Dynamics of CD4 and CD8 T-Cell Subsets and Inflammatory Biomarkers during Early and Chronic HIV Infection in Mozambican Adults

Abstract

During primary HIV infection (PHI), there is a striking cascade response of inflammatory cytokines and many cells of the immune system show altered frequencies and signs of extensive activation. These changes have been shown to have a relevant role in predicting disease progression; however, the challenges of identifying PHI have resulted in a lack of critical information about the dynamics of early pathogenic events. We studied soluble inflammatory biomarkers and changes in T-cell subsets in individuals at PHI (n = 40), chronic HIV infection (CHI, n = 56), and HIV-uninfected (n = 58) recruited at the Manhiça District Hospital in Mozambique. Plasma levels of 49 biomarkers were determined by Luminex and ELISA. T-cell immunophenotyping was performed by multicolor flow cytometry. Plasma HIV viremia, CD4, and CD8 T cell counts underwent rapid stabilization after PHI. However, several immunological parameters, including Th1-Th17 CD4 T cells and activation or exhaustion of CD8 T cells continued decreasing until more than 9 months postinfection. Importantly, no sign of immunosenescence was observed over the first year of HIV infection. Levels of IP-10, MCP-1, BAFF, sCD14, tumor necrosis factor receptor-2, and TRAIL were significantly overexpressed at the first month of infection and underwent a prompt decrease in the subsequent months while, MIG and CD27 levels began to increase 1 month after infection and remained overexpressed for almost 1 year postinfection. Early levels of soluble biomarkers were significantly associated with subsequently exhausted CD4 T-cells or with CD8 T-cell activation. Despite rapid immune control of virus replication, the stabilization of the T-cell subsets occurs months after viremia and CD4 count plateau, suggesting persistent immune dysfunction and highlighting the potential benefit of early treatment initiation that could limit immunological damage.

Expansion of Stem Cell-Like CD4+Memory T Cells during Acute HIV-1 Infection Is Linked to Rapid Disease Progression

“…Studies conducted in nonhuman primates and humans demonstrated that HIV-1/ SIV-1 preferentially infects highly mature subsets, causing a reduction in their frequencies during the acute phase of the disease. At the same time, less differentiated subsets, such as naive cells and CM, are less likely to be infected but can be stimulated to proliferate and expand (3,(25)(26)(27)(28). In line with these findings, we found that the frequencies of naive cells, SCM, and CM remain elevated during the late acute HIV-1 infection, whereas those of EM and TE progressively decrease.…”

TLR9 polymorphism correlates with immune activation, CD4 decline and plasma IP10 levels in HIV patients

“…LPS, sCD14, IL6 and IP10 are some of the plasma biomarkers that have been shown to be elevated in HIV patients [7, 47]. In fact, these inflammatory biomarkers are reliable predictors of HIV disease progression correlating consistently with CD4 decline and plasma viral load [3, 48].…”

“…Furthermore, TLR9 stimulation via CpG has been shown to induce IP10 production from monocytes, plasmacytoid dendritic cells and B cells [49, 50]. Interestingly, IP10 has been shown to be elevated in HIV infections [7, 47] and associated with CD4 decline [65], immune activation [66] and plasma viral load [65]. Recent studies have also shown IP10 to be a highly sensitive marker of viremia in acute HIV infections [52, 67].…”

Reduction of inflammation and T cell activation after 6 months of cART initiation during acute, but not in early chronic HIV-1 infection

“…Studies have associated the elevated immune activation with CD4 + T cell depletion and progression to AIDS [2–7]. During primary HIV-1 infection (PHI), viral loads can reach values higher than one million HIV-1 RNA copies/mL, and a significant decrease in CD4 + T cell counts occurs [8, 9]. A high production of pro-inflammatory cytokines, called a “cytokine storm”, arises in response to virus replication [10].…”