Programmed Death 1 Receptor ChangesEx Vivoin HIV-Infected Adults following Initiation of Highly Active Antiretroviral Therapy

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>This study investigates the short-term effects of highly active antiretroviral therapy (HAART) on programmed death 1 receptor (PD-1) expression and lymphocyte function. We compared lymphocytes from human immunodeficiency virus (HIV)-infected adults prior to the initiation of HAART with lymphocytes from the same subjects following 2 months of treatment. Short-term HAART resulted in a moderate increase in the expression of PD-1 on both CD4<jats:sup>+</jats:sup>and CD8<jats:sup>+</jats:sup>T cells; yet, there was still a significant reduction in viral load and recovery of CD4<jats:sup>+</jats:sup>T cells. After 2 months of HAART, lymphocytes from the subjects had a reduction in lymphoproliferative responses to phytohemagglutinin (PHA) and an increased response to the<jats:named-content content-type="genus-species">Candida</jats:named-content>recall antigen and the HIV antigen p24 compared to pretreatment lymphocytes. PHA-stimulated peripheral blood mononuclear cells (PBMCs) from samples obtained 2 months after HAART produced higher levels of Th-1 cytokines (gamma interferon [IFN-γ] and tumor necrosis factor alpha[TNF-α]) than the levels observed for samples taken before treatment was initiated. There were no significant changes in the proinflammatory cytokine interleukin-2 (IL-2) or Th-2 cytokines (IL-4, IL-5, and IL-10) in the corresponding samples.<jats:italic>Ex vivo</jats:italic>PD-1 blockade significantly augmented PHA-induced lymphoproliferation as well as the levels of Th-1 cytokines and to a lesser extent the levels of Th-2 cytokines in PBMC cultures. The ability to downregulate PD-1 expression may be important in enhancing immune recovery in HIV infection.</jats:p>

Low antigen-specific CD4 T-cell immune responses despite normal absolute CD4 counts after long-term antiretroviral therapy an African cohort

“…Our cohort initiated ART at CD4 < 200 cells/μl, an advanced stage of HIV disease that is associated with loss of the fibroblastic reticular cell network due to excess collagen deposition, subsequently affecting CD4 T-cell function including IL-2 cytokine production [20]. In a study done by Spitsin et al IL-2 production by CD4 T-cells did not improve after 2 months on ART in the USA, where patients had elevated levels of programmed death 1 (PD-1) and ex vivo blockade of PD-1 augmented T-cell cytokine production [21]. Therefore, down regulation of PD-1 expression may be important in enhancing immune recovery in HIV infection [21].…”

“…In a study done by Spitsin et al IL-2 production by CD4 T-cells did not improve after 2 months on ART in the USA, where patients had elevated levels of programmed death 1 (PD-1) and ex vivo blockade of PD-1 augmented T-cell cytokine production [21]. Therefore, down regulation of PD-1 expression may be important in enhancing immune recovery in HIV infection [21]. Our results and previous reports suggest that normalization of CD4 T-cell immune responses may not be achieved by ART alone, especially when individuals initiate ART at advanced stages of HIV disease.…”

“…It is likely that prolonged ART (beyond seven years) could further restore the immune responses to levels comparable to healthy HIV-negative individuals. We may also have to consider other clinical interventions to enhance recovery of immune responses; for example, reduction of cell death mechanisms using adjuvant blockade of PD-1 that has been promising in in vitro experiments [21]. Furthermore, there is need to understand functional recovery of the innate immune system including monocytes and natural killer cells that could contribute to functional recovery of the adaptive T-cell responses.…”

Functional Plasticity of Th17 Cells: Implications in Gastrointestinal Tract Function

“…More strikingly, a newly described group of immune cells, named innate lymphoid cells (ILCs), has been revealed as an important source of IL-17 and Il-22, particularly in the intestine and other mucosal surfaces [71]. ILCs are especially prevalent at mucosal sites, where they regulate epithelial homeostasis in relation to the intestinal microbiota, and they have been found to be deregulated in inflammatory disease in both mice and humans [72,73].…”

May viral (antigen) load be the real crucial tool leading to anergy in a “micro-evolutionary” model of host/virus interaction?

“…1). Although the loss of CD4+ T cells (by apoptosis [37]) is still considered the hallmark of HIV infection, and directly correlated to the progression to AIDS, the role of viral load is emerging in many studies also dealing with vaccines production attempts [40][41][42]. On another hand, the ART era has changed the rules in clinical and researches fields, acting directly on viral load thus facilitating the chronic phase of HIV infection and prolonging the survival of infected people.…”