Multiomics of HIV nonprogressives reveals the immunity behind AIDS evasion

A multiomic analysis led by the IrsiCaixa AIDS Research Institute has uncovered genetic and immune mechanisms in some HIV-positive individuals, known as viremic non-progressors (VNPs), to prevent disease progression without antiretroviral therapy.

Since its introduction in 1987, antiretroviral therapy has transformed human immunodeficiency virus (HIV) from a fatal disease to a manageable condition. Despite advances in treatment, millions of people still struggle with incomplete immune system recovery.

VNPs are extremely rare, accounting for less than 0.1% of HIV-infected adults. Unlike progressives, people who experience the expected progression from HIV to AIDS, VNPs exhibit relatively stable CD4⁺ T cell counts for extended periods without antiretroviral therapy, even when there are significant levels of viral replication. Understanding how VNPs maintain stable CD4⁺ Increasing T cell counts despite high viral loads may provide new options for treatment.

In the study, “Host genetic and immune factors mediate evasion of HIV-1 pathogenesis in viremic non-progressors,” published in the journal Medresearchers performed single-cell and multiomic analyzes involving 16 VNPs and 29 progressives.

Observations in viremic nonprogressor omics

VNPs were more likely to carry one copy of the CCR5 gene with a Δ32 deletion and one copy without (53.8% heterozygosity) compared to progressives (16.0%). The CCR5Δ32 variant reduces the expression of CCR5 receptors on CD4⁺ T cells, which HIV normally uses to invade cells. Individuals carrying this variant showed lower CCR5 expression and lower rates of HIV-1 infection in their cells.

Before starting ART, VNPs showed significantly lower total and intact HIV-1 DNA levels in their peripheral blood mononuclear cells (PBMCs) and several CD4 cells.⁺ T cell subsets. This also suggests partial protection against HIV infection at the cellular level.

VNPs had higher percentages of naive CD8⁺ T cells and less activated memory CD8⁺ T cells compared to progressives. Naive CD8⁺ T cells have not yet encountered an antigen (something that triggers an immune response).

Memory CD8⁺ T cells are the mature version that has previously encountered an antigen and create an immune response if it is encountered again. Lower levels of apoptosis were also seen in CD4⁺ T cells from VNPs.

By avoiding chronic immune system activation and excessive cell death, the VNPs were able to maintain a healthier functional immune system, essentially ignoring changing levels of HIV replication.

Single-cell RNA sequencing revealed that VNPs showed widespread downregulation of interferon-stimulated genes across multiple immune cell types. Interferons are proteins that cells produce in response to viral infections and signal neighboring cells to boost their antiviral defenses. This effect occurred in several immune cells, including myeloid cells, CD4⁺ T cells, CD8⁺ T cells and NK cells (natural killer).

Measurements showed that VNPs had lower levels of zonulin, a marker indicating disruption of the intestinal mucosa, implying better intestinal integrity than progressives. Metabolomic analysis revealed that VNPs had lower levels of anthranilic acid, a byproduct of tryptophan breakdown linked to immune activation and CD4⁺ Depletion of T cells in the progression of HIV disease.

The research shows that by maintaining lower levels of immune system activation, VNPs avoid the damaging effects of chronic inflammation and immune exhaustion. In turn, preserving immune function allows VNPs to prevent the progression of HIV to AIDS without antiretroviral therapy.

In figuring out the mechanisms of natural protection in this small group of individuals, future researchers now have a successful model from which to design interventions that can restore immune function to the larger HIV community.

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