Age and laboratory variables at baseline of patients on ART (n = 43) or ART and MVC (n = 45).

<p>Results are presented as median and range.</p>*<p>p = 0.013 for direct comparison (Mann-Whitney).</p>§<p>p = 0.003 for direct comparison (Mann-Whitney).</p

Median (range) levels of sEPCR.

<p>Median (range) levels of sEPCR.</p

CD4⁺ cell counts (solid line) and D-dimer levels (broken line) in ART treated (panel a) or ART with MVC treated (panel b) patients, by sEPCR levels at week 48 (high levels = red lines, low levels = blue lines).

<p>High or low sEPCR levels were defined as sEPCR ≥ or <300 ng/mL (corresponding to the 95^th percentile of the normal distribution). As specified in the text, D-dimers levels were measured in all patients up to week 24, while sEPCR was measured in all patients up to weel 48.</p

Changes in metabolic variables and CD4⁺ cell counts over time in patients on ART (solid line, squares) or ART with MVC (broken line, circles).

<p>* denotes p<0.05 and ** p<0.01 for differences between the two patient groups at the time shown (Mann-Whitney test after non parametric analysis of variance for repeated measures).</p

Beneficial Effects of cART Initiated during Primary and Chronic HIV-1 Infection on Immunoglobulin-Expression of Memory B-Cell Subsets

<div><p>Introduction</p><p>During HIV-1 infection the B-cell compartment undergoes profound changes towards terminal differentiation, which are only partially restored by antiretroviral therapy (cART).</p><p>Materials and Methods</p><p>To investigate the impact of infection as early as during primary HIV-1 infection (PHI) we assessed distribution of B-cell subsets in 19 PHI and 25 chronic HIV-1-infected (CHI) individuals before and during 48 weeks of cART as compared to healthy controls (n = 23). We also analysed Immunoglobulin-expression of memory B-cell subsets to identify alterations in Immunoglobulin-maturation.</p><p>Results</p><p>Determination of B-cell subsets at baseline showed that total and Naive B-cells were decreased whereas Activated Memory (AM), Tissue-like Memory (TLM) B-cells and Plasma cells were increased in both PHI and CHI patients. After 4 weeks of cART total B-cells increased, while AM, TLM B-cells and Plasma cells decreased, although without reaching normal levels in either group of individuals. This trend was maintained until week 48, though only total B-cells normalized in both PHI and CHI. Resting Memory (RM) B-cells were preserved since baseline. This subset remained stable in CHI, while was expanded by an early initiation of cART during PHI. Untreated CHI patients showed IgM-overexpression at the expenses of switched (IgM-IgD-) phenotypes of the memory subsets. Interestingly, in PHI patients a significant alteration of Immunoglobulin-expression was evident at BL in TLM cells, and after 4 weeks, despite treatment, in AM and RM subsets. After 48 weeks of therapy, Immunoglobulin-expression of AM and RM almost normalized, but remained perturbed in TLM cells in both groups.</p><p>Conclusions</p><p>In conclusion, aberrant activated and exhausted B-cell phenotypes rose already during PHI, while most of the alterations in Ig-expression seen in CHI appeared later, despite 4 weeks of effective cART. After 48 weeks of cART B-cell subsets distribution improved although without full normalization, while Immunoglobulin-expression normalized among AM and RM, remaining perturbed in TLM B-cells of PHI and CHI.</p></div

Viro-immunological follow-up of study groups.

<p>CD4+ T-cell count (cells/mm³) and plasma viremia (log copies/ml) for PHI and CHI patients are here represented. Left panels show medians with IQR of each parameter; right panels show median values of each time-point to highlight the trend over time. P values are * = 0.01–0.05, ** = 0.001–0.01, *** = <0.001, obtained with Mann-Whitney test for left panels and with Two-sample paired sign test for right panels.</p

HIV-RNA copy levels by time and treatment group.

<p>Data is presented as median and range. 49 copies is the lower limit of detection of the assay, and it was written in the database to indicate that the HIV-RNA was undetectable.</p

Baseline characteristics of study participants.

<p>PHI are individuals recruited at Fiebig stage III to V of HIV-1 infection before donating baseline samples. CHI are chronically HIV-1 infected individuals having been infected for at least 0.8 years (median 2.9, IQR 0.8–5.3 years,) and not receiving cART at recruitment. MSM means Men having sex with men; IVDU means intravenous drug user; WBC means White Blood Cells; AST means aspartate aminotransferase; ALT means alanine aminotransferase. Statistical analysis was performed using (a) Mann-Whitney test and (b) Chi-square test. P values <0.05 were considered significant differences.</p

B-cell subsets distribution and trend of study groups.

<p>Indicated are frequencies of B-cells subsets in PHI and CHI at baseline and after 4 and 48 weeks of cART, as well as values of healthy controls (CS). Column A shows medians with IQR of each parameter; Column B shows median values of each time-point to highlight the trend over time. Dotted horizontal line represents the mean of the CS individuals for a given cell population. P values are * = 0.01–0.05, ** = 0.001–0.01, *** = <0.001, obtained with Mann-Whitney test for results of column A and with Two-sample paired sign test for results of column B.</p

Proportion of patients achieving a HIV-RNA ≤500 copies/mL at 6 months from the date of starting cART.

<p>Proportion of patients achieving a HIV-RNA ≤500 copies/mL at 6 months from the date of starting cART.</p