Plasma Levels of Bacterial DNA Correlate with Immune Activation and the Magnitude of Immune Restoration in Persons with Antiretroviral‐Treated HIV Infection

Abstract

The significance of elevated plasma levels of bacterial lipopolysaccharide (LPS) in persons with chronic HIV infection remains undefined. We measured LPS levels by use of limulus lysate assay, and DNA sequences encoding bacterial ribosomal 16S RNA (16S rDNA) were assessed by quantitative polymerase chain reactions in plasma samples obtained from 242 donors. Plasma levels of 16S rDNA were significantly higher in human immunodeficiency virus (HIV)–infected subjects than in uninfected subjects, and they correlated with LPS levels. Higher levels of 16S rDNA were associated with higher levels of T cell activation and with lower levels of CD4 T cell restoration during antiretroviral therapy. Antiretroviral therapy reduces but does not fully normalize plasma levels of bacterial 16S rDNA, an index of microbial translocation from the gastrointestinal tract. High levels of 16S rDNA during therapy are strongly associated with reduced increases in the CD4+ T lymphocyte count, irrespective of plasma HIV RNA levels. These findings are consistent with the importance of microbial translocation in immunodeficiency and T cell homeostasis in chronic HIV infection.

IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

“…However, the underlying pathogenic mechanisms are still a topic of debate. Three potential causes of immune activation have been identified, as follows: 1) increased translocation of microbial products across the gut wall (12), 2) CMV coinfection (13,14), and 3) residual low-level HIV replication, identified in studies of ART intensification therapy with HIV integrase inhibitors (15,16). Irrespective of whether one or more of these factors cause persistent immune activation, we and others have demonstrated that elevated expression of IFNstimulated genes (ISG) in separated CD4 + T cells (17), separated accessory cells (18), or PBMC (19) is the strongest correlate of persistent CD4 + T cell deficiency in treated HIV patients.…”

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

“…So as CD4+ T-cell numbers decrease in HIV condition, HLA-DR+ and CD38+ CD8+ T lymphocytes rather appreciate in numbers [5]. Further studies has also established that viral load cannot separately determine the rate of progression to AIDS, and that immune activation better reflects variations in CD4+ T-cell stronger and independent of viral load [6][7][8][9].…”

Heart–Lung Interaction via Infection

“…Bacterial translocation from the GI tract to the peripheral circulation has been extensively studied in HIV infection, but is also common in liver disease and other conditions (24)(25)(26)(27). Translocation occurs early in HIV infection due to depletion of gut CD41 lymphocytes and is not completely eradicated by ART, particularly in patients with a suboptimal CD4 cell count or HIV viral level responses (25,28). Persistent systemic exposure to bacterial antigens from MT triggers immune activation and inflammation in HIVinfected adults (25,26).…”

“…Translocation occurs early in HIV infection due to depletion of gut CD41 lymphocytes and is not completely eradicated by ART, particularly in patients with a suboptimal CD4 cell count or HIV viral level responses (25,28). Persistent systemic exposure to bacterial antigens from MT triggers immune activation and inflammation in HIVinfected adults (25,26). MT is associated with T-cell activation, which predicts systemic inflammation, mortality, HIV progression, and progression of comorbidities such as cardiovascular disease (25,26,(29)(30)(31).…”

“…Persistent systemic exposure to bacterial antigens from MT triggers immune activation and inflammation in HIVinfected adults (25,26). MT is associated with T-cell activation, which predicts systemic inflammation, mortality, HIV progression, and progression of comorbidities such as cardiovascular disease (25,26,(29)(30)(31).…”