Abstract
Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV+ patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count < 100/µL) HIV+ patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements. A group of 19 healthy controls (HC, n = 19) was used as a comparator. T-cell and B-cell lymphopenia was present in PB pre-ART in HIV+ patients. CD4:CD8 and CD4 T- and B-cell PB subsets partly normalized compared to HC post-ART as viral load decreased. Strikingly in LN, ART led to a rapid decrease in interferon signaling pathways and an increase in Tfh, germinal center and IgD-CD27- B cells, consistent with histological findings of post-ART follicular hyperplasia. However, there was evidence of cTfh cells with decreased helper capacity and of limited B-cell receptor diversification post-ART. In conclusion, we found early signs of immune reconstitution, evidenced by a surge in LN germinal center cells, albeit limited in functionality, in HIV+ patients who initiate ART late in disease.
Highlights
Effective antiretroviral therapy (ART) has changed the management of HIV infection from a progressive immune deficiency with life-threatening opportunistic infections to a chronic inflammatory disease [1, 2]
B-cell counts were lower in the HIV+ patients before initiation of ART compared to healthy controls (HC)
We examined the dynamics of early immune reconstitution after ART in patients with advanced HIV
Summary
Effective antiretroviral therapy (ART) has changed the management of HIV infection from a progressive immune deficiency with life-threatening opportunistic infections to a chronic inflammatory disease [1, 2]. ART successfully suppresses viral replication, morbidity and mortality remain high the first 6-12 months of therapy in patients who have severe CD4 T-cell lymphopenia before initiating therapy [3,4,5]. Restoration of full immunologic function is rarely achieved in patients presenting late for ART initiation [6, 7], who appear to be at higher risk for non-communicable complications of HIV such as cardiovascular disease, nonAIDS malignancies, frailty and neurocognitive disorders despite virologic suppression [8,9,10]. Several studies have focused on the peripheral blood in an attempt to delineate the dynamics of immune cell restoration following initiation of ART. In advanced HIV disease, immature/transitional B cells are over-represented in the absence of ART and associate with CD4 T-cell lymphopenia [18]
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