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*Corresponding author: E-mail: samueladavba@gmail.com; 
 
Cite as: Adavba, Samuel Adinoyi. 2025. “The Role of Monocytes and Macrophages in the Pathogenesis of Non-AIDS Defining 
Events: Mechanisms and Therapeutic Implications”. Asian Journal of Immunology 8 (1):120-33. 
https://doi.org/10.9734/aji/2025/v8i1166. 
 

 
 

Asian Journal of Immunology 
 
Volume 8, Issue 1, Page 120-133, 2025; Article no.AJI.136909 
 

 
 

 

 

The Role of Monocytes and 
Macrophages in the Pathogenesis  

of Non-AIDS Defining Events: 
Mechanisms and Therapeutic 

Implications 
 

Samuel Adinoyi Adavba a* 
 

a Kaduna State University, Kaduna, Nigeria. 
 

Author’s contribution  
 

The sole author designed, analysed, interpreted, and prepared the manuscript. 
 

Article Information 
 

DOI: https://doi.org/10.9734/aji/2025/v8i1166 
 

Open Peer Review History: 
This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers,  

peer review comments, different versions of the manuscript, comments of the editors, etc, are available here: 
https://pr.sdiarticle5.com/review-history/136909 

 
 
 

Received: 25/03/2025 
Published: 06/06/2025 

 
 

ABSTRACT 
 

Monocytes and macrophages play a pivotal role in the pathogenesis of HIV infection, contributing 
not only to viral persistence but also to the development of non-AIDS-defining events (nADEs) in 
People Living with HIV (PLWH). These innate immune cells act as long-lived viral reservoirs, driving 
chronic inflammation through persistent immune activation, oxidative stress, and tissue-specific 
damage. HIV-infected monocytes infiltrate tissues, including the cardiovascular system, liver, 
kidneys, and central nervous system, where they differentiate into macrophages and release pro-
inflammatory cytokines (e.g., TNF-α, IL-6), reactive oxygen species (ROS), and matrix 
metalloproteinases (MMPs). These mediators promote endothelial dysfunction, fibrosis, and organ 
damage, underpinning conditions such as atherosclerosis, neurocognitive disorders, and 

Review Article 

https://doi.org/10.9734/aji/2025/v8i1166
https://pr.sdiarticle5.com/review-history/136909


 
 
 
 

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121 

 

hepatorenal disorder. Emerging evidence highlights the role of macrophage polarization (M1/M2 
imbalance) and epigenetic modifications in sustaining inflammation despite antiretroviral therapy 
(ART). Understanding these mechanisms provides critical insights for developing targeted 
therapies, including immunomodulators (e.g., IL-6 inhibitors), antioxidant agents, and reservoir-
elimination strategies. This review synthesizes current knowledge on monocyte/macrophage-driven 
pathogenesis in HIV-associated nADEs. It explores plausible novel therapeutic approaches to 
mitigate chronic inflammation and improve clinical outcomes in PLWH. 
 

 
Keywords: HIV; monocyte; macrophages; inflammation; immune activation; viral reservoirs; tissue-

specific damage; non-AIDS-defining events; reservoir elimination. 
 

1. INTRODUCTION 
 
Human Immunodeficiency Virus (HIV) infection 
continues to pose a significant global health 
challenge, despite the remarkable success of 
ART in reducing AIDS-related morbidity and 
mortality. Individuals living with HIV now face an 
increased risk of certain chronic illnesses 
collectively referred to as non-AIDS defining 
events (nADEs), which are disproportionately 
common among PLWH (Deeks et al., 2013; 
Serrano-Villar et al., 2014). This spectrum 
includes cardiovascular disease, neurocognitive 
disorders, liver/kidney fibrosis, metabolic 
syndrome, and non-AIDS cancers, which can 
arise despite effective ART, contributing to 
morbidity and mortality in the post-ART era 
(Deeks et al., 2013). 
 
These conditions occur in PLWH at a younger 
age than in the general population. They are 
driven mainly by chronic immune activation, 
inflammation, and immune dysregulation, in 
which monocytes and macrophages play a 
central role (Campbell et al., 2014; Joseph et al., 
2022).  
 
Monocytes and macrophages, integral members 
of the myeloid lineage, are HIV tropic and 
express HIV entry receptors, CD4 and CCR5 
(Ancuta et al., 2008). These cells not only serve 
as targets for the infection and propagation of 
HIV but also contribute to the virus's persistence 
and disease progression over the long term 
(Campbell et al., 2014; Kruize & Kootstra, 2019). 
Following their differentiation from monocytes, 
HIV-infected macrophages migrate into tissues 
where they help spread the infection to nearly 
every tissue in the body, including the gut, testes, 
lung, gut-associated lymphoid tissue, brain, liver, 
urethra, and lymph nodes (Tso et al., 2018; Rose 
et al., 2016; Ganor et al., 2019). Additionally, 
macrophages reside in anatomical sanctuaries 
with restricted ART penetration, which benefits 
viral persistence even during therapy (Clayton et 

al., 2018; Borkham-Kamphorst & Weiskirchen, 
2016). 
 
 Human monocytes were first identified in 1880 
when Paul Ehrlich and Ilya Metchnikoff 
recognized them based on their distinct 
morphological features (Teh et al., 2023; 
Gramegna et al., 2011). However, the 
development of flow cytometry in the 1970s 
enabled the creation of a specific antibody panel 
that classifies monocytes according to the 
degree of expression of specific surface proteins, 
namely the pattern recognition receptor CD14 
and the Fc gamma III receptor CD16 (Kapellos et 
al., 2019). This parameter categorizes circulating 
monocytes into three key subpopulations: 
classical, non-classical, and intermediate. These 
subpopulations, which differ in abundance and 
primary functions, can be identified by their size, 
granularity, and expression of these specific 
surface markers (Ziegler-Heitbrock et al., 2010; 
Liberale et al., 2020). 
 
Classical monocytes, characterized by the 
expression profile CD14++CD16−, constitute the 
majority (80–90%) of monocytes. They are the 
first responders to infections or tissue damage 
and primarily initiate immune responses through 
phagocytosis, antigen presentation, and the 
release of pro-inflammatory cytokines (Ziegler-
Heitbrock et al., 2010; Potula et al., 2008). 
 
Non-classical monocytes exhibit a 
CD14+CD16++ expression pattern and are the 
least abundant (2-8%). They respond to viral 
infections, play a crucial role in antibody-
dependent cellular cytotoxicity (ADCC), patrol the 
endothelial lining of blood vessels, and 
participate in tissue repair and regeneration. The 
intermediate subset, designated CD14++CD16+, 
shows characteristics that bridge classical and 
non-classical monocytes (Tanwar et al., 2020). 
They possess enhanced capabilities for antigen 
presentation, aid in tissue repair and 
angiogenesis, and engage in resolving 



 
 
 
 

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inflammation, making them significant in various 
inflammatory diseases (Wong et al., 2011). 
 

Macrophages are specialized, long-lived 
phagocytic cells of the innate immune system 
involved in recognizing, engulfing, and degrading 
cellular debris, pathogens, and other foreign 
substances. Until recently, they were thought to 
differentiate solely from monocytes, but newer 
findings have shed light on the complexities of 
their differentiation and immunological profiles. 
Macrophages can originate from two distinct 
sources: from classical monocytes, which 
migrate into tissues to differentiate into 
macrophages or dendritic cells (monocyte-
derived macrophages [MDM]), and from self-
renewing tissue-resident macrophages that arise 
from primitive embryonic precursors (Sattentau & 
Stevenson, 2016). 
 

This article explores the mechanisms by which 
monocytes and macrophages contribute to the 
pathogenesis of HIV and the development of 
nADEs, with a focus on their roles as viral 
reservoirs, mediators of inflammation, and 
drivers of tissue damage. 
 

2. HIV INFECTION OF MONOCYTES AND 
MACROPHAGES: KEY FACTORS IN 
THE PATHOGENESIS OF HIV 

 

Monocytes and macrophages are significant 
targets for HIV-1 infection and play crucial roles 
in viral transmission, dissemination, and 
persistence. While monocytes can be infected by 
HIV-1, their susceptibility to the virus varies 
depending on their differentiation status. As 
monocytes differentiate into macrophages, they 
become more receptive to infection, acting as 
important reservoirs for the virus. These 
macrophages can productively replicate HIV-1 
even in the presence of antiretroviral therapy 
(ART) (Parihar et al., 2010).  
 

In contrast to CD4+ T cells, which are rapidly 
depleted during acute infections, HIV-infected 
monocytes and macrophages exhibit greater 
resistance to the cytopathic effects of the virus. 
This resilience allows them to harbor HIV for 
extended periods, contributing to viral 
persistence (Miguel et al., 2023). This, in turn, 
hinders efforts to achieve a cure and drives 
chronic immune activation and inflammation, 
leading to various consequences (Campbell et 
al., 2014).  
 

The causes of chronic immune activation in HIV 
infection are complex and not yet completely 

understood, encompassing both direct factors 
(such as the enduring presence of HIV RNA) and 
indirect triggers (microbial translocation and co-
infections) (Mazzuti et al., 2022). But ultimately, 
the persistent antigenic stimulation leads to 
sustained elevations of pro-inflammatory 
cytokines, such as IL-6 and TNF-α, along with 
immune activation markers like CD38 and HLA-
DR (Paiardini & Müller-Trutwin, 2013; Lederman 
et al., 2013). Monocytes, particularly the CD16+ 
intermediate and non-classical subsets, play a 
vital role in this inflammatory environment, 
exhibiting an activated phenotype characterized 
by increased expression of adhesion molecules, 
chemokine receptors, and toll-like receptors 
(TLRs), which enhances their migration into 
tissues and responsiveness to microbial products 
(Ancuta et al., 2008). The ongoing inflammation 
contributes to tissue damage and plays a role in 
the development of non-AIDS events (nADEs) 
(Burdo et al., 2011). 
 
Moreover, HIV infection alters the functional 
properties of monocytes and macrophages, 
diminishing their ability to eliminate pathogens 
and regulate immune responses. For instance, 
HIV-infected macrophages demonstrate reduced 
phagocytosis and impaired antigen presentation 
capabilities, while monocytes exhibit 
downregulated MHC II expression. This 
downregulation inhibits the formation of MHC II-
antigen complexes and diminishes the ability of 
monocytes to uptake antigens for processing and 
presentation to T cells (Nabatanzi et al., 2018). 
Such impairments contribute to immune 
exhaustion, increasing susceptibility to 
opportunistic infections (Kedzierska & Crowe, 
2001). Additionally, HIV can induce a pro-fibrotic 
phenotype in macrophages, potentially leading to 
organ fibrosis and dysfunction in conditions such 
as liver cirrhosis and chronic kidney disease 
(Kaspar & Sterling, 2017). 
 
In HIV infection, excessive production of reactive 
oxygen species (ROS) and impaired antioxidant 
defenses in macrophages and monocytes lead to 
oxidative stress, which exacerbates chronic 
inflammation, immune dysfunction, and organ-
specific injury, even in individuals receiving 
antiretroviral therapy (ART) (Ivanov et al., 2016). 
Several mechanisms contribute to this issue.  
 
One key mechanism is the upregulation of 
NADPH oxidase, a significant ROS-producing 
enzyme in macrophages, induced by HIV 
proteins such as tat and gp120. This results in 
the overproduction of superoxide and hydrogen 



 
 
 
 

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peroxide, which can damage lipids, proteins, and 
DNA. Additionally, HIV disrupts mitochondrial 
electron transport, causing an increase in 
mitochondrial ROS (Harshithkumar et al., 2024). 
It also depletes glutathione, the primary cellular 
antioxidant, by reducing the expression of 
glutamate-cysteine ligase in macrophages (Lin et 
al., 2023). 
 

These mechanisms vary in intensity across 
different organs and contribute to the organ-
specific damage observed in people living with 
HIV (PLWH), forming the basis for the 
development of non-AIDS-related events 
(nADEs). 
 

3. ORGAN-SPECIFIC EFFECTS OF 
MONOCYTES AND MACROPHAGES IN 
HIV DISEASE: MECHANISMS OF 
TISSUE DAMAGE 

 

3.1 Cardiovascular Disease (CVD)  
 

HIV is the main contributing factor to CVD in 
PLWH, accounting for approximately a two-fold 
increase in the relative risk of this disease 
(Ancuta et al., 2008). CVD is the leading cause 
of death worldwide, and has atherosclerosis as 
the main underlying pathology (Jebari-
Benslaiman et al., 2022).  
 

Atherosclerosis is a condition in which plaque, 
made up of fat, cholesterol, and other 
substances, accumulates in the intima of 
arteries, causing them to narrow and stiffen. This 
process begins with damage to the endothelium, 
accompanied by the retention and modification of 
low-density lipoprotein (LDL) in the intima (Mundi 
et al., 2017). The recruitment of monocytes into 
the intima triggers an inflammatory state critical 
to the development of atherosclerosis. 
Monocytes recruited into the arterial wall 
differentiate into macrophages and foam cells, 
facilitating plaque formation (Subramanian et al., 
2012).  
 

Moreover, the increased elaboration of pro-
inflammatory cytokines by HIV-infected 
monocytes and macrophages maintains a 
systemic inflammatory state, accelerating 
atherosclerosis and endothelial dysfunction 
(Deeks et al., 2013). Elevated levels of           
markers of macrophage activation, soluble 
CD163 and soluble CD14, are strongly 
associated with subclinical atherosclerosis and 
cardiovascular events in PLWH (Serrano-Villar et 
al., 2014). 

Furthermore, the increased expression of 
adhesion molecules (ICAM-1, VCAM-1) and 
chemokine receptors (CCR2, CX3CR1) by HIV-
infected monocytes enhances their adhesion to 
and infiltration into the vascular endothelium. 
This endothelial barrier disruption promotes 
vascular inflammation, exacerbates endothelial 
dysfunction, and vascular remodeling, thereby 
increasing cardiovascular risk (Hsue et al., 
2012). Additionally, cytokines derived from 
macrophages (TNF-α, IL-6) and HIV proteins 
(Tat, Nef) directly activate endothelial cells, 
resulting in increased permeability that 
accelerates leukocyte recruitment (Ganor et al., 
2019).  
 
In addition, HIV infection and ART disrupt lipid 
metabolism, leading to elevated levels of 
triglycerides and LDL cholesterol. Macrophages 
in PLWH accumulate lipids and exhibit impaired 
cholesterol efflux due to downregulation of 
ABCA1 and ABCG1 transporters (Clayton et al., 
2018). These proteins are crucial ATP-binding 
cassette transporters in macrophages that 
facilitate cholesterol efflux and play a role in 
reverse cholesterol transport. Deficiency or 
downregulation of these transporters can lead to 
increased cholesterol accumulation in 
macrophages, contributing to foam cell formation 
and potentially accelerating atherosclerosis 
(Yvan-Charvet et al., 2007). 
 
HIV is a major contributing factor to 
cardiovascular disease (CVD) in PLWH, resulting 
in approximately a two-fold increase in the 
relative risk of this condition (Ancuta et al., 2008). 
CVD is the leading cause of death worldwide, 
with atherosclerosis being the primary underlying 
pathology (Jebari-Benslaiman et al., 2022). 
 
Atherosclerosis occurs when plaque, composed 
of fat, cholesterol, and other substances, 
accumulates in the intima of arteries, causing 
them to narrow and stiffen. This process begins 
with damage to the endothelium, leading to the 
retention and modification of low-density 
lipoprotein (LDL) in the intima (Mundi et al., 
2017). The recruitment of monocytes into the 
intima triggers a critical inflammatory response 
that is essential for the development of 
atherosclerosis. Once in the arterial wall, these 
monocytes differentiate into macrophages and 
foam cells, which aid in plaque formation 
(Subramanian et al., 2012). 
 
Additionally, HIV-infected monocytes and 
macrophages produce increased levels of pro-



 
 
 
 

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inflammatory cytokines, maintaining a systemic 
inflammatory state that accelerates 
atherosclerosis and endothelial dysfunction 
(Deeks et al., 2013). Elevated levels of markers 
for macrophage activation, such as soluble 
CD163 and soluble CD14, have a strong 
association with subclinical atherosclerosis and 
cardiovascular events in PLWH (Serrano-Villar et 
al., 2014). 
 
Furthermore, the increased expression of 
adhesion molecules (like ICAM-1 and VCAM-1) 
and chemokine receptors (such as CCR2 and 
CX3CR1) on HIV-infected monocytes enhances 
their ability to adhere to and infiltrate the vascular 
endothelium. This disruption of the endothelial 
barrier promotes vascular inflammation, worsens 
endothelial dysfunction, and contributes to 
vascular remodeling, all of which increase 
cardiovascular risk (Hsue et al., 2012). Cytokines 
released from macrophages (like TNF-α and IL-
6) and HIV proteins (such as Tat and Nef) 
directly activate endothelial cells, resulting in 
increased permeability and accelerated 
recruitment of leukocytes (Hsue et al., 2012). 
 
Lastly, HIV infection and ART can disrupt lipid 
metabolism, leading to elevated levels of 
triglycerides and LDL cholesterol. In PLWH, 
macrophages accumulate lipids and demonstrate 
impaired cholesterol efflux, largely due to the 
downregulation of critical ATP-binding cassette 
transporters, ABCA1 and ABCG1 (Yvan-Charvet 
et al., 2007). These transporters play a vital role 
in cholesterol efflux and reverse cholesterol 
transport. Their deficiency or downregulation can 
lead to increased cholesterol accumulation in 
macrophages, promoting foam cell formation and 
potentially accelerating atherosclerosis (Yvan-
Charvet et al., 2007). 
 

3.2 Neurocognitive Disorders  
 
HIV-associated neurocognitive disorders (HAND) 
refer to a range of neurological and cognitive 
impairments linked to HIV infection and AIDS. 
These disorders remain common despite ART 
and can affect up to 50% of PLWH. HAND 
ranges from mild cognitive deficits to severe 
dementia and can significantly impact daily 
functioning (Adhikary et al., 2025). 
 

The blood-brain barrier (BBB) is compromised in 
HIV infection, allowing for the establishment of 
viral reservoirs in the brain. The HIV-1 envelope 
glycoprotein, gp120, plays a key role in 
damaging the integrity of the BBB by altering 

tight junction proteins in human brain 
microvascular endothelial cells (Said & 
Venketaraman, 2025). However, the initial trigger 
for HAND is the movement of HIV-infected 
monocytes across the BBB into the central 
nervous system (CNS), where they differentiate 
into perivascular macrophages (León-Rivera et 
al., 2021). 
 
Perivascular macrophages are long-lived, tissue-
resident cells that occupy the spaces around 
blood vessels. They express CD14, CD16, and 
CD163, and, together with microglia, contain HIV 
even in individuals receiving ART, contributing to 
chronic low-level viral replication (Kruize & 
Kootstra, 2019). Additionally, HIV-infected 
monocytes secrete matrix metalloproteinases 
(MMP-9), which degrade tight junction proteins 
(such as claudin-5 and occludin), thereby 
increasing BBB permeability. Similar to the 
pathogenesis of cardiovascular disease, the 
increased expression of adhesion molecules and 
chemokine receptors (such as CCR2 and 
CX3CR1) in HIV-infected monocytes enables 
their adhesion to and crossing of the BBB. 
Activated astrocytes and endothelial cells 
produce chemokines like CCL2, also known as 
monocyte chemoattractant protein-1 (MCP-1), 
which help recruit monocytes into the CNS 
(Hernandez et al., 2024). 
 
The degradation of tight junctions, the apoptosis 
of endothelial cells, and the consequent BBB 
leakage allow plasma proteins (e.g., fibrinogen) 
and peripheral immune cells to infiltrate the CNS, 
exacerbating neuroinflammation and white 
matter damage (Salimi & Klein, 2019). Moreover, 
activated microglia can engage in "synaptic 
stripping," phagocytizing dendritic spines and 
synapses, causing synaptic loss, especially in 
the hippocampus and prefrontal cortex areas 
critical for memory and executive function 
(Schlachetzki et al., 2022). Soluble viral proteins 
(such as gp120, Tat, and Nef) secreted by 
infected macrophages contribute to excitotoxicity, 
oxidative stress, and synaptic damage (Marino et 
al., 2020). The CD16+ monocyte subset, which 
has a pro-inflammatory profile (Ong et al., 2018), 
plays a critical role in HIV neuroinvasion                  
due to its high MMP-9 secretion (which leads to 
BBB breakdown) (Campos et al., 2014)           
and enhanced chemotaxis (Kruize & Kootstra, 
2019). 
 
However, inflammation and immune activation 
are central mechanisms driving the development 
of HAND, with various contributing factors. HIV-



 
 
 
 

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infected macrophages release pro-inflammatory 
cytokines (such as TNF-α, IL-1β, and IL-6) and 
chemokines (like MCP-1/CCL2), activating 
astrocytes and microglia while recruiting 
additional monocytes into the CNS, sustaining 
chronic neuroinflammation (Saylor et al.,         
2016). 
 
Additionally, HIV RNA and proteins activate the 
NLRP3 inflammasome in macrophages, 
increasing the release of IL-1β and IL-18. NLRP3 
is primarily found in myeloid cells (monocytes, 
macrophages, and neutrophils) and acts as a 
sensor for pathogen-associated molecular 
patterns (PAMPs) and damage-associated 
molecular patterns (DAMPs), initiating an 
inflammatory response (Swanson et al., 2019). 
This activation occurs in two steps:                         
first, HIV infection primes macrophages by 
increasing NLRP3 expression, and then          
specific viral components activate the 
inflammasome, resulting in the maturation          
and release of IL-1β and IL-18 (Chivero et al., 
2017). 
 
Activated macrophages and microglia              
produce quinolinic acid, an N-Methyl-D-aspartate 
(NMDA) receptor agonist that induces 
excitotoxicity by overstimulating neurons. NMDA 

receptors, which are the primary excitatory 
neurotransmitter receptors in the human brain, 
play a crucial role in synaptic plasticity, a 
neuronal mechanism thought to be fundamental 
for memory formation. Quinolinic acid also 
generates ROS, leading to mitochondrial 
dysfunction and neuronal apoptosis (Lugo-
Huitrón et al., 2013). 
 
These pathological processes ultimately result in 
a range of cognitive deficits, including 
asymptomatic neurocognitive impairment (subtle 
deficits detectable only through 
neuropsychological testing), mild neurocognitive 
disorder (functional impairment in daily          
activities), and HIV-associated dementia           
(severe cognitive and motor decline, which is 
now rare in the ART era) (Adhikary et al.,         
2025). 
 

3.3 Liver and Kidney Disease 
 

Common to the mechanism of tissue damage in 
other organs, chronic inflammation and immune 
activation driven by HIV-infected monocytes and 
macrophages play a central role in liver and 
kidney pathology among PLWH. However, the 
dynamics underlying the damage differ between 
the two organs. 

 

 
 

Fig. 1. Mechanisms of HAND. HIV-infected CD16+ monocytes migrate across the BBB enabled 
by CCR2/MMP-9 expression, seeding CNS reservoirs. Persistent viral proteins (Tat/gp120) and 

cytokines (TNF-α/IL-1β) drive neuroinflammation, oxidative stress, and synaptic damage, 
culminating in cognitive decline 



 
 
 
 

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Most of the focus on liver disease has been on 
individuals co-infected with HCV or HBV. 
However, even though the apparent net effect of 
HIV on liver fibrosis is most evident in the 
presence of a second contributor, such as HCV 
infection, HBV infection, excessive alcohol use, 
or metabolic liver disease, HIV infection itself 
biases the liver toward fibrosis and synergistically 
promotes these other processes. There is also 
significant evidence suggesting that even without 
primary liver disease, HIV itself may cause liver 
steatosis and fibrosis (Sherman & Thomas, 
2022). 
 

Various seemingly overlapping mechanisms 
have been proposed to explain how HIV may 
potentiate or cause liver fibrosis, but they all 
converge on the central role of the hepatic 
stellate cell (HSC). HSCs are pivotal in liver 
fibrosis, where the liver develops scar tissue 
secondary to chronic injury. When HSCs are 
activated, they can transdifferentiate from a 
quiescent to an activated phenotype, producing 
excess extracellular matrix (ECM), which 
contributes to the development of fibrosis, 
cirrhosis, and other liver diseases (Hoffmann et 
al., 2020). 
 

HIV-infected Kupffer cells (resident liver 
macrophages) and circulating monocytes that 
migrate to the liver become chronically activated 
due to viral persistence. They create a pro-
inflammatory microenvironment in the liver by 
releasing TNF-α, IL-6, IL-1β, and CCL2. 
(Mosoian et al., 2016), while HIV proteins (Tat, 
Nef), which directly enhance macrophage 
activation, may stimulate signaling pathways 
such as NF-κB, amplifying cytokine production. 
Additionally, activated macrophages secrete 
TGF-β, a key fibrogenic cytokine, and platelet-
derived growth factor (PDGF), a potent mitogen 
(Mosoian et al., 2016). These factors are crucial 
in transitioning HSCs from a quiescent to an 
activated state.  
 

Furthermore, HIV-infected macrophages 
generate ROS, which directly activate HSCs and 
enhance TGF-β signaling, exacerbating the 
process of tissue damage. In addition, HIV-
induced gut barrier dysfunction allows 
translocation of microbial components, especially 
lipopolysaccharides (LPS), to the liver. These 
bind to TLR4 on Kupffer cells, further amplifying 
cytokine production (e.g., IL-1β via NLRP3 
inflammasome activation) (Hoffmann et al., 
2020). Ultimately, the resulting accumulation of 
ECM disrupts liver architecture, leading to 
cirrhosis and impaired hepatic function.   

HIV-infected monocytes and macrophages 
significantly contribute to HIV-associated            
kidney disease, particularly HIV-associated 
nephropathy (HIVAN) and immune-                
complex-mediated glomerulonephritis, through 
direct viral infection, chronic inflammation, and 
podocyte injury. HIVAN, characterized by             
focal segmental glomerulosclerosis with 
collapsing glomerulopathy and tubulointerstitial 
inflammation, is underpinned by various 
pathological processes. HIV-infected 
macrophages expressing pro-inflammatory 
cytokines (TNF-α, IL-6, and TGF-β) promote 
fibrosis and glomerular scarring (Medapalli,           
He & Klotman, 2011). Additionally, infected 
macrophages release IL-1β via NLRP3 
inflammasomes, amplifying glomerular damage 
(Ekabe et al., 2021). Podocytes can also be 
infected, but through non-conventional 
mechanisms (HIV-receptor-independent). One 
such mechanism is through virological synapses 
and tunneling nanotubes between CD4+ T cells, 
macrophages, and renal cells. These facilitate 
HIV spread among these different cell types 
(Hughes et al., 2021). Infection of podocytes 
triggers apoptosis, loss of function, and 
dedifferentiation, all contributing to glomerular 
damage (Hughes et al., 2021). 
 

3.4 Cancer 
 

While ART has reduced the incidence of AIDS-
defining cancers, PLWH still experience an 
elevated risk for certain non-AIDS-defining 
cancers due to multiple mechanisms, including 
improvements in life expectancy with ART, 
immunosenescence, and the loss of control over 
oncogenic infections due to HIV-related immune 
suppression. But additionally, macrophage-
derived chronic inflammation and immune 
activation create a microenvironment conducive 
to carcinogenesis (Grulich et al., 2007). Hodgkin 
lymphoma and cancers of the lung, anus, liver, 
which are non-AIDS malignancies have become 
more prevalent in PLWH (Wang, Silverberg & 
Abrams, 2014). 
 

While ART has significantly reduced the 
incidence of AIDS-defining cancers, PLWH still 
face an increased risk for certain non-AIDS-
defining cancers. This heightened risk arises 
from various factors, including the prolonged life 
expectancy associated with ART, 
immunosenescence, and diminished control over 
oncogenic infections due to HIV-related immune 
suppression (Wang, Silverberg & Abrams, 2014). 
Furthermore, macrophage-driven immune 
dysregulation contributes to a microenvironment 



 
 
 
 

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127 

 

 
 

Fig. 2. Mechanisms of HIV-associated nephropathy (HIVAN) 
 
that favors carcinogenesis (Grulich et al., 2007). 
Consequently, non-AIDS malignancies, such as 
Hodgkin lymphoma and cancers of the lung, 
anus, and liver, have become more prevalent 
among PLWH (Wang, Silverberg & Abrams, 
2014). 
 
The chronic inflammatory state induced by the 
increased secretion of proinflammatory cytokines 
from HIV-infected monocytes and macrophages 
promotes DNA damage, inhibits apoptosis in 
malignant cells, and supports tumor cell 
proliferation (Grivennikov, Greten & Karin, 2010). 
For instance, IL-6 activates JAK-STAT3 signaling 
in epithelial cells by binding to its receptor (IL-
6R). Activating this signaling pathway leads to 
downstream effects on gene expression and 
cellular behavior, including driving the expression 
of genes involved in cell survival, proliferation, 
angiogenesis, and metastasis, ultimately 
facilitating oncogenic transformation in certain 
cells (Thuya et al., 2025). 
 
Secondly, HIV alters macrophage polarization, 
steering them toward a pro-tumor M2-like 
phenotype, characterized by increased PD-L1, 
IL-10, and TGF-β expression. These factors 
suppress the cytotoxic T-cell responses and 
encourage the expansion of regulatory T-cells 
(Tregs), which favors immune escape by 
tumours (Li et al., 2024). Furthermore, chronic 
HIV activation boosts the population of 

monocyte-derived myeloid-derived suppressor 
cells (MDSCs), which impede the functions of NK 
and CD8+ T-cells. MDSCs are linked to 
aggressive tumor growth and poorer outcomes in 
HIV-related cancers (Tumino et al., 2022). 
 
Moreover, metabolic reprogramming within the 
tumor microenvironment—exemplified by 
increased glycolysis in HIV-infected monocytes 
and macrophages—results in the production of 
lactate. The lactate acidifies the tumor 
environment, suppresses antitumor immunity, 
and promotes metastasis. Additionally, the 
elevated production of ROS from dysfunctional 
mitochondria in these HIV-infected cells causes 
DNA damage in adjacent cells. This damage 
affects oncogenes and tumor suppressor genes, 
thereby increasing the risk of carcinogenesis 
(Zhou et al., 2022). 
 

4. THERAPEUTIC IMPLICATIONS 
 
Given the substantial evidence highlighting the 
crucial involvement of monocytes and 
macrophages in the development of nADEs, 
targeting the mechanisms by which these cells 
contribute to these pathologies presents a 
promising strategy for alleviating chronic 
inflammation and enhancing clinical outcomes in 
PLWH in the era of viral suppression. Non-
specific, potential therapeutic approaches 
include: 



 
 
 
 

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Fig. 3. Conceptual Basis for Employing Reservoir Targeting Strategies 
 

Table 1. Plausible mechanisms of amelioration of nADEs following successful reservoir 
reduction/elimination 

 

nADE Mechanism of amelioration 

Neurocognitive (HAND) ↓ HIV-infected microglia, ↓ neuroinflammation 
Cardiovascular ↓ IL-6/TNF-α → ↓ endothelial dysfunction 
Liver/Kidney Fibrosis ↓ TGF-β → ↓ collagen deposition 

 
4.1 Reservoir-Targeting Strategies  
 
The persistence of latent or transcriptionally 
active viruses in myeloid cells despite ART 
remains a major barrier to cure efforts and a 
major contributor to the chronic immune 
dysfunction underlying the development of 
nADEs. Reservoir-targeting strategies aim to 
eliminate persistent HIV and reduce chronic 
inflammation, directly addressing the root cause 
of nADEs. While challenges remain (e.g., 
myeloid reservoir penetration (Chun, Moir & 
Fauci, 2015)), combined approaches promise to 
improve long-term outcomes for PLWH. 
Eliminating HIV reservoirs in monocytes and 
macrophages is critical for achieving a cure and 
lowering the risk of nADEs.  
 
Recent research provides evidence supporting 
strategies to target these reservoirs by employing 
latency-reversing agents such as TLR agonists 
(Li et al., 2023) and gene-editing technologies 
using CRISPR to excise HIV DNA from infected 
macrophages (Das et al., 2019). The ultimate 
aim is to reduce reservoir load, lower immune 
activation and inflammation, and decrease the 
incidence of nADEs. 
 

4.2 Anti-Inflammatory Therapies 
 
Agents that modulate the activation of monocytes 
and macrophages, such as statins, aspirin, and 
cytokine inhibitors (e.g., IL-6 and TNF-α 
blockers), may help reduce inflammation and 
lower the risk of nADEs. Specifically, statins can 
influence vascular atherosclerotic inflammation 

by directly enhancing the function of endothelial 
cells, vascular smooth muscle cells, platelets, 
and immune cells. Additionally, rosiglitazone, a 
PPAR-gamma agonist, has demonstrated 
potential in halting brain inflammation and 
inhibiting HIV replication in murine models of HIV 
encephalitis. 
 

4.3 Restoring Immune Homeostasis 
 
Interventions designed to restore the functional 
properties of monocytes and macrophages, such 
as enhancing phagocytosis and promoting anti-
inflammatory phenotypes, may contribute to 
mitigating tissue damage and improving overall 
outcomes. In particular, modulating macrophage 
function by shifting polarization from pro-
inflammatory M1 to anti-inflammatory M2 (and 
vice versa) could have significant implications for 
HIV pathogenesis and the development of non-
antibody-dependent enhancement (nADEs) (Luo 
et al., 2024). 
 

5. CONCLUSION 
 
Monocytes and macrophages play crucial roles 
in the pathogenesis of HIV disease and the 
development of nADEs. Their functions as viral 
reservoirs, drivers of chronic inflammation, and 
mediators of tissue damage underscore the need 
for targeted therapeutic strategies to address 
these mechanisms. While current challenges 
such as low myeloid cell penetration, reservoir 
heterogeneity, and limited CNS penetration still 
need to be overcome, understanding and 
modulating the functions of monocytes and 



 
 
 
 

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129 

 

macrophages presents a promising strategy for 
reducing the burden of nADEs and enhancing 
the long-term health outcomes of PLWH. 
 

CONSENT AND ETHICAL APPROVAL 
 
It is not applicable. 
 

DISCLAIMER (ARTIFICIAL INTELLIGENCE) 
 

The author hereby declares that NO generative 
AI technologies such as Large Language Models 
(ChatGPT, COPILOT, etc.) and text-to-image 
generators have been used during the writing or 
editing of this manuscript.  
 

COMPETING INTERESTS 
 

Author has declared that no competing interests 
exist. 
 

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