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

Manuela Pogliaghi,Giuseppe Tambussi,Silvia Nozza,Monica Tolazzi,Marco Ripa,Gabriella Scarlatti,Simone Pensieroso,Adriano Lazzarin,Stefania Chiappetta,D William Cameron

doi:10.1371/journal.pone.0140435

Manuela Pogliaghi, Giuseppe Tambussi + Show 8 more

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https://doi.org/10.1371/journal.pone.0140435

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Abstract

IntroductionDuring HIV-1 infection the B-cell compartment undergoes profound changes towards terminal differentiation, which are only partially restored by antiretroviral therapy (cART).Materials and MethodsTo 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.ResultsDetermination 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.ConclusionsIn 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.

Highlights

MethodsTo 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 combined antiretroviral therapy (cART) as compared to healthy controls (n = 23)
During HIV-1 infection the B-cell compartment undergoes profound changes towards terminal differentiation, which are only partially restored by antiretroviral therapy
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 primary HIV-1 infection (PHI) and chronic HIV-1-infected (CHI) patients

Summary

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 included 19 patients diagnosed with PHI at Fiebig stage III to V, 25 cART-naïve patients with CHI diagnosed at least 0.8 years (median 2.9, IQR 0.8–5.3 years) before enrollment, and 23 healthy controls (CS), defined as HIV-1-negative volunteers reporting no morbidities (age 23 to 67 years) (Table 1). The MAIN study enrolled patients with PHI, who were randomized to receive a PI-based triple-regimen with or without maraviroc (12 and 7 patients, respectively). The VEMAN study enrolled CHI cART-naïve patients randomly assigned to receive once-daily maraviroc plus lopinavir/ritonavir or tenofovir/emtricitabine plus lopinavir/ritonavir regimen (12 and 13 patients, respectively). All patients provided written informed consent approved by the Ethics Board according to national legislation

Results

Discussion

Conclusion