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1.  A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection 
AIDS (London, England)  2015;29(10):1127-1135.
To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity.
This was a pilot, open-label, three-arm prospective phase 1 study.
We recruited 28 patients with low plasma vitamin D (<50 nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200 000 IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4+ T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation.
One month of vitamin D supplementation restored plasma levels to sufficiency (>75 nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1β – an important anti-HIV blocking chemokine – were observed, with a concomitant increase in plasma MIP-1β, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin – a vitamin D response gene with broad antimicrobial activity – was enhanced.
Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy.
PMCID: PMC4516350  PMID: 25870995
cathelicidin; CCL4; CD4+ T cells; HIV; MIP-1β; regulatory T cells; vitamin D
2.  ARV regimen choice and co-morbidities 
BMC Infectious Diseases  2014;14(Suppl 2):S9.
PMCID: PMC4221080
4.  A Cross-Sectional Randomised Study of Fracture Risk in People with HIV Infection in the Probono 1 Study 
PLoS ONE  2013;8(10):e78048.
To determine comparative fracture risk in HIV patients compared with uninfected controls.
A randomised cross-sectional study assessing bone mineral density (BMD), fracture history and risk factors in the 2 groups.
Hospital Outpatients.
222 HIV infected patients and an equal number of age-matched controls. Assessments: Fracture risk factors were assessed and biochemical, endocrine and bone markers measured. BMD was assessed at hip and spine. 10-year fracture probability (FRAX) and remaining lifetime fracture probability (RFLP) were calculated.
Main Outcome Measures
BMD, and history of fractures.
Reported fractures occurred more frequently in HIV than controls, (45 vs. 16; 20.3 vs. 7%; OR=3.27; p=0.0001), and unsurprisingly in this age range, non-fragility fractures in men substantially contributed to this increase. Osteoporosis was more prevalent in patients with HIV (17.6% vs. 3.6%, p<0.0001). BMD was most reduced, and predicted fracture rates most increased, at the spine. Low BMD was associated with antiretroviral therapy (ART), low body mass index and PTH. 10-year FRAX risk was <5% for all groups. RLFP was greater in patients with HIV (OR=1.22; p=0.003) and increased with ART (2.4 vs. 1.50; OR= 1.50; p=0.03).
The increased fracture rate in HIV patients in our relatively youthful population is partly driven by fractures, including non-fragility fractures, in men. Nonetheless, these findings may herald a rise in osteoporotic fractures in HIV patients. An appropriate screening and management response is required to assess these risks and identify associated lifestyle factors that are also associated with other conditions such as cardiovascular disease and diabetes.
PMCID: PMC3812175  PMID: 24205086
5.  How Representative Are Research Tissue Biobanks of the Local Populations? Experience of the Infectious Diseases Biobank at King's College, London, UK 
Biopreservation and Biobanking  2011;9(3):287-288.
Biobanks have a primary responsibility to collect tissues that are a true reflection of their local population and thereby promote translational research, which is applicable to the community. The Infectious Diseases BioBank (IDB) at King's College London is located in the southeast of the city, an area that is ethnically diverse. Transplantation programs have frequently reported a low rate of donation among some ethnic minorities. To determine whether patients who volunteered peripheral venous blood samples to the IDB were representative of the local community, we compared local government demographic data to characteristics of patients who have donated to the IDB. There was a good match between these statistics, indicating that the IDB's volunteer population of human immunodeficiency virus patients was similar to local demographics.
PMCID: PMC3178420  PMID: 21977243
6.  Increased Sensitivity of CD4+ T-Effector Cells to CD4+CD25+ Treg Suppression Compensates for Reduced Treg Number in Asymptomatic HIV-1 Infection 
PLoS ONE  2010;5(2):e9254.
In HIV infection, uncontrolled immune activation and disease progression is attributed to declining CD4+CD25+FoxP3+ regulatory T-cell (Treg) numbers. However, qualitative aspects of Treg function in HIV infection, specifically the balance between Treg cell suppressive potency versus suppressibility of effector cells, remain poorly understood. This report addresses this issue.
Methodology/Principal Findings
A classic suppression assay to measure CD4+CD45RO+CD25hi Treg cells to suppress the proliferation of CD4+CD45RO+CD25− effectors cells (E) following CD3/CD28 polyclonal stimulation was employed to compare the suppressive ability of healthy volunteers (N = 27) and chronic, asymptomatic, treatment naïve, HIV-infected subjects (N = 14). HIV-infected subjects displayed significantly elevated Treg-mediated suppression compared to healthy volunteers (p = 0.0047). Cross-over studies comparing Treg cell potency from HIV-infected versus control subjects to suppress the proliferation of a given population of allogeneic effector cells demonstrated increased sensitivity of CD4+CD25− effector cells from HIV-infected subjects to be suppressed, associated with reduced production of the Treg counter-regulatory cytokine, IL-17, rather than an increase in the suppressive potential of their CD4+CD25+ Treg cells. However, compared to controls, HIV+ subjects had significantly fewer absolute numbers of circulating CD4+CD25+FoxP3+ Treg cells. In vitro studies highlighted that one mechanism for this loss could be the preferential infection of Treg cells by HIV.
Together, novel data is provided to support the contention that elevated Treg-mediated suppression may be a natural host response to HIV infection
PMCID: PMC2822868  PMID: 20174666
7.  Heterosexual and Homosexual Partners Practising Unprotected Sex May Develop Allogeneic Immunity and to a Lesser Extent Tolerance 
PLoS ONE  2009;4(11):e7938.
Epidemiological studies suggest that allogeneic immunity may inhibit HIV-1 transmission from mother to baby and is less frequent in multiparous than uniparous women. Alloimmune responses may also be elicited during unprotected heterosexual intercourse, which is associated ex vivo with resistance to HIV infection.
Methodology/Principal Findings
The investigation was carried out in well-defined heterosexual and homosexual monogamous partners, practising unprotected sex and a heterosexual cohort practising protected sex. Allogeneic CD4+ and CD8+ T cell proliferative responses were elicited by stimulating PBMC with the partners' irradiated monocytes and compared with 3rd party unrelated monocytes, using the CFSE method. Significant increase in allogeneic proliferative responses was found in the CD4+ and CD8+ T cells to the partners' irradiated monocytes, as compared with 3rd party unrelated monocytes (p≤0.001). However, a significant decrease in proliferative responses, especially of CD8+ T cells to the partners' compared with 3rd party monocytes was consistent with tolerization, in both the heterosexual and homosexual partners (p<0.01). Examination of CD4+CD25+FoxP3+ regulatory T cells by flow cytometry revealed a significantly greater proportion of these cells in the homosexual than heterosexual partners practising unprotected sex (p<0.05). Ex vivo studies of infectivity of PBMC with HIV-1 showed significantly greater inhibition of infectivity of PBMC from heterosexual subjects practising unprotected compared with those practising protected sex (p = 0.02).
Both heterosexual and homosexual monogamous partners practising unprotected sex develop allogeneic CD4+ and CD8+ T cell proliferative responses to the partners' unmatched cells and a minority may be tolerized. However, a greater proportion of homosexual rather than heterosexual partners developed CD4+CD25FoxP3+ regulatory T cells. These results, in addition to finding greater inhibition of HIV-1 infectivity in PBMC ex vivo in heterosexual partners practising unprotected, compared with those practising protected sex, suggest that allogeneic immunity may play a significant role in the immuno-pathogenesis of HIV-1 infection.
PMCID: PMC2775923  PMID: 19956755
8.  Intracellular Accumulation of Human Immunodeficiency Virus Protease Inhibitors 
Antimicrobial Agents and Chemotherapy  2002;46(10):3228-3235.
Intracellular accumulation of the protease inhibitors (PIs) saquinavir (SQV), ritonavir (RTV), and indinavir (IDV) was determined in 50 human immunodeficiency virus-positive patients. Following extraction, PIs were quantified by mass spectrometry. Paired plasma and intracellular samples were collected over a full dosing interval from patients (13 on SQV, 6 on RTV, 8 on IDV, 16 on SQV plus RTV, 7 on IDV plus RTV) with a plasma viral load of <400 copies/ml. Data were expressed as intracellular/plasma drug concentration ratios. A hierarchy of intracellular accumulation was demonstrated by the following medians: 9.45 for SQV > 1.00 for RTV > 0.51 for IDV. Coadministration of RTV did not boost ratios of SQV or IDV within the cell or in plasma, although absolute plasma and intracellular SQV concentrations were increased by RTV. Seven individuals receiving SQV in hard-gel capsule form (median, 32 months) had higher intracellular/plasma drug ratios than all other patients receiving SQV (median, 17.62 versus 4.83; P = 0.04), despite consistently low plasma SQV concentrations. How this occurs may provide insight into the mechanisms that limit adequate drug penetration into sanctuary sites.
PMCID: PMC128776  PMID: 12234849
9.  156 HIV and metabolic disease: Clues to control of HIV infection from the immune and virological response to high dose Vitamin D challenge 
Effective use of HAART markedly reduces morbidity and mortality due to classical HIV disease. The 4 key emerging diseases in people with HIV that are amenable to prevention & therapy are Coronary Heart Disease, Renal Disease, Fragility Fractures, Diabetes.
These constitute an increasing burden of morbidity and mortality in HIV uninfected people due to an aging population and are becoming even more prevalent in people with chronic HIV.
The issue is exemplified by fragility fractures, a major cause of mortality in the elderly, and emerging as a manifestation occurring earlier in people with HIV, and increasing in incidence.
The Probono Study from Kings College London demonstrated among 222 patients with matched controls that reported fractures at any site during adulthood occurred more frequently in HIV than controls, 45 (20.3%) vs. 16 (7.2%) (OR = 3.27; P = 0.0001). Osteoporosis was more prevalent in HIV (17.6% vs. 3.6%, P < 0.0001). In HIV, use of highly active antiretroviral therapy (HAART), low body mass and serum PTH were significantly related to low BMD in multivariate analysis.
The changing patterns of morbidity and mortality in HIV, driven by the metabolic consequences of HIV infection itself, and the HAART therapy requires development of an appropriate screening and management response.
PMCID: PMC4149618

Results 1-9 (9)