Multi-omics in HIV: searching insights to understand immunological non-response in PLHIV

Abstract

Antiretroviral therapy (ART) induces persistent suppression of HIV-1 replication and gradual recovery of T-cell counts, and consequently, morbidity and mortality from HIV-related illnesses have been significantly reduced. However, in approximately 30% of people living with HIV (PLHIV) on ART, CD4⁺ T-cell counts fail to normalize despite ART and complete suppression of HIV viral load, resulting in severe immune dysfunction, which may represent an increased risk of clinical progression to AIDS and non-AIDS events as well as increased mortality. These patients are referred to as "immune inadequate responders", "immunodiscordant responders" or "immune nonresponders (INR)". The molecular mechanisms underlying poor CD4⁺ T-cell recovery are still unclear. In this sense, the use of omics sciences has shed light on possible factors involved in the activity and metabolic dysregulation of immune cells during the failure of CD4⁺ T-cell recovery in INR. Moreover, identification of key molecules by omics approaches allows for the proposal of potential biomarkers or therapeutic targets to improve CD4⁺ T-cell recovery and the quality of life of these patients. Hence, this review aimed to summarize the information obtained through different omics concerning the molecular factors and pathways associated with the INR phenotype to better understand the complexity of this immunological status in HIV infection.

Keywords: PLHIV; genomics; immunological non-response; metabolomics; proteomics; transcriptomics.

Figure 1

Overview of the physiological and molecular features of INR condition. (A) Important processes describing INR that enhance clinical consequences. The mechanisms of the INR condition are characterized by a set of biological processes that eventually lead to different pathologies such as cancers (8, 9), cardiovascular diseases (10), opportunistic infections (11, 12) or other coinfections (13, 14), contributing to the increased mortality and morbidity associated to INR condition. (B) Overview of applicability of omics science in INR. Omics can answer biological questions of different layers of knowledge to identify factors that confer a specific environment in the INR phenotype in PLHIV, such as 1) understanding the influence of several SNPs in the specific response to infection; 2) analysing perturbations of cell function under infection; 3) how cell communication activates the immune system; and 4) how the coordination among cells allows tissues to perform their function correctly. The combination of these factors provided by different omics adds complexity to understanding the real causes of poor CD4⁺ T-cell recovery in INR patients, even though these patients achieve viral suppression by antiretroviral therapy (ART). Each molecule associated with the INR phenotype is listed below with the omics approach used to identify it, as well as the different techniques (in red bold) used in the different studies identified in this review.