translational researchers a novel method of obtaining clinical research materials, patient data, and relevant ethical and legal permissions. However, such tissue collections are expensive to establish and maintain. Current opinion is that such initiatives can only survive with core funding from Government or major funding bodies. Given the present climate of financial austerity, funding agencies may be tempted to invest in fast-return research projects rather than in maintaining tissue collections, whose benefits will only become apparent in much longer timescales. Thus, securing additional funding for biobanks could provide a valuable boost enabling an extension of core services. Here we suggest that using biobank expertise to offer contract services to clinicians and industry may be an alternative approach to obtaining such extra funding.

Lack of effect of Maraviroc intensification on blood and gut reservoir

We show that intensification of treatment with maraviroc in patients chronically infected with HIV-1 receiving successful long-term antiretroviral therapy was not associated with improvements in HIV-related morbidity, HIV reservoir, microbial translocation, immune activation, or immune exhaustion in either gut or peripheral blood. The measurement of reservoir in both gut and blood longitudinally contributes to a paucity of data in the area.Abstract We show that intensification of treatment with maraviroc in patients chronically infected with HIV-1 receiving successful long-term antiretroviral therapy was not associated with improvements in HIV-related morbidity, HIV reservoir, microbial translocation, immune activation, or immune exhaustion in either gut or peripheral blood. The measurement of reservoir in both gut and blood longitudinally contributes to a paucity of data in the area.

Ethical and Legal Considerations in Human Biobanking: Experience of the Infectious Diseases BioBank at King’s College London, UK

Since the dawn of time Homo sapiens have collected human body-parts for a variety of reasons (Lassila B Aquaron et al., 2009; Daily Telegraph, 2011). Similarly, representations of pathological lesions have been collected for educational purposes for at least three hundred years (e.g. the Hunterian Museum in Glasgow has preserved plaster casts of diseased tissues). A biobank is a generic term to describe any collection of biological materials and may take many forms, ranging from the preservation of plant seeds (e.g the Svalbard Global Seed Vault, Norway) or, the storage of human materials for transplants (e.g. corneal biobanks). Others collect human materials for artificial insemination (sperm, eggs and embryos), for forensic investigations and animal materials to assist in the preservation of endangered species such as the Iberian lynx (Leon-Quinto et al., 2009). Some biobanks only collect a single type of sample such as DNA (genebanks), whilst others archive a wide variety of clinical materials. Until recently the modus operandi of most medical researchers was to use fresh clinical materials to test a specific hypothesis. The premise was either proven, or not, and then the process repeated to answer subsequent questions. This approach is incredibly wasteful since materials not directly needed to test each argument were discarded. In contrast, clinical biobanks can archive and distribute complete sets of materials from patients with diseases to multiple researchers thereby maximising the benefit of every donation. They can also revolutionise the understanding of very rare conditions by gradually accumulating sufficient numbers of samples –or, by the exchange of samples between multiple biobanks (networking) to permit statistically-significant conclusions to be derived. These advantages of biobanks were recognized by Time magazine as ‘one of the ten ideas that are changing the world right now’ (Park, 2009). This Chapter will be confined to those issues confronting biobanks which collect human materials for medical research. Such

Early antiretroviral therapy reduces HIV DNA following perinatal HIV infection

&NA; The impact of antiretroviral therapy (ART) on the size of the HIV reservoir has implications for virological remission in adults, but is not well characterized in perinatally acquired infection. In a prospective observational study of 20 children with perinatally acquired infection and sustained viral suppression on ART for more than 5 years, proviral DNA was significantly higher in deferred (>4 years) versus early (first year of life) ART recipients (P = 0.0062), and correlated with age of initiation (P = 0.13; r = 0.57). No difference was seen in cell-associated viral RNA (P = 0.36). Identifying paediatric populations with smaller reservoirs may inform strategies with potential to induce ART-free remission.

No Benefit of Standard Vitamin D/Calcium Supplementation in HIV-infectedIndividuals

Juan Tiraboschi1*, Fowzia Ibrahim2, Alistair Teague1, Christine Mant2, Tracy Dew2, John Cason2, and Julie Fox1 1Guy ́s and St Thomas ́Hospital NHS Foundation Trust, HIV Services, United Kingdom 2Kings College London, United Kingdom *Corresponding author: Juan Tiraboschi, Guy ́s and St Thomas ́Hospital NHS Foundation Trust, HIV Services, Westminster Bridge Road, United Kingdom, Tel: 004420-7188-2608/9; E-mail: juanmanuel.tiraboschi@gstt.nhs.uk