HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis

Abstract

The mechanisms of CD4+ T-cell count decline, the hallmark of HIV disease progression, and its relationship to elevated levels of immune activation are not fully understood. Massive depletion of CD4+ T cells occurs during the course of HIV-1 infection, so that maintenance of adequate CD4+ T-cell levels probably depends primarily on the capacity to renew depleted lymphocytes, that is, the lymphopoiesis. We performed here a comprehensive study of quantitative and qualitative attributes of CD34+ hematopoietic progenitor cells directly from the blood of a large set of HIV-infected persons compared with uninfected donors, in particular the elderly. Our analyses underline a marked impairment of primary immune resources with the failure to maintain adequate lymphocyte counts. Systemic immune activation emerges as a major correlate of altered lymphopoiesis, which can be partially reversed with prolonged antiretroviral therapy. Importantly, HIV disease progression despite elite control of HIV replication or virologic success on antiretroviral treatment is associated with persistent damage to the lymphopoietic system or exhaustion of lymphopoiesis. These findings highlight the importance of primary hematopoietic resources in HIV pathogenesis and the response to antiretroviral treatments.

Factors Contributing to HIV-1 Induced Pathogenesis in the Human Thymus

“…Notably, insufficient T cell regeneration may not only be at the level of the thymus, but also at the level of hematopoietic stem cells. This is illustrated by the recent finding that the function and numbers of CD34 + hematopoietic stem cells in peripheral blood of HIV infected individuals are impaired despite control of viral replication (Sauce et al, 2011). Also, impaired progenitor cell function of umbilical cord blood CD34 + cells, including decreased cloning efficiency and generation of CD4+ T lymphocytes in fetal thymic organ culture, was observed in HIV-negative infants born to HIV-positive mothers (Nielsen et al, 2001).…”

Lymphocyte Subset (CD3, CD4 and CD8 Cells) and their Ratios in HIV patients on Highly Active Antiretroviral Therapy (HAART) and HAART Naïve Patients

“…Immune activation is highly related to high incidence of diseases and death in successfully HAARTtreated patients with undetectable viremia [12]. Certain stage of infection records complete absence CD4+ T cells both in the lymphoid and circulation sites.…”

Invecchiamento cellulare e infezione da HIV

“…La frequenza delle cellule T naive rappresenta un ottimo marker per definire l'età immunologica negli individui e la progressiva riduzione nei pazienti HIV+ è direttamente associata alla progressione della malattia. La riduzione di tali cellule è correlata ad alto indice di proliferazione omeostatica (ad esempio espressione di Ki67), probabilmente come mezzo per mantenere un livello adeguato di queste cellule, come avviene nell'età avanzata (16). Nell'infezione da HIV le cellule T naive presentano anche deficit funzionali, per esempio una minore capacità di essere attivate dall'antigene per le cellule TCD8+ naive, di conseguenza il paziente HIV positivo, come il paziente anziano, mostra una ridotta risposta immunologica alla vaccinazione antinfluenzale (9).…”