Inflammatory profile of vertically HIV-1 infected adolescents receiving ART in Cameroon: a contribution toward optimal pediatric HIV control strategies

Abstract

Antiretroviral therapy (ART) has improved the lifespan of people living with HIV. However, their immune system remains in a state of sustained activation/inflammation, which favors viral replication and depletion of helper T-cells with varying profiles according to ART-response. We herein sought to ascertain the inflammatory profile of adolescents living with perinatal HIV-1 infection (ALPHI) receiving ART in an African context. In this cross-sectional and comparative study among ART-experienced ALPHI in Yaoundé-Cameroon, HIV-1 RNA was measured by Abbott Real-time PCR; CD4 cells were enumerated using flow cytometry; serum cytokines were measured by ELISA; HIV-1 proviral DNA was genotyped by Sanger-sequencing; and archived drug resistance mutations (ADRMs) were interpreted using Stanford HIVdb.v9.0.1. Overall, 73 adolescents were enrolled (60 ALPHI and 13 HIV-1 negative peers) aged 15 (13-18) years; 60.00% were female. ART median duration was 92 (46-123) months; median viral load was 3.99 (3.17-4.66) RNA Log₁₀ (copies)/mL and median CD4 count was 326 (201-654) cells/mm³. As compared to HIV-negative adolescents, TNFα was highly expressed among ALPHI (p<0.01). Following a virological response, inflammatory cytokines (IFNγ and IL-12), anti-inflammatory cytokines (IL-4 and IL-10) and inflammation-related cytokines (IL-6 and IL-1β) were highly expressed with viral suppression (VS) vs. virological failure (VF), while the chemokine CCL3 was highly expressed with VF (p<0.01). Regarding the immune response, the inflammatory cytokine TNFα was highly expressed in those that are immunocompetent (CD4≥500 cell/mm³) vs. immunocompromised (CD4<500 cell/mm³), p ≤ 0.01; while chemokine CCL2 was highly expressed in the immunocompromised (p<0.05). In the presence of ADRMs, IL-4 and CCL3 were highly expressed (p=0.027 and p=0.043 respectively). Among ART-experienced ALPHI in Cameroon, the TNFα cytokine was found to be an inflammatory marker of HIV infection; IFNγ, IL-1β, IL-6, and IL-12 are potential immunological markers of VS and targeting these cytokines in addition to antiretroviral drugs may improve management. Moreover, CCL3 and CCL2 are possible predictors of VF and/or being immunocompromised and could serve as surrogates of poor ART response.

Keywords: CD4; HIV-1; adolescents; antiretroviral therapy; cytokines; inflammation; viral load.

Figure 1

Cytokine profile according to virological response. VF, Virological failure (viral load ≥3 Log₁₀(copies/mL)); VS, Viral suppression (viral load <3 Log₁₀(copies/mL)); IL, interleukin; TGF, transformative growth factor; TNF, tumor necrosis factor; (p<0.05), ** (p<0.01). This graph shows the significant low level of inflammatory cytokines IL-12 and IFNy; anti-inflammatory cytokines IL-4 and IL-10 and the inflammation related cytokines IL-1β, IL-6 while the level of chemokine CCL3 was high in adolescents with VF as compared to those with VS.

Figure 2

Correlation between cytokines (IL-1β and IL-4) and viral load. IL, interleukin. This graph shows the negative correlation between cytokines IL-1β/IL-4 and the plasmatic viral load highlighting the decrease of such interleukins with increasing levels of viral load.

Figure 3

Cytokine profile according to immunocompetence. IL, interleukin; TGF, transformative growth factor; TNF, tumor necrosis factor; Immunocompetent: CD4≥500 cells/mm³; immunodeficiency: CD4<500 cells/mm³; * (p<0.05); N=32. This graph shows the significant high level of the inflammatory cytokine TNFα in immunocompetent adolescents as compared to those with immunodeficiency while, the level of the chemokine CCL2 was high in adolescents with immunodeficiency as compared to those with good immune response.

Figure 4

Profile of IL-4 and CCL3 according to the occurrence of ADRMs. ADRMs, Archived Drug Resistance Mutations; IL,interleukin. This graph shows the significant high level of the chemokine CCL3 as well as the cytokine IL-4 among adolescents with ADRMs.