HIV-1 Tropism Test Evaluation: Assessment and Clinical Implications

CCR5 and CXCR4 chemokines receptors are critical coreceptors for the binding of HIV to specific host cells. Guidelines recommend its assessment in case of virological failure or before prescription of CCR5 inhibitors. Strategies to assess viral tropism may be divided into phenotypic and genotypic assays; registrative trials of CCR5 inhibitors used phenotypic assay, but recently genotypic ones have been used in clinical practice. The presence of CXCR4 is increasing in naïve patients, with both acute and chronic HIV-1 infections; this coreceptor usage is associated with CD4 depletion. The assessment of viral tropism should be considered in every stage of HIV-1 infection

Levels of Soluble Endothelial Protein C Receptor Are Associated with CD4+ Changes in Maraviroc-Treated HIV-Infected Patients

BACKGROUND: Inflammation is a key feature of HIV infection and is correlated with long-term negative cardiovascular outcomes. Therapy-induced increases in CD4(+) cell counts can control inflammation, as shown by decreases of coagulation and inflammation markers during efficacious therapy. Maraviroc, a CCR5-antagonist, has resulted in larger increases in CD4(+) counts both in naïve and experienced subjects compared to traditional antiretroviral therapy. OBJECTIVES AND METHODS: To examine if a member of the protein C anticoagulant and anti-inflammatory pathway, and marker of coagulation and inflammation, the soluble endothelial protein C receptor, is modified by infection and therapy-related variables in patients treated with Maraviroc. Endothelial protein C receptor, together with other established markers of inflammation and coagulation (CRP, IL-6, D-dimer and soluble thrombomodulin) was studied in 43 patients on traditional antiretroviral therapy and in 45 on Maraviroc during 48 weeks of follow-up. RESULTS: Soluble endothelial protein C receptor was the only marker that could discriminate at least partially between patients with a good response to Maraviroc and patients who did not respond with an adequate increase in CD4(+) cell counts (more than 500 cells/µL by week 48). CONCLUSIONS: Elevated levels of soluble endothelial protein C receptor, a sensitive marker of endothelial damage, indicated a low level of inflammation and coagulation activation in Maraviroc treated patients not picked up by other widely used markers. Persistent elevated levels of this marker at 48 weeks from beginning of treatment with Maraviroc were related to a poor increase in CD4(+) cells

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

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

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

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

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

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

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