Volume 9, Issue 8, August – 2024 International Journal of Innovative Science and Research Technology

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HIV-Associated Immune Dysfunction and

Hematological Abnormalities: A Detailed
Examination of Pathophysiology and
Clinical Implications
Zakaria EL KODMIRI1*
Immunopathology-Immunotherapy-Immunomonitoring Laboratory, Faculty of Medicine,
Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
Department of Hematology, Cheikh Khalifa Ibn Zaid International University Hospital, Casablanca, Morocco

Dr. Bouchra Ghazi2 (Professor)

Immunopathology-Immunotherapy-Immunomonitoring Laboratory, Faculty of Medicine,
Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
Mohammed VI International University Hospital, Bouskoura, Morocco

Dr. Abdelati Ouamani3 (Professor)

Institute of Nursing Professions and Health Techniques (ISPITS), Marrakech, Morocco

Dr. Maryame Ahnach 4 (Professor)

Immunopathology-Immunotherapy-Immunomonitoring Laboratory, Faculty of Medicine,
Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
Department of Hematology, Cheikh Khalifa Ibn Zaid International University Hospital, Casablanca, Morocco

Corresponding Author:- Zakaria EL KODMIRI*1

Abstract:- Human Immunodeficiency Virus (HIV) exerts I. INTRODUCTION

profound effects on both the immune and hematological
systems, leading to a range of complications that Human Immunodeficiency Virus (HIV) remains one of
significantly influence patient outcomes and quality of the foremost global health challenges, with approximately 39
life. This review examines the intricate interplay between million individuals living with the virus as of 2023 [1].
HIV infection, immune system dysfunction, and Despite considerable advancements in treatment, notably
hematological abnormalities. We detail the mechanisms through the widespread adoption of antiretroviral therapy
underlying these complications, including the direct (ART), HIV continues to exert a significant burden on public
impact of HIV on CD4+ T lymphocytes, the persistent health [2]. The virus's capacity to compromise the immune
immune activation observed despite antiretroviral system leads to a spectrum of infections and associated
therapy (ART), and the diverse etiologies of HIV- complications, underscoring the critical need for a deeper
associated anemia, thrombocytopenia, and leukopenia. understanding of HIV pathogenesis and its clinical
Additionally, we address the clinical implications of these ramifications [3].
issues, emphasizing their role in disease progression and
the current therapeutic approaches. This review HIV predominantly targets the immune system, with a
highlights the imperative for continued research and the particular emphasis on CD4+ T lymphocytes, which are
advancement of integrated care strategies to enhance crucial for orchestrating the body’s immune responses [4].
long-term outcomes for individuals living with HIV. The progressive depletion of these cells by the virus impairs
the immune system's ability to combat infections, thereby
Keywords:- HIV; Immune Dysfunction; Hematological increasing susceptibility to opportunistic infections and other
Abnormalities; CD4+ T Lymphocytes; Antiretroviral diseases [2]. Concurrently, HIV infection induces persistent
Therapy (ART); Chronic Immune Activation; Anemia; immune activation, characterized by sustained inflammation
Thrombocytopenia; Leukopenia; Pathophysiology; Clinical that persists even in the presence of effective ART [3]. This
Implications; Inflammation; Opportunistic Infections. chronic inflammatory state is implicated in the development
of non-AIDS-related comorbidities, such as cardiovascular
disease and accelerated aging [4].

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Additionally, HIV is linked to various hematological variability in the virus. The newly synthesized viral DNA is
abnormalities, including anemia, thrombocytopenia, and then integrated into the host cell's genome by the enzyme
leukopenia [1]. These hematological disorders result from integrase, allowing the virus to hijack the host cell's
both the direct effects of the virus on hematopoiesis and machinery to produce new viral particles. The integrated viral
secondary factors such as chronic inflammation and ART- DNA, known as a provirus, can remain latent for an extended
related side effects [2]. The clinical implications of these period, evading detection by the immune system.
hematological conditions are substantial, as they not only Alternatively, it can become transcriptionally active, leading
serve as indicators of disease severity but also exacerbate the to the production of new viral particles that bud from the host
overall health challenges faced by individuals living with cell and go on to infect other CD4+ cells [5].
HIV [3]. This review provides a comprehensive analysis of
the complications associated with HIV, with a focus on C. HIV-Induced CD4+ T Cell Depletion
immune dysfunction and hematological abnormalities. By The depletion of CD4+ T cells is a hallmark of HIV
elucidating the underlying biological mechanisms, exploring infection and a major contributor to immune system
the clinical consequences, and evaluating current therapeutic dysfunction. CD4+ T cells, also known as helper T cells, play
approaches, this article aims to enhance our understanding of a central role in the immune response by coordinating the
these intricate interactions and inform future research and activity of other immune cells, such as CD8+ cytotoxic T
treatment strategies. lymphocytes, B cells, and macrophages. The loss of CD4+ T
cells disrupts this coordination, leading to a weakened
II. LITERATURE REVIEW immune response and increased susceptibility to
opportunistic infections and certain cancers [6].
A. HIV and Immune System Dysfunction
HIV, or Human Immunodeficiency Virus, is a retrovirus
that causes significant immune system deterioration by
primarily targeting CD4+ T lymphocytes, a subset of white
blood cells essential for orchestrating the body’s immune
response. Since its discovery in the early 1980s, HIV has
become a global health crisis, with millions of people affected
worldwide. The profound impact of HIV on the immune
system is primarily due to its unique ability to target and
destroy CD4+ T cells, leading to a cascade of immunological
failures that culminate in Acquired Immunodeficiency
Syndrome (AIDS) [5].

B. The Biology of HIV

To understand how HIV causes immune system
dysfunction, it is crucial to examine its biology. HIV is an
RNA virus that belongs to the lentivirus family, a subgroup
of retroviruses known for their slow replication cycle. The
virus contains two copies of single-stranded RNA as its
genetic material, surrounded by a protein capsid and an outer
lipid envelope derived from the host cell membrane. The
envelope contains glycoproteins, such as gp120 and gp41,
which play a vital role in the virus's ability to infect host cells
[5].

HIV primarily infects cells that express the CD4

molecule on their surface. CD4 is a glycoprotein found on the
surface of immune cells, including T helper cells,
macrophages, and dendritic cells. The gp120 protein on the
Fig 1 Mechanism of HIV entry into CD4+ T cells,
surface of HIV binds to the CD4 receptor, facilitating viral
highlighting the role of CD4 receptors and co-receptors
attachment to the host cell. Following this initial attachment,
CCR5/CXCR4.
gp120 undergoes a conformational change, allowing it to
interact with a co-receptor, either CCR5 or CXCR4,
 Several Mechanisms Contribute to the Depletion of CD4+
depending on the strain of HIV. This interaction is critical for
T cells in HIV Infection:
the fusion of the viral envelope with the host cell membrane,
mediated by the gp41 protein, which facilitates the entry of
the viral RNA into the host cell [5].  Direct Viral Killing of Infected Cells:
HIV directly kills CD4+ T cells through various
Once inside the host cell, the viral RNA is reverse- mechanisms. Once the virus has entered the cell and
transcribed into DNA by the enzyme reverse transcriptase, a integrated its genome, the production of viral proteins can
process that is error-prone and leads to high genetic induce cell death. This process, known as pyroptosis, is a

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form of programmed cell death associated with inflammation. macrophages. These reservoirs serve as a source of viral
HIV-infected CD4+ T cells can also undergo apoptosis, antigens that continuously stimulate the immune system,
another form of programmed cell death, in response to viral contributing to chronic immune activation [8].
replication and the expression of viral proteins on the cell
surface [6].  Microbial Translocation:
HIV causes significant damage to the mucosal barriers
 Chronic Immune Activation: of the gut, leading to increased permeability and the
HIV infection leads to a state of chronic immune translocation of microbial products, such as
activation, characterized by the continuous activation of the lipopolysaccharide (LPS), into the bloodstream. These
immune system, even in the absence of active infection. This microbial products act as potent activators of the immune
persistent activation is driven by several factors, including the system, driving chronic inflammation and immune activation
presence of viral RNA and proteins, the translocation of [9].
microbial products from the gut into the bloodstream, and the
production of pro-inflammatory cytokines. Chronic immune  Production of Pro-Inflammatory Cytokines:
activation leads to the exhaustion and eventual death of CD4+ HIV infection leads to the dysregulation of cytokine
T cells, contributing to their depletion [6]. production, with increased levels of pro-inflammatory
cytokines, such as IL-6, TNF-α, and IFN-γ. These cytokines
 Immune-Mediated Destruction: contribute to the activation of the immune system and the
In addition to direct viral killing, HIV-infected CD4+ T induction of chronic inflammation, further driving the
cells are targeted for destruction by the immune system. depletion of CD4+ T cells and the exhaustion of CD8+ T cells
CD8+ cytotoxic T lymphocytes, which recognize and kill [9].
infected cells, play a significant role in this process. However,
chronic activation and exhaustion of CD8+ T cells impair  Co-Infections:
their ability to control the virus effectively, leading to the Co-infections with other viruses, such as
persistence of infected cells [7]. cytomegalovirus (CMV) and hepatitis C virus (HCV), are
common in individuals with HIV and contribute to chronic
 Bystander Apoptosis: immune activation. These co-infections lead to the activation
HIV infection also induces apoptosis in uninfected of additional immune pathways and the production of pro-
CD4+ T cells, a phenomenon known as bystander apoptosis. inflammatory cytokines, exacerbating the inflammatory
This occurs when the immune system mistakenly targets environment in the body [10].
uninfected cells due to the inflammatory environment created
by chronic immune activation. The release of pro-  Immune Checkpoint Dysregulation:
inflammatory cytokines, such as TNF-α and IFN-γ, Immune checkpoints, such as PD-1 and CTLA-4, are
contributes to the induction of apoptosis in these bystander molecules that regulate the immune response by preventing
cells [7]. overactivation. In HIV infection, these checkpoints are
dysregulated, leading to the chronic activation and eventual
 Destruction of Lymphoid Tissue: exhaustion of immune cells, particularly CD8+ T cells. This
HIV causes significant damage to lymphoid tissues, exhaustion impairs the ability of the immune system to
particularly in the gut-associated lymphoid tissue (GALT), control HIV and other infections effectively [11].
where a large proportion of the body's CD4+ T cells reside.
The destruction of these tissues leads to the loss of a  Consequences of Chronic Immune Activation:
significant number of CD4+ T cells early in infection,
contributing to the overall depletion of these cells in the body  Immune Exhaustion:
[7]. Chronic immune activation leads to the exhaustion of T
cells, particularly CD8+ T cells, which are crucial for
 Chronic Immune Activation in HIV Infection controlling viral infections. Exhausted T cells lose their
Chronic immune activation is a defining feature of HIV ability to proliferate and produce cytokines, rendering them
infection and a major driver of disease progression. Even in less effective in clearing infected cells. This exhaustion is
individuals receiving effective ART, which suppresses viral characterized by the upregulation of inhibitory receptors,
replication to undetectable levels, immune activation persists. such as PD-1, and the downregulation of co-stimulatory
This chronic state of immune activation is associated with molecules [11].
several adverse outcomes, including accelerated aging,
increased risk of cardiovascular disease, neurocognitive  Tissue Damage:
decline, and other non-AIDS-related comorbidities [7]. The persistent activation of the immune system leads to
tissue damage, particularly in lymphoid organs, such as the
 Mechanisms of Chronic Immune Activation: spleen and lymph nodes. This damage impairs the ability of
these organs to function properly, further weakening the
 Persistent Low-Level Viral Replication: immune system [12].
Despite effective ART, low-level viral replication can
occur in reservoirs, such as latently infected CD4+ T cells and

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 Increased Susceptibility to Infections:  Increased Risk of Non-AIDS-Related Comorbidities:

The depletion of CD4+ T cells and the exhaustion of In addition to opportunistic infections, chronic immune
CD8+ T cells leave individuals with HIV more susceptible to activation is associated with an increased risk of non-AIDS-
opportunistic infections, such as Pneumocystis pneumonia, related comorbidities, such as cardiovascular disease, kidney
tuberculosis, and cytomegalovirus retinitis. These infections disease, and certain cancers. These conditions are thought to
are often severe and can be life-threatening in individuals result from the persistent inflammatory environment in the
with advanced HIV disease [12]. body, which contributes to the development of
atherosclerosis, renal dysfunction, and tumorigenesis [13].
 Accelerated Aging:
Chronic immune activation is associated with D. HIV's Impact on Different Immune Cells
accelerated aging in individuals with HIV. This is evidenced While CD4+ T cells are the primary targets of HIV, the
by the premature onset of age-related comorbidities, such as virus also affects other immune cells, including CD8+
cardiovascular disease, osteoporosis, and neurocognitive cytotoxic T cells, B cells, natural killer (NK) cells, and
decline. The mechanisms underlying this accelerated aging monocytes/macrophages. Each of these cell types plays a
are complex and likely involve a combination of chronic crucial role in the immune response, and their dysfunction
inflammation, immune exhaustion, and the direct effects of contributes to the overall immune deficiency observed in HIV
HIV on cellular function [12]. infection [13].

Fig 2 The impact of HIV on various immune cells, including CD4+ T cells, CD8+ T cells, B cells, and NK cells, showing
downstream effects on immune function.

 CD3+ T Cells: such as PD-1 and CTLA-4, further contributes to the

CD3+ T cells include both CD4+ and CD8+ T cells, dysfunction of CD8+ T cells. Despite these impairments,
which are critical for adaptive immunity. The CD3 complex CD8+ T cells play a critical role in controlling viral
is a component of the T cell receptor (TCR), which is replication, particularly during the early stages of infection
essential for recognizing antigens presented by other cells. [13].
HIV infection leads to the dysregulation of CD3+ T cells,
resulting in impaired T cell signaling and function [13].  CD19+ B Cells:
B cells, marked by CD19 expression, are responsible for
 CD3+CD4+ T Cells: producing antibodies that neutralize pathogens. In HIV
As previously discussed, HIV directly targets CD4+ T infection, B cell function is significantly impaired, leading to
cells, leading to their depletion and the subsequent collapse dysregulated antibody responses and increased susceptibility
of the immune system. The loss of CD4+ T cells disrupts the to infections [14].
coordination of the immune response, making it difficult for
the body to mount an effective defense against infections  Polyclonal B Cell Activation:
[13]. HIV infection induces polyclonal B cell activation,
resulting in the production of large quantities of non-specific
 CD3+CD8+ T Cells: antibodies. This dysregulated response reduces the
CD8+ T cells are responsible for killing infected cells, effectiveness of the immune system in targeting specific
including those harboring HIV. However, in the context of pathogens and contributes to the hypergammaglobulinemia
chronic HIV infection, these cells become functionally observed in individuals with HIV [15].
exhausted. This exhaustion is characterized by reduced
cytokine production, impaired proliferation, and decreased
cytotoxic activity. The upregulation of inhibitory receptors,

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 Impaired Germinal Center Function:  HIV Evasion of NK Cell-Mediated Killing:

Germinal centers are specialized structures within HIV has evolved several mechanisms to evade NK cell-
lymphoid tissues where B cells undergo maturation and mediated killing. For example, the virus downregulates the
differentiation into memory B cells and plasma cells. HIV expression of ligands for activating NK cell receptors on the
infection disrupts the formation and function of germinal surface of infected cells, making them less susceptible to NK
centers, leading to impaired B cell maturation and reduced cell-mediated lysis. Additionally, HIV can upregulate the
production of high-affinity antibodies. This disruption is expression of inhibitory ligands, such as HLA-E, which bind
primarily due to the depletion of follicular helper T cells to inhibitory receptors on NK cells and suppress their activity
(Tfh), a subset of CD4+ T cells that provide essential signals [18].
for B cell maturation [16].
 Monocytes/Macrophages:
 Increased Risk of B Cell Lymphomas: Monocytes and macrophages are components of the
Individuals with HIV are at an increased risk of innate immune system and play a critical role in the early
developing B cell lymphomas, a type of cancer that originates response to infection. These cells are also important in
from B cells. The chronic activation and dysregulation of B antigen presentation, the process by which foreign particles
cells, combined with immune suppression, create an are presented to T cells, triggering an adaptive immune
environment conducive to the development of these response. HIV affects monocytes and macrophages in several
malignancies [16]. ways, contributing to immune dysfunction [19].

 Reduced Vaccine Efficacy:  HIV Infection of Monocytes and Macrophages:

The impaired function of B cells in HIV-infected Unlike CD4+ T cells, which are killed by HIV,
individuals reduces the efficacy of vaccines, as the production monocytes and macrophages can be infected by the virus but
of protective antibodies is compromised. This presents a often survive, becoming reservoirs for HIV. These cells
significant challenge for immunization strategies in this harbor the virus and can disseminate it throughout the body,
population, particularly for vaccines against common particularly to tissues where HIV is difficult to eradicate, such
pathogens such as influenza and pneumococcus [17]. as the central nervous system [19].

 CD56+ Natural Killer (NK) Cells:  Altered Cytokine Production:

NK cells, characterized by the expression of CD56, are HIV infection alters the cytokine production of
a crucial component of the innate immune system, monocytes and macrophages, leading to a pro-inflammatory
responsible for the rapid elimination of infected or state. This chronic inflammation contributes to tissue damage
transformed cells without prior sensitization. HIV infection and the development of HIV-associated comorbidities, such
impairs the function of NK cells, contributing to immune as cardiovascular disease [19].
dysfunction and the persistence of the virus [18].
 Impaired Phagocytosis:
 Altered NK Cell Subset Distribution: Phagocytosis, the process by which macrophages engulf
HIV infection leads to changes in the distribution of NK and digest pathogens, is impaired in HIV infection. This
cell subsets, with a decrease in the CD56^bright^ NK cells, impairment reduces the ability of the immune system to clear
which are primarily responsible for cytokine production, and infections, contributing to the increased susceptibility to
an increase in the CD56^dim^ NK cells, which have greater opportunistic infections observed in individuals with HIV
cytotoxic activity. However, the overall cytotoxic function of [20].
NK cells is diminished, reducing their ability to eliminate
HIV-infected cells [18].  Role in Chronic Immune Activation:
Monocytes and macrophages play a key role in the
 Impaired Cytotoxicity: chronic immune activation observed in HIV infection. These
The cytotoxic activity of NK cells is impaired in HIV cells produce pro-inflammatory cytokines, such as IL-6 and
infection, partly due to the downregulation of activating TNF-α, that contribute to the persistent activation of the
receptors, such as NKG2D, on the surface of NK cells. immune system. Additionally, infected macrophages can
Additionally, the chronic activation and inflammatory present HIV antigens to T cells, driving their activation and
environment in HIV infection contribute to the functional contributing to immune exhaustion [20].
exhaustion of NK cells, similar to what is observed in CD8+
T cells [18]. E. HIV-Associated Hematological Complications
HIV infection is associated with a range of
 Decreased Production of Cytokines: hematological abnormalities, including anemia,
NK cells produce cytokines, such as IFN-γ and TNF-α, thrombocytopenia, leukopenia, and lymphopenia. These
that play a critical role in controlling viral infections. In HIV complications contribute to the morbidity and mortality
infection, the production of these cytokines is reduced, associated with HIV and can complicate the management of
further compromising the ability of NK cells to control viral the disease [21].
replication and contribute to the overall immune response
[18].

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 Anemia in HIV  Nutritional Deficiencies:

Anemia is a common complication of HIV infection, Nutritional deficiencies, particularly of iron, vitamin
particularly in individuals with advanced disease. It is B12, and folate, are common in individuals with HIV and
associated with increased mortality and reduced quality of contribute to the development of anemia. Malabsorption due
life. The prevalence of anemia in HIV-infected individuals to HIV-associated enteropathy and the side effects of ART,
varies widely, depending on the population studied and the such as gastrointestinal disturbances, can exacerbate these
stage of the disease, but it is estimated to affect 20-70% of deficiencies [23].
people with HIV [21].
 Bone Marrow Suppression by ART:
 Causes of Anemia in HIV: Certain antiretroviral drugs, particularly zidovudine
(AZT), can cause bone marrow suppression, leading to
 Direct Viral Effects on Bone Marrow: reduced production of red blood cells and anemia. The
HIV can directly infect bone marrow progenitor cells, mechanism of this suppression is thought to involve
leading to impaired erythropoiesis, the process by which red mitochondrial toxicity and the inhibition of DNA synthesis in
blood cells are produced. The infection of these progenitor bone marrow progenitor cells [23].
cells can lead to their apoptosis or dysfunction, resulting in
reduced red blood cell production [21].  Opportunistic Infections:
Opportunistic infections, such as Mycobacterium avium
 Chronic Inflammation and Anemia of Chronic Disease complex (MAC) and Parvovirus B19, can infect the bone
(ACD): marrow and impair erythropoiesis, leading to anemia. These
Chronic inflammation in HIV infection contributes to infections are more common in individuals with advanced
anemia through the development of anemia of chronic disease HIV disease and contribute to the severity of anemia in this
(ACD). In ACD, the inflammatory cytokines produced during population [23].
chronic immune activation, such as IL-6, lead to increased
production of hepcidin, a hormone that inhibits iron  Clinical Consequences of Anemia in HIV:
absorption and sequestration in macrophages. This results in Anemia in HIV is associated with several adverse
reduced iron availability for erythropoiesis, leading to anemia outcomes, including increased mortality, reduced physical
[22]. function, and impaired cognitive function. It also complicates
the management of HIV, as severe anemia may limit the use
of certain ARTs, such as AZT, which can exacerbate the
condition. The presence of anemia also increases the risk of
other comorbidities, such as cardiovascular disease, due to
the increased workload on the heart [24].

Fig 3 Prevalence of Anemia Among HIV-Infected Individuals at Different Stages.

 Thrombocytopenia in HIV is associated with an increased risk of bleeding, particularly

Thrombocytopenia, defined as a platelet count of less in individuals with severe thrombocytopenia (platelet count
than 150,000/μL, is a common hematological complication of <20,000/μL) [25].
HIV infection, affecting 10-30% of individuals with HIV. It

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Fig 4 Mechanisms leading to thrombocytopenia in HIV, including direct viral effects on megakaryocytes and immune-mediated
destruction of platelets.

 Causes of Thrombocytopenia in HIV: the treatments for these malignancies, such as chemotherapy,
can further reduce platelet counts [27].
 Immune-Mediated Destruction of Platelets:
HIV-associated thrombocytopenia is often immune-  Clinical Consequences of Thrombocytopenia in HIV:
mediated, similar to immune thrombocytopenic purpura Thrombocytopenia in HIV is associated with an
(ITP). The immune system produces antibodies against increased risk of bleeding, particularly mucocutaneous
platelets, leading to their destruction in the spleen. The bleeding, such as petechiae, purpura, and epistaxis. Severe
mechanism underlying this immune response is not fully thrombocytopenia can lead to life-threatening hemorrhages,
understood but is thought to involve the formation of immune particularly in the gastrointestinal tract or central nervous
complexes containing HIV antigens and anti-platelet system. The presence of thrombocytopenia also complicates
antibodies [26]. the management of HIV, as certain ARTs and treatments for
opportunistic infections may exacerbate the condition [28].
 Direct Viral Effects on Megakaryocytes:
HIV can directly infect megakaryocytes, the bone  Leukopenia and Lymphopenia in HIV
marrow cells responsible for producing platelets. This Leukopenia, defined as a white blood cell count of less
infection can lead to impaired platelet production, than 4,000/μL, and lymphopenia, defined as a lymphocyte
contributing to thrombocytopenia. The virus may also induce count of less than 1,500/μL, are common hematological
apoptosis in these cells, further reducing platelet production abnormalities in HIV infection. These conditions are
[26]. associated with an increased risk of infections and are
indicative of advanced immune system dysfunction [28].
 Increased Platelet Destruction by ART:
Certain antiretroviral drugs, particularly zidovudine  Causes of Leukopenia and Lymphopenia in HIV:
(AZT), can cause bone marrow suppression, leading to
reduced platelet production and thrombocytopenia.  Direct Viral Effects on Bone Marrow Progenitor Cells:
Additionally, ART can induce immune reconstitution HIV can infect bone marrow progenitor cells, leading to
inflammatory syndrome (IRIS), a condition characterized by impaired production of white blood cells and lymphocytes.
an exaggerated immune response to opportunistic infections, This infection can result in the apoptosis or dysfunction of
which can exacerbate thrombocytopenia [27]. these progenitor cells, contributing to leukopenia and
lymphopenia [29].
 HIV-Associated Malignancies:
HIV-infected individuals are at increased risk of  Chronic Immune Activation:
developing certain malignancies, such as non-Hodgkin Chronic immune activation in HIV infection leads to the
lymphoma and Kaposi's sarcoma, which can infiltrate the exhaustion and eventual depletion of immune cells,
bone marrow and impair platelet production. Additionally, particularly lymphocytes. The persistent activation of the

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