Spanish scientists from IrsiCaixa AIDS Research Institute have discovered multiomic reasons why some HIV-positive patients, viremic non-progressors (VNPs), fail to develop progressive disease on this basis.
From the time it was developed in 1987, antiretroviral therapy has made Human Immunodeficiency Virus (HIV) a chronic illness rather than an acutely fatal disease. However, as the data show, millions of patients still have insufficient immune restoration even today.
Analysis was done at the single cell and multiomic level including 16 VNPs and 29 progressors in the study titled “Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors” published in the journal Med.
The analysis of omics of viremic non-progressor patients
VNPs had higher (53.8%) heterozygous CCR5 genotype of having one gene with Δ32 deletion and one without than the progressors (16.0%). The CCR5Δ32 variant results in the down regulation of CCR5 receptors on CD4 + T cells that HIV enters commonly.
These frequencies were associated with lower levels of CCR5 expression and slower rates of HIV-1 infections in those individuals.
We found that before starting ART VNPs had significantly lower total and intact HIV-1 DNA in their PBMCs as well as in different subsets of CD4+ T cells.
This also implies partial prevention against a human immunodeficiency virus infection at the cellular level.
VNPs had higher frequencies of naïve CD8+ T cells and lower frequencies activated memory CD8+ T cells compared to progressors. Naïve CD8+ T cells are those that are not sensitised by an antigen – anything that can stimulate an immune response.
Memory CD8+ T cells are the mature T cells which have met the antigen before and respond to the immune system by forming an immune response if the antigen is met again. Deso and colleagues also described significantly reduced apoptosis levels in CD4+ T cells from VNPs.
The VNPs were able to sustain a healthier functional immune system, or ignore variations in the amount of HIV replication and never get stuck in a constant state of intense immune activation and cell death.
In particular, scRNA-seq of VNPs and controls indicated a global suppression of Type I IFN response in multiple immune lineages. Interferons are proteins produced by cells in reaction to an infecting virus and they stimulate other cells to kick up their antiviral activity. This effect was noticeable in the myeloid compartment, CD4 T cells, CD8 T cells and the NK cells.
Several comparisons were made and values achieved revealed that VNPs of the study had significantly lower zonulin levels, which is associated with disrupted gut mucosa, than progressors.
In metabolite profiling, it was found that VNPs had significantly reduced levels of AA, a metabolite derived from the degradation of tryptophan which has been associated with immune activation and CD4+ T cell decline in HIV pathogenesis.
This paper also demonstrates that VNPs are able to sustain adequately low degrees of immune system activation, and therefore, are less likely to experience the inflammatory and immune costs associated with these processes.
Similarly, the possibility to maintain the immune function enables VNPs to avoid the shift from HIV to AIDS without using antiretroviral medications.
In understanding more on how natural protection works in this small group of individuals, future researchers are now left with a successful model on which they can build interventions that could further put back the immune function for the larger HIV+ populace.
Reference:
Bayón-Gil Á, Hernández I, Dalmau J, Nieto JC, Urrea V, Garrido-Sanz L, et al. Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors. Medicine
