Pre-exposure Prophylaxis for HIV Prevention: Why, What, Who and How

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Waist circumference and cardiometabolic parameters in people of African/Caribbean ancestry with HIV in South London (CKD-AFRICA study)

Background There are no validated waist circumference (WC) cut-offs to define metabolic syndrome in Black people with HIV. Methods Cross-sectional analyses within the CKD-AFRICA study. We used Pearson correlation coefficients and receiver operating characteristic (ROC) curves to describe the relationship between WC and cardiometabolic parameters including triglycerides, cholesterol, glucose, glycated haemoglobin (HbA1c), and homeostatic model assessment for insulin resistance (HOMA-IR), and to identify optimal WC cut-offs for each of these outcomes. Results We included 383 participants (55% female, median age 52 years) with generally well controlled HIV. Female and male participants had similar WC (median 98 vs. 97 cm, p = .16). Generally weak correlations (r2 < 0.2) between WC and other cardiometabolic parameters were observed, with low (<0.7) areas under the ROC curves. The optimal WC cut-offs for constituents of the metabolic syndrome, HbA1c and HOMA-IR ranged from 92 to 101 cm in women and 89-98 cm in men, respectively; these cut-offs had variable sensitivity (52%–100%) and generally poor specificity (28%–72%). Conclusions In this cohort of Black people with HIV, WC cut-offs for cardiometabolic risk factors in male participants were in line with the recommended value of 94 cm while in female participants they vastly exceeded the recommended 80 cm for white women

Supplemental Material - Waist circumference and cardiometabolic parameters in people of African/Caribbean ancestry with HIV in South London (CKD-AFRICA study)

Supplemental Material for Waist circumference and cardiometabolic parameters in people of African/Caribbean ancestry with HIV in South London (CKD-AFRICA study) by Laura Cechin, Lourdez Dominguez-Dominguez, Lucy Campbell, Lisa Hamzah, Julie Fox, Royce P Vincent, Georgios K Dimitriadis, Louise Goff and Frank A Post in International Journal of STD & AIDS.</p

HDACi treatment of CD4 T cells induces NK cell degranulation.

<p>Uninfected CD4 T cells were treated or not with HDACi for 24h and then cultured with NK cells for 5h and stained for extracellular CD107a. A) Representative plot showing CD107a expression in NK cells alone, NK cells treated with 100nM panobinostat for 5h, untreated NK cells co-cultured with CD4 T cells at a 1:1 ratio and untreated NK cells co-cultured with 100nM panobinostat treated CD4 T cells at a 1:1 ratio. B) Mean of four experiments. A Mann-Whitney U test was used. C) CD4 T cells were treated with 20nM panobinostat and 10nM romidepsin and co-cultured with NK cells as in A (n = 9). A Friedman’s test with Dunn’s test for multiple comparisons was performed. D) NK cells were co-cultured with untreated CD4 T or CD4 T cells treated with 333nM vorinostat, 20nM panobinostat, or 10nM romidepsin in the presence of 10μg/mL brefeldin A and cells were intracellularly stained with antibodies against IFN-γ.</p

HDACi treatment of CD4 T cells increases NK mediated killing.

<p>HIV-1 LAI infected CD4 T cells +/- HDACi (targets) were cultured overnight with uninfected CD4 T cells (non-targets) with or without NK cells (effectors) at an E:T:NT ratio of 10:1:1. A) CD4 T cells were treated with 100nM panobinostat and co-cultured with NK cells overnight. The percent p24 reduction with NK co-culture is shown (n = 5). A Mann-Whitney U test was used. B) A representative FATAL assay with Cell Trace Violet (CTV) stained infected CD4 T cells (targets), CFSE stained uninfected CD4 T cells (non-targets) +/- NK cells. C) Mean of four experiments using the FATAL assay. A Mann-Whitney U test used. D) CD4 T cells were treated with 333nM vorinostat (n = 7), 20nM panobinostat (n = 10) and 10nM romidepsin (n = 8) before culture with NK cells. Percent p24 reduction is shown. A Kruskal-Wallis test with Dunn’s test for multiple comparisons was performed. E-G) Uninfected CD4 T cells and infected cells 48 hours post infection were treated for 24 hours with 20nM panobinostat or 10nM romidepsin. Cells were then stained for levels of E) MICA/B, F) ULBP1, and G) ULBP2 (n = 3).</p

HDACi down-regulate HLA class I expression in patient samples.

<p>Fresh CD4 T cells from eight ART treated patients were treated for 24 hours with vorinostat (1uM, 333nm and 50nM), panobinostat (100nM, 20nM, and 5nM), romidepsin (100nM, 10nM, and 5nM) or 300nM prostratin. A) Median fluorescent intensity (MFI) values after treatment with clinically relevant doses are shown. A repeated measures one-way ANOVA with a Greenhouse-Geisser correction with Dunnett’s multiple comparison test was performed. B-D) MFI values reported as a percent reduction compared to untreated levels for vorinostat, panobinostat, and romidepsin dilution series, respectively.</p

HDACi down-regulate HLA class I in uninfected primary CD4 T cells.

<p>A) Unstimulated CD4 T cells from eight HIV negative donors were treated with 1uM vorinostat, 100nm panobinostat or 10nM romidepsin for 24h. Cells were stained for HLA class I. Median fluorescent intensity (MFI) is shown (n = 8). A Friedman test with Dunn’s test for multiple comparisons was performed. B) Data from A was normalized to the MFI of the untreated control and shown as a percentage. C) Culture of primary CD4 T cells from seven new donors was repeated using 333nM vorinostat and 20nM panobinostat (n = 7). A Friedman test with Dunn’s test for multiple comparisons was performed. D) Data from C was normalized to the MFI of the untreated control and shown as a percent.</p

Mechanism of HLA class I down-regulation.

<p>(A, B) Fold up-regulation of HLA class I and β₂ microglobulin RNA, respectively, by qPCR of DMSO and 1uM vorinostat treated samples normalized to untreated controls. All amounts were normalized to 18S copies (n = 3). A Mann-Whitney U test used to compare levels of mRNA expression. C) MFI of total levels (after cell permeabilization) of HLA class I after 24h of culture with HDACi-free media (n = 7), 1uM vorinostat (n = 7), 100nM panobinostat (n = 3) and 10nM romidepsin (n = 3). A Kruskal Wallis test with Dunn’s test for multiple comparisons was performed. D) Kinetics of extracellular and total levels of HLA class I are shown. Extracellular and total values were calculated as a percentage of their respective 0h timepoint MFI (n = 3). E) Cells were treated with 1uM vorinostat or 100nM panobinostat for 24h. Cells were then either washed 3 times or left alone and cultured until HLA class I levels matched untreated controls. Times shown are post wash. Percent down-regulation of HLA class I compared to untreated controls is shown for vorinostat (n = 3) and panobinostat (n = 5).</p

Effects of treating both CD4 T cells and NK cells with HDACi depends on the chosen HDACi.

<p>A) An NK co-culture assay was performed overnight at a 10:1:1 E:T:NT ratio with either infected, untreated CD4 T (targets) and untreated NK cells (effectors) or with 20nM panobinostat treated targets and HDACi treated effectors. Intracellular p24 was measured and compared between the samples with and without NK cells. The difference in p24 expression was then converted to percent killing as described. A Wilcoxon matched-pairs signed rank test was performed (n = 5). In B, a similar co-culture assay was performed using 2 doses of vorinostat (333nM and 50nM), 2 doses of panobinostat (20nM and 5nM), 2 doses of romidepsin (10nM and 5nM) and 300nM prostratin. A Friedman test with Dunn’s multiple comparison test was performed (n = 5). Different colors represent different donors.</p

HDACi do not inhibit CD4 T cell susceptibility to CTL killing.

<p>HIV-1 LAI infected CD4 T cells with or without HDACi treatment (targets) were cultured overnight with uninfected CD4 T cells with or without HDACi treatment (non-targets) and SL9 transduced CD8 T cells (effectors) at an E:T:NT ratio of 1:1:1. HLA class I A*02 negative donors (n = 3) were used as a control. A) Representative plots of infected CD4 T cells in the absence (left) or presence (right) of CD8 T cells. B) Percent p24 reduction was calculated based on the percentage of p24 positive target cells before and after CD8 T cell co-culture, using 100nM panobinostat treated targets (n = 7) and 10nM romidepsin treated targets (n = 6). Different colors represent different donors. Separate Mann-Whitney U tests were performed.</p