Despite the widespread success of combination antiretroviral therapy (cART) in suppressing plasma viremia to undetectable levels, people living with HIV-1 (PLWH) continue to face a significantly elevated risk of chronic inflammation and Serious Non-AIDS Events (SNAEs). In this narrative review, we bridge the critical gap between molecular virology, immunometabolism, and clinical pathology by examining the complex interface of intrinsic immunity and viral persistence. We analyzed the evolutionary “arms race” between conserved host restriction factors, including TRIM5α, APOBEC3G, SAMHD1, BST-2, MX2, and SERINC, and the sophisticated viral evasion mechanisms that facilitate reservoir establishment. We further examined the role of bacterial translocation and gut barrier dysfunction in perpetuating systemic inflammation, emphasizing how HIV-1-mediated depletion of mucosal Th17 cells and disruption of tight junction proteins create a “leaky gut” that permits microbial product translocation despite suppressive therapy. Among viral proteins that may contribute to residual pathology during suppressive cART, we focused on the HIV-1 matrix protein p17, which has been proposed to function as a secreted “viral cytokine” from latent reservoirs, acting through CXCR1/CXCR2 receptors and the RACK1-JAK1-STAT1 pathway. Although primarily characterized in in vitro and ex vivo models, emerging data suggested that p17 may sustain systemic immune activation and metabolic reprogramming; however, its relative contribution compared with other viral proteins (Tat, Nef, gp120) in virologically suppressed patients remains to be fully delineated in human studies.
Furthermore, we examined how HIV-1 hijacks cellular bioenergetics by shifting host cells from oxidative phosphorylation to aerobic glycolysis. We present an integrative model that connects restriction factor biology, p17-mediated chronic inflammation, immunometabolic dysregulation, and gut barrier dysfunction into a unified pathogenic framework, distinguishing established mechanisms from working hypotheses. Last, we assessed emerging therapeutic strategies, including CRISPR/Cas9-mediated enhancement of restriction factors, modulation of the mTOR pathway, and novel “Shock and Kill” approaches, stratified by development stage and demonstrated endpoints, offering potential pathways toward a functional cure.
Citation: Thomas Nitsotolis, Stelios F Assimakopoulos, Elli Kouriannidi, Maria Lagadinou, Alexia Papalexandrou, Petros Ioannou, Markos Marangos, Haralampos Milionis, Eirini Christaki. Host restriction factors and p17-Driven inflammaging in HIV-1: From molecular pathogenesis to functional cure[J]. AIMS Microbiology, 2026, 12(1): 92-125. doi: 10.3934/microbiol.2026004
Despite the widespread success of combination antiretroviral therapy (cART) in suppressing plasma viremia to undetectable levels, people living with HIV-1 (PLWH) continue to face a significantly elevated risk of chronic inflammation and Serious Non-AIDS Events (SNAEs). In this narrative review, we bridge the critical gap between molecular virology, immunometabolism, and clinical pathology by examining the complex interface of intrinsic immunity and viral persistence. We analyzed the evolutionary “arms race” between conserved host restriction factors, including TRIM5α, APOBEC3G, SAMHD1, BST-2, MX2, and SERINC, and the sophisticated viral evasion mechanisms that facilitate reservoir establishment. We further examined the role of bacterial translocation and gut barrier dysfunction in perpetuating systemic inflammation, emphasizing how HIV-1-mediated depletion of mucosal Th17 cells and disruption of tight junction proteins create a “leaky gut” that permits microbial product translocation despite suppressive therapy. Among viral proteins that may contribute to residual pathology during suppressive cART, we focused on the HIV-1 matrix protein p17, which has been proposed to function as a secreted “viral cytokine” from latent reservoirs, acting through CXCR1/CXCR2 receptors and the RACK1-JAK1-STAT1 pathway. Although primarily characterized in in vitro and ex vivo models, emerging data suggested that p17 may sustain systemic immune activation and metabolic reprogramming; however, its relative contribution compared with other viral proteins (Tat, Nef, gp120) in virologically suppressed patients remains to be fully delineated in human studies.
Furthermore, we examined how HIV-1 hijacks cellular bioenergetics by shifting host cells from oxidative phosphorylation to aerobic glycolysis. We present an integrative model that connects restriction factor biology, p17-mediated chronic inflammation, immunometabolic dysregulation, and gut barrier dysfunction into a unified pathogenic framework, distinguishing established mechanisms from working hypotheses. Last, we assessed emerging therapeutic strategies, including CRISPR/Cas9-mediated enhancement of restriction factors, modulation of the mTOR pathway, and novel “Shock and Kill” approaches, stratified by development stage and demonstrated endpoints, offering potential pathways toward a functional cure.
adeno-associated virus
antibody-dependent cellular cytotoxicity
antibody-dependent cellular phagocytosis
acquired immunodeficiency syndrome
protein kinase B
adaptor protein 2
apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G
analytical treatment interruption
blood-brain barrier
broadly neutralizing antibody
bone marrow stromal antigen 2
capsid
combination antiretroviral therapy
CRISPR-associated protein 9 endonuclease
C-C chemokine receptor type 5
cluster of differentiation
cyclin-dependent kinases 1 and 2
cyclic GMP-AMP
cyclic GMP-AMP synthase
chronic kidney disease
central nervous system
cleavage and polyadenylation specificity factor 6
circulating recombinant form
clustered regularly interspaced short palindromic repeats
C-terminal domain
cytotoxic T lymphocyte
C-X-C motif chemokine receptor 1
C-X-C motif chemokine receptor 2
C-X-C chemokine receptor type 4
cyclophilin A
DDB1 and CUL4 associated factor 1
deoxyribonucleoside triphosphate
extracellular matrix
envelope glycoprotein
endoplasmic reticulum
farnesoid X receptor
group-specific antigen
gut-associated lymphoid tissue
guanosine monophosphate
glycoprotein 41
glycoprotein 120
glycoprotein 160
glycosylphosphatidylinositol
guide RNA
HIV-associated neurocognitive disorders
hepatocellular carcinoma
histone deacetylase inhibitor
human immunodeficiency virus
heptad repeat 1
heptad repeat 2
hematopoietic stem and progenitor cell
heparan sulfate proteoglycans
intestinal fatty acid-binding protein
intercellular adhesion molecule 1
interferon gamma inducible protein 16
interferon
interleukin-17
interleukin-22
integrase
interferon regulatory factor 3
immune reconstitution inflammatory syndrome
interferon-stimulated gene
Janus kinase 1
junctional adhesion molecules
lipopolysaccharide-binding protein
lipid nanoparticle
latency-promoting agent
lipopolysaccharide
latency-reversing agent
long terminal repeat
matrix protein
mitogen-activated protein kinase
metabolic dysfunction-associated steatotic liver disease
monocyte chemoattractant protein 1
major histocompatibility complex
myosin light chain kinase
matrix metalloproteinase 2/9
mechanistic target of rapamycin
mTOR complex 1
myxovirus resistance protein 2
nucleocapsid
negative regulatory factor
nuclear factor kappa B
natural killer
nuclear pore complex
N-terminal domain
open reading frame
oxidative phosphorylation
pathogen-associated molecular patterns
plasmacytoid dendritic cell
pre-integration complex
protein kinase C
people living with HIV
polymerase
protein-protein interaction
protease
peroxiredoxin 2
pre-exposure prophylaxis
pattern recognition receptor
receptor for activated C kinase 1
regulator of expression of virion proteins
retinoic acid-inducible gene I
reactive oxygen species
Rev response element
reverse transcriptase
SAM and HD domain-containing protein 1
soluble CD14
short-chain fatty acids
serine incorporator
simian immunodeficiency virus
serious non-AIDS events
signal transducer and activator of transcription 1
stimulator of interferon genes
surface subunit
transactivation response element
transactivator of transcription
T helper 17 cells
Toll-like receptor
transmembrane
tissue macrophage reservoir
tumor necrosis factor alpha
viral infectivity factor
viral protein R
viral protein U
viral protein X
zinc finger antiviral protein
zonula occludens-1
zonula occludens-2
zonula occludens-3
bromodomain-containing protein 4.
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Figures(3) / Tables(5)
Thomas Nitsotolis, Stelios F Assimakopoulos, Elli Kouriannidi, Maria Lagadinou, Alexia Papalexandrou, Petros Ioannou, Markos Marangos, Haralampos Milionis, Eirini Christaki. Host restriction factors and p17-Driven inflammaging in HIV-1: From molecular pathogenesis to functional cure[J]. AIMS Microbiology, 2026, 12(1): 92-125. doi: 10.3934/microbiol.2026004
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