Increased Monocyte Activation With age Among HIV-Infected Long Term Non-Progressor Children

Implications for Early Treatment Initiation

RR D'Souza; BP Gopalan; N Rajnala; C Phetsouphanh; A Shet

Disclosures

HIV Medicine. 2019;20(8):513-522. 

In This Article

Abstract and Introduction

Abstract

Objectives: The key to newer therapeutic and eradication approaches often lies in understanding slow disease progression in HIV infection. The paediatric population has been poorly studied in this regard. We aimed to describe a cohort of perinatally infected long-term nonprogressor (LTNP) children living with HIV in India and to evaluate the immune biomarkers of disease progression.

Methods: LTNPs (ART-naïve, with a CD4 count ≥ 500 cells/μL at age ≥ 7 years) among the cohort of HIV-infected children were identified and monitored longitudinally, and their CD4 T-cell counts and plasma viral loads were measured every 6 months. The plasma monocyte/macrophage activation markers, namely soluble CD14 (sCD14), soluble CD163 (sCD163) and interferon-inducible protein-10 (IP-10) were measured by enzyme-linked immunosorbent assay (ELISA) in LTNPs and progressors. The Mann–Whitney U-test was used to compare the two groups and P values < 0.05 were considered statistically significant. Spearman's rank or Pearson's correlation coefficient (r) was calculated to determine the associations between variables.

Results: Among 378 children living with HIV-1 surveyed in our cohort, 40 (10.6%) were LTNPs. Longitudinal analysis of the LTNP data showed that both CD4 count and viral load declined significantly with age (P < 0.0001 for both). Plasma sCD14 levels were significantly (P < 0.005) higher in progressors and sCD163 levels were significantly (P < 0.0001) higher in LTNPs.

Conclusions: The prevalence of LTNPs in our cohort of perinatally infected children living with HIV was 10.6%. We observed a trend for associations between the increasing sCD163 monocyte/macrophage activation marker levels, declining CD4 counts and the gradual loss of nonprogressor status with age in the LTNPs. These findings underscore the need for early antiretroviral therapy in those children with proven slow disease progression.

Introduction

Globally, 36.9 million people are living with HIV; among them, 2.1 million are children below the age of 15 years.[1] In India, 2.11 million people living with HIV were registered up to March 2015; of these, 137 994 (6.54%) were children under the age of 15 years.[2] The HIV epidemic in India is attributed mainly to HIV-1 subtype C, the viral clade that accounts for approximately half of all global infections.[3,4] Multiple lines of evidence suggest that subtype C may have greater replicative fitness than other subtypes,[5] with a greater magnitude of transcription[6] and high transmissibility.[7,8]

Long-term nonprogressors (LTNPs) are defined as children with perinatally acquired HIV-1 infection who are antiretroviral therapy (ART) naïve, maintain normal-for-age CD4 counts (≥ 500 cells/μL at age ≥ 7 years) and remain free of manifestations of disease progression. Several large paediatric LTNP cohorts similar to our cohort have been described in South Africa/Durban,[9,10] Uganda,[11] Thailand and Cambodia,[12] France and seven other European countries,[13] Brazil,[14] Puerto Rico and the USA.[15] In India, there are limited reports on paediatric LTNP cohorts and analysis of their immune biomarkers.[16–18]

Host genetics, immune markers and viral factors play a role in nonprogression, yet these components fail to provide a comprehensive explanation. In paediatric HIV infection, despite successful treatment with ART, there is persistent elevated immune activation directly linked to disease progression. The systemic immune activation levels in LTNPs are lower than in progressors, but remain significantly higher compared with uninfected individuals irrespective of their viral loads.[19,20] Hence, in the long run, understanding the mechanism of slow disease progression and its effects on the developing immune system by studying LTNPs is of particular importance. Additionally, evaluating the key biomarkers of immune activation and disease progression is fundamental in view of their association with an increased incidence of non-AIDS-related mortality and morbidities.[21–23] Studies have implicated monocyte and macrophage-related inflammatory biomarkers such as soluble CD14 (sCD14), soluble CD163 (sCD163) and interferon-inducible protein-10 (IP-10) as predictors and probable causes of disease progression in addition to viral load and CD4 count.[24–26]

We first identified children with this rare LTNP phenotype, with no clinical progression to AIDS for the first one or two decades of life, among the overall cohort of children living with HIV-1 subtype C. Current implementation of the new protocol for universal treatment of LTNPs may preclude elucidation of the immune mechanism and viral control in this group, and hence we found that samples collected prior to ART initiation were of most value for our purpose. Moreover, non-AIDS-related events, including those involving the cardiovascular and central nervous systems and cancers, were frequently described in the LTNPs/controllers with no relevant clinical signs readily detected by the patient or the clinician. Hence, after conducting a literature review, we determined that sCD14, sCD163 and IP-10 were suitable biomarkers of immune activation and, in order to elucidate disease progression trends, we compared levels of these plasma biomarkers in paediatric LTNPs and progressors using cross-sectional analysis.

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