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

Pogliaghi M, Ripa M, Pensieroso S, Tolazzi M, Chiappetta S, Nozza S, Lazzarin A, Tambussi G, Scarlatti G - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Università Vita-Salute San Raffaele, Milan, Italy; Department of Infectious and Tropical Diseases, IRCCS Ospedale San Raffaele, Milan, Italy.

ABSTRACT

Introduction: During HIV-1 infection the B-cell compartment undergoes profound changes towards terminal differentiation, which are only partially restored by antiretroviral therapy (cART).

Materials and methods: 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.

Results: 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.

Conclusions: 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.

No MeSH data available.


Related in: MedlinePlus

B-cell subsets distribution and trend of study groups.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.
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pone.0140435.g002: B-cell subsets distribution and trend of study groups.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.

Mentions: Given previous reports that HIV-1 infection is associated with increased terminal differentiation of B-cells [3, 22, 23], we wished to determine the impact on B-cell subsets of PHI in comparison to CHI as well as to healthy controls. Already at BL the frequencies of total B-cells of PHI individuals were significantly lower compared to those of CHI and healthy controls (Fig 2, panel A). Moreover, some of the major B-cell subsets of both PHI and CHI were significantly different compared to those of healthy controls. Specifically, frequency of the immature TR B-cells was preserved in PHI, but was increased in CHI compared to healthy controls. Whereas NV B-cells, the most represented compartment among healthy controls, were decreased in PHI compared to CHI and healthy controls. RM B-cells were preserved and had comparable frequencies in PHI and CHI. Interestingly, AM and TLM B-cells were increased in PHI to levels to those of CHI. Finally, PHI had a significantly expanded pool of Plasma cells compared to CHI, while, as expected, in healthy controls this subset constituted a negligible portion. Thus, a differentiation toward exhausted B-cells subsets and Plasma cells is already evident during PHI.


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

Pogliaghi M, Ripa M, Pensieroso S, Tolazzi M, Chiappetta S, Nozza S, Lazzarin A, Tambussi G, Scarlatti G - PLoS ONE (2015)

B-cell subsets distribution and trend of study groups.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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608708&req=5

pone.0140435.g002: B-cell subsets distribution and trend of study groups.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.
Mentions: Given previous reports that HIV-1 infection is associated with increased terminal differentiation of B-cells [3, 22, 23], we wished to determine the impact on B-cell subsets of PHI in comparison to CHI as well as to healthy controls. Already at BL the frequencies of total B-cells of PHI individuals were significantly lower compared to those of CHI and healthy controls (Fig 2, panel A). Moreover, some of the major B-cell subsets of both PHI and CHI were significantly different compared to those of healthy controls. Specifically, frequency of the immature TR B-cells was preserved in PHI, but was increased in CHI compared to healthy controls. Whereas NV B-cells, the most represented compartment among healthy controls, were decreased in PHI compared to CHI and healthy controls. RM B-cells were preserved and had comparable frequencies in PHI and CHI. Interestingly, AM and TLM B-cells were increased in PHI to levels to those of CHI. Finally, PHI had a significantly expanded pool of Plasma cells compared to CHI, while, as expected, in healthy controls this subset constituted a negligible portion. Thus, a differentiation toward exhausted B-cells subsets and Plasma cells is already evident during PHI.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Università Vita-Salute San Raffaele, Milan, Italy; Department of Infectious and Tropical Diseases, IRCCS Ospedale San Raffaele, Milan, Italy.

ABSTRACT

Introduction: During HIV-1 infection the B-cell compartment undergoes profound changes towards terminal differentiation, which are only partially restored by antiretroviral therapy (cART).

Materials and methods: 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.

Results: 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.

Conclusions: 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.

No MeSH data available.


Related in: MedlinePlus