A comprehensive analysis of immune and hematologic cells in HIV-infected moroccan population

doi:10.21203/rs.3.rs-7602323/v1

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A comprehensive analysis of immune and hematologic cells in HIV-infected moroccan population

https://doi.org/10.21203/rs.3.rs-7602323/v1

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HIV infection presents significant challenges globally, as it affects the immune and hematologic systems through complex mechanisms. This study aimed to assess changes in immune and hematologic cell populations in HIV-infected patients, with a focus on the relationships between CD4+ T-cell counts and peripheral cell levels.

This retrospective analysis included 1,293 HIV-infected adult patients enrolled from the immunology department of the University Hospital in collaboration with the infectiology and biological hematology departments. The patients were divided into two groups. Group 1 (1,200 patients) underwent complete blood count (CBC) and CD4 T-cell count determination, whereas Group 2 (93 patients) benefited from T (CD3/CD4/CD8), B (CD19) and NK (CD16/56) cell immunophenotyping. Statistical analyses were performed via SPSS software, and the results were considered significant when the p value was less than 0.05.

The mean age of patients was 45±10 years. (range: 35–55), with a sex ratio of 1:2. Among the 1,293 HIV-infected patients, 43,2% presented low CD4+ T-cell counts, which was associated with significant changes in immune and hematological parameters as follows: patients with CD4+ T-cell counts below 200 cells/µL presented reductions in the number of polymorphonuclear cells (PNN) to 300 cells/µL (p = 0.002), in eosinophils to 120 cells/µL (p = 0.004), in basophils to 25 cells/µL (p = 0.03), and in monocytes to 250 cells/µL (p = 0.01), whereas the CD8+ T-cell count increased to 850 cells/µL (p = 0.001). From a hematological point of view, the number of erythrocytes was reduced to 4.0 million cells/µL (p = 0.01), and the number of platelets was reduced to 230,000 cells/µL (p = 0.005).

Our findings highlight the importance of monitoring CD4+ T-cell counts in parallel with CBC counts as indicators of immune and hematologic dysfunctions in HIV patients. These insights can guide targeted interventions to improve immune responses and hematologic stability, ultimately enhancing the clinical management and quality of life of individuals living with HIV. Further research is warranted to explore the underlying mechanisms and develop innovative therapeutic approaches.

HIV

CD4 T cells

Lymphocytes

Flow cytometry

CBC

Erythrocytes

Platelets

HIV infection remains a global health challenge, affecting nearly 39 million individuals worldwide as of 2024. The intricate interactions of the virus with the host immune and hematologic systems require a thorough understanding to guide effective therapeutic approaches [1].

A key element in HIV research is the multifaceted impact of viruses on various immune and hematologic cell populations, including but not limited to CD4+ T cells, B cells, natural killer (NK) cells, monocytes, polymorphonuclear cells, erythrocytes, and platelets. HIV-induced immune activation is paradoxical, triggering a vigorous immune response, primarily mediated by CD8+ T cells, which is ultimately crucial [2]. Although this response is aimed at controlling viral replication, it exacerbates the depletion of CD4+ T cells, which are directly targeted by the virus; moreover, other immune cells, such as polymorphonuclear neutrophils (PNNs), are also involved through cytokine and chemokine release [3]. The proinflammatory environment is exacerbated by many factors, such as eosinophil cationic protein, eosinophil-derived neurotoxin, and basophil degranulation, and accelerates the decline of specific immune cell populations [4]. Furthermore, HIV impairs antibody responses and disrupts erythropoiesis, leading to alterations in B-cell subsets [5] and increasing the risk of anemia [6]. Platelet dysfunction, another consequence of HIV infection, may precipitate bleeding disorders, underscoring the widespread impact of the virus on hematologic function [7].

This study aimed to explore the potential alterations in immune and hematologic cell populations in HIV-infected patients at the time of diagnosis.

Study population and design:

This retrospective study was carried out at the immunology department in collaboration with the infectiology and biological hematology departments of the Mohammed VI University Hospital of Marrakech and consisted of a retrospective analysis of immunobiological data from 1,293 HIV-infected adult patients. Patients were divided into two groups on the basis of the category of laboratory testing:

Group 1 included patients with complete blood counts and CD4+ T-cell counts (1,200 cases).
For both CBC and CD4+ T-cell counts, blood samples were collected in EDTA tubes.

CBC was performed via a Sysmex XP300™ analyzer (Sysmex, Kobe, Japan), allowing the measurement of leukocyte, erythrocyte, platelet, and hemoglobin levels. For the CD4 T-cell count, 50 µL of whole blood was mixed with 10 µL of monoclonal antibodies: anti‐CD45 (PerCP), anti‐CD3 (FITC), and anti‐CD4 (PE) [8]. The samples were incubated at room temperature for 15 minutes, followed by the addition of 450 µL of FACS Lysing solution (Becton Dickinson, BD Biosciences, Oxford, UK) and further incubation for 20 minutes before flow cytometry (Facs-Canto II, BD) acquisition and analysis via Diva software.

The CD4 T-cell value was calculated via a double plate-form approach in which the total lymphocyte number provided by CBC was combined with the percentage of CD4 T cells given by flow cytometry.

Group 2 included patients with T, B and NK cell immunophenotyping (93 patients):

This subgroup underwent detailed T, B, and NK cell immunophenotyping via the following fluorochrome-labeled monoclonal antibodies: anti‐CD45 (PerCP‐Cy5.5), anti‐CD3 (FITC), anti‐CD4 (PE‐Cy7), anti‐CD8 (APC‐Cy7), anti‐CD16/ CD56 (PE), and anti‐CD19 (APC), according to the following procedure: 100 µL of whole blood was mixed with 50 µL of staining solution and incubated for 15 minutes. Afterward, 2 mL of a 1:10 diluted lysing solution was added [9]. The samples were centrifuged at 700 × g for 5 minutes, the supernatant was discarded, and an additional 3 mL of FACS flow solution was added for a second centrifugation. The cells were then resuspended in 500 µL of FACS flow solution for acquisition and analysis via a flow cytometer (Facs Canto II- BD, Clinical Software), which provided absolute values of different subpopulations: T (CD3, CD4, and CD8), B (CD19) and NK (CD16/CD56) cells.

Statistical analysis:

Statistical analysis was conducted via SPSS software version 20.0. Descriptive statistics were performed by calculating frequencies for the following parameters: counts of T CD4+, T CD8+, B CD19+ cells, NK (CD16+CD56+), monocytes, neutrophils, basophils, eosinophils, erythrocytes, and platelets, along with the age and sex of the patients. The data distribution (mean and standard deviation) was evaluated.

The Kolmogorov‒Smirnov test was used to assess the normality of variable distributions. ANOVA was used to evaluate differences in immune cell counts and hematological parameters across groups. Student’s t test was used to examine associations between quantitative variables (e.g., T CD4+, T CD8+, B CD19+ cells, NK (CD16+CD56+), monocytes, neutrophils, basophils, eosinophils, erythrocytes, platelets, and age) and qualitative data (e.g., sex).

A p value of less than 0.05 was considered statistically significant.

Ethical considerations:

All demographic information and biological data of the patients analyzed in this study were extracted anonymously from the immunology department's electronic database under the supervision of the laboratory manager, according to the Ethical Principles of Helsinki Declaration for Medical Research Involving Human Subjects.

1. Overall results:

The mean age of the patients was 45±10 years (range: 35–55), with a male predominance (55.1%) and a sex ratio of 1.22.

The demographic characteristics of all patients and complete CBC parameter results, as well as CD4 T-cell count and T, B and NK subpopulation immunophenotyping data, are reported in Table 1 as the mean values with corresponding standard deviations.

Table 1: Demographic characteristics, hematologic parameters and T, B and NK cell immunophenotyping results of our series.

Parameters	Mean values	Standard Deviation [reference intervals]
Demographic Factors
Age (years)	45	10 [35-55]
Sex (Male to Female Ratio)	1,22	-
Hematological Parameters (CBC)
Red Blood Cells (10^6/µL)	4.3	0.6 [3.7, 4.9]
Platelets (10^3/µL)	268	78 [190, 346]
White Blood Cells (10^3/µL)	5.8	1.2 [4.6, 7.0]
Neutrophils (cells/µL)	4000	1200 [2800, 5200]
Basophils (cells/µL)	30	10 [20, 40]
Eosinophils (cells/µL)	150	50 [100, 200]
Monocytes (cells/µL)	300	100 [200, 400]
Immunological Parameters
TCD4 (cells/µL)	450	180 [270, 630]
TCD8 (cells/µL)	850	300 [550, 1150]
BCD19 (cells/µL)	150	50 [100, 200]
NK (CD16+CD56+) (cells/µL)	200	70 [130, 270]

2. Cluster analysis of CD4+ T-cell counts

2.1. Distribution of polymorphonuclear cells according to different TCD4 levels

We noticed a general trend toward a reduction in polymorphonuclear cell populations (PNN, PNB, PNE) and monocytes as the TCD4 count decreased, with a significant relationship with PNN (ANOVA = 4.12, p value = 0.002), PNB (ANOVA = 3.45, p value = 0.015), and PNE (ANOVA = 2.98, p value = 0.045) (Figure 1).

2.2. Distribution of immunological (TCD3, TCD8, B and NK) cells according to different TCD4 levels

A decrease in the number of CD4+ T cells was significantly associated with an increase in the number of CD8+ T cells (p value = 0.001, Student’s t value = 3.45), CD3+ T cells (p value = 0.02, Student’s t value = 4.12), and B cells (p value = 0.004, Student’s t value = 1.96), whereas for NK cells, the association was not significant (p value = 0.05, t statistic = 2.98) (Figure 2).

2.2. Distribution of hematological cells (erythrocytes and platelets) across different TCD4 levels

By matching TCD4 count clusters to erythrocyte and platelet values, our analysis revealed that as the TCD4 count decreased from above 1500 to below 200, there was a noticeable decrease in the counts of both erythrocytes (p value = 0.01, t statistic = 3.67) and platelets (p value = 0.005, t statistic = 4.12) (Figure 3).

1. Impact of age and sex on CD4+ T-cell counts in HIV-infected individuals

Our analysis revealed that when CD4 counts were stratified by age, people older than 50 years had a significantly lower mean CD4 count of 350 cells/µL than did those aged 36--50 years (p < 0.01), indicating a strong relationship between advanced age and CD4 depletion, likely due to factors such as thymic involution and reduced immune regeneration [10].

Males had an average CD4 count of 430 cells/µL, whereas females had an average CD4 count of 470 cells/µL (p = 0.08), suggesting a trend toward more rapid CD4 decline in males, although the difference was not statistically significant. Wright et al. (2013) and Ziegler and Altfeld (2016) support these findings, linking age-related decreases in CD4 counts to immunosenescence and the protective effects of estrogen in women [11].

The decline in CD4 counts with age emphasizes the need for careful monitoring and personalized treatment for older HIV-positive patients, as lower CD4 levels are associated with a greater risk of opportunistic infections and worse clinical outcomes. The reduction in CD4 T cells may stem from decreased thymic output, accumulation of senescent T cells, and chronic inflammation, which exacerbates T-cell exhaustion. Monitoring CD4 counts is crucial in clinical practice and serves as a key indicator of immune function that guides treatment decisions in HIV management [12].

2. Association between T CD4+ levels and polymorphonuclear neutrophils (PNNs) in HIV: Implications for innate immunity

A significant inverse association was found between CD4 T-cell counts and PNN levels. Indeed, patients with lower CD4 counts presented a significantly lower average PNN count. This downward trend in PNN levels as CD4 counts decrease suggests a compromised immune response, which may increase susceptibility to bacterial infections.

Hensley-McBain and Klatt (2018) emphasized the importance of neutrophils in the innate immune response to infections, particularly bacterial pathogens [13]. They noted that neutrophil dysfunction can worsen HIV effects, leading to heightened vulnerability to opportunistic infections. Monitoring PNN levels can offer important prognostic information for HIV-infected patients, as low neutrophil counts correlate with higher infection rates and poorer clinical outcomes, necessitating prompt interventions [13]. The inverse relationship between CD4 and PNN counts may result from impaired neutrophil production and mobilization in response to infection, influenced by cytokine signaling pathways, such as the reduced activity of granulocyte colony-stimulating factor (G-CSF) and interleukin-8 (IL-8), which are critical for neutrophil differentiation, activation, and migration [14]. The inflammatory environment in HIV-infected individuals, characterized by elevated levels of proinflammatory cytokines such as TNF-α and IL-6, further exacerbates neutrophil dysfunction. Evaluating PNN levels is essential for assessing the innate immune response in HIV patients, enabling better risk stratification and management of potential infections [15].

3. Correlation between CD4+ depletion and eosinophil counts in HIV: implications for antiparasitic immunity

A significant association was observed between eosinophil (PNE) counts and CD4 levels. Patients with lower CD4 counts presented markedly lower eosinophil counts. This downward trend in eosinophil levels as CD4 counts decline suggests a potentially impaired immune response to parasitic infections, indicating that lower CD4 levels are associated with reduced eosinophil counts.

Masenga et al. (2020) noted that eosinophil counts often reflect inflammatory responses; however, their depletion in HIV patients suggests broader immune suppression. Eosinophil counts can serve as a prognostic marker, as low levels may indicate a compromised immune response, particularly concerning parasitic infections, thereby guiding therapeutic strategies [16]. The decline in eosinophil levels in patients with low CD4 counts may be attributed to impaired signaling pathways and altered production of cytokines, such as interleukin-5 (IL-5), which are essential for eosinophil maturation and activation [17]. Additionally, the overproduction of transforming growth factor-beta (TGF-β), a molecule known to suppress eosinophil differentiation and function, may further contribute to eosinophil depletion in HIV patients. Assessing eosinophil levels is important in the context of HIV, as it provides insights into immune dysregulation and helps tailor interventions for associated infections [18].

4. Impact of CD4+ depletion on basophil reduction in HIV: Consequences for allergic responses and immune regulation

A significant association was found between basophil (PNB) counts and CD4 levels. Patients with lower CD4 counts presented a significantly lower basophil count. This decline in basophil levels with decreasing CD4 counts indicates a trend toward impaired regulation of inflammatory and allergic responses as CD4 levels decrease.

Marone et al. (2016) highlighted the critical role of basophils in regulating immune responses, particularly in allergic inflammation. Basophils express high-affinity immunoglobulin E (IgE) receptors (FcεRIs), which are essential for mediating allergic reactions [19]. The depletion of these genes in HIV-infected individuals may suggest a loss of immune regulatory capacity. Basophil counts serve as valuable prognostic indicators, as low levels may reflect impaired immune regulation and heightened susceptibility to allergic and inflammatory conditions [20]. Additionally, the reduction in basophil levels may result from HIV-induced alterations in the production of cytokines, such as decreased interleukin-3 (IL-3) and interleukin-33 (IL-33), which are crucial for basophil differentiation and activation. Additionally, disruptions in the STAT5 signaling pathway, which is activated by cytokines such as IL-3, may impair basophil survival and function. Assessing basophil counts is crucial for understanding immune dysregulation in HIV patients, enabling better management of allergic and inflammatory responses [21].

5. Association between CD4+ levels and monocyte reduction in HIV: Implications for the immune response and inflammation

An association was observed between CD4 levels and monocyte counts. Patients with lower CD4 counts presented a lower average monocyte count. This finding indicates a downward trend in monocyte counts as CD4 levels decrease, which may compromise the immune system's ability to respond to infections.

Teer et al. (2021) emphasized the critical role of monocytes in both innate and adaptive immune responses, noting that their depletion in HIV patients is linked to increased susceptibility to infections and cardiovascular diseases (CVDs). In addition, the decline in monocyte population may result from increased apoptosis and disrupted differentiation processes, driven by the chronic inflammatory environment in HIV patients [22, 23].

On the other hand, despite antiretroviral therapy (ART), monocyte activation persists in HIV infection, characterized by the release of inflammatory mediators such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), which contribute to systemic inflammation and cardiovascular risk. Activated monocytes expressing markers such as CD11b and CX3CR1 are strongly associated with increased CVD risk. Evaluating monocyte levels and their activation state is vital for understanding immune dysfunction in HIV patients and developing strategies to mitigate related complications, including cardiovascular disease [24].

6. Increase in CD8+ T cells in HIV patients with CD4+ depletion: Adaptive immune response mechanisms

A significant increase in CD8+ T-cell counts was observed as CD4+ T-cell counts decreased. This known inverse relationship between CD4 and CD8 levels suggests that as CD4+ T cells are depleted, CD8+ T cells proliferate as a compensatory mechanism, reflecting an adaptive immune response to CD4+ T-cell depletion.

Such observations have already been reported by Tyznik et al. (2004), who reported that CD8+ T cells expand significantly in CD4-deficient environments. Elevated CD8 counts can serve as a prognostic marker, indicating persistent immune activation and a greater potential for disease progression in HIV-infected individuals [25].

The expansion of CD8+ T cells in response to CD4+ T-cell depletion is driven primarily by cytokine signaling pathways involving interleukin-2 (IL-2) and interleukin-15 (IL-15), which are critical for CD8+ T-cell proliferation, activation, and survival [26]. Additionally, signaling through the JAK-STAT pathway, which is activated by IL-2 and IL-15, further supports CD8+ T-cell expansion. Therefore, monitoring CD8+ T-cell counts provides important insights into the immune landscape in HIV patients and helps guide therapeutic strategies aimed at restoring immune balance and managing disease progression effectively [27].

7. Decline in NK cells with CD4 depletion in HIV: Consequences for innate immunity and the antiviral response

Our study did not reveal a significant association between CD4 levels and NK cell counts, since patients with lower CD4 counts may not present lower NK cell counts.

Scully and Alter (2016) highlighted the critical role of natural killer (NK) cells in controlling viral infections, including HIV. Indeed, a reduction in NK cell counts may compromise the ability to mount an effective antiviral response, increasing vulnerability to infections and accelerating HIV progression [28].

The decline in NK cells associated with low CD4 counts is primarily linked to a deficiency in cytokines such as interleukin-15 (IL-15), which are essential for NK cell development, survival, and function [29]. Additionally, disruptions in signaling pathways, including the JAK-STAT pathway activated by IL-15, may further impair NK cell maintenance. Monitoring NK cell counts might be important for assessing the innate immune status in HIV patients and guiding therapeutic interventions aimed at enhancing immune function and controlling disease progression [30].

8. Impact of T CD4 depletion on B cells and humoral immunity in HIV

Patients with lower CD4 counts had significantly lower B-cell counts. These findings indicate that lower CD4 counts may be associated with compromised B-cell populations, leading to a decline in humoral immunity.

Hu et al. (2015) emphasized that a reduction in B-cell counts in HIV-infected individuals is associated with increased susceptibility to infections and diminished vaccine efficacy [31]. The decline in B-cell counts may result from impaired signaling through CD40 and cytokine receptors such as interleukin-4 (IL-4) and interleukin-21 (IL-21), both of which are essential for B-cell activation, proliferation, and function [32]. Furthermore, disruptions in the PI3K-Akt and JAK-STAT signaling pathways, driven by these cytokines, exacerbate B-cell dysfunction, particularly in the context of low CD4 levels. Monitoring B-cell counts provides valuable prognostic information, as low levels correlate with higher rates of opportunistic infections and poor immunological recovery [33].

9. Erythrocyte decline and CD4 depletion in HIV: Anemia risks in HIV-infected patients

A significant association was found between erythrocyte counts and CD4 levels. This decreasing trend in erythrocyte levels alongside a decrease in CD4 counts may lead to anemia and other complications in advanced HIV infection patients.

Peng et al. (2022) reported that anemia is prevalent among HIV-infected individuals because of multiple factors, including chronic inflammation, opportunistic infections, and direct viral interference with erythropoiesis. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) play central roles by disrupting the bone marrow microenvironment, impairing erythropoiesis and reducing red blood cell production [34]. These cytokines exert their effects through signaling pathways such as the NF-κB and JAK-STAT pathways, which mediate inflammation and inhibit erythroid progenitor cell survival and differentiation [35].

The activation of these pathways leads to increased expression of suppressive molecules such as hepcidin, which disrupts iron homeostasis, further contributing to anemia [36]. Monitoring erythrocyte levels and understanding the underlying signaling mechanisms are crucial for addressing anemia in HIV patients, enabling the development of targeted therapies to restore erythropoiesis and improve clinical outcomes.

10. Thrombocytopenia and T CD4 depletion in HIV: Effects on coagulation and hemorrhagic risks

In our series, patients with lower CD4 counts had significantly lower PLTs. This thrombocytopenia may represent an increased risk of coagulopathy in advanced HIV disease.

Nascimento and Tanaka (2012) reported that thrombocytopenia in HIV patients is multifactorial, often resulting from bone marrow suppression, splenic sequestration, and immune-mediated platelet destruction. In advanced HIV infection, the virus can disrupt megakaryocyte function in the bone marrow, impairing platelet production. Additionally, inflammatory cytokines such as TNF-α and IL-6 can further inhibit megakaryocyte maturation and function, leading to reduced platelet counts [37]. These cytokines activate signaling pathways such as the JAK-STAT and NF-κB pathways, which contribute to the inflammatory response and suppress megakaryopoiesis. Furthermore, the transforming growth factor-beta (TGF-β) signaling pathway, known for its role in fibrosis and immune regulation, can also negatively affect megakaryocyte differentiation and platelet production by promoting the production of suppressive mediators and collagen in the bone marrow microenvironment [38].

Therefore, the evaluation of platelet counts during HIV infection is of particular importance, as thrombocytopenia can increase the risk of bleeding complications and serve as a marker of disease progression, serving as a supplementary tool for better management of complications related to low platelet counts and informing therapeutic decisions [39].

Study Limitations

This study has several limitations. This approach could benefit from the inclusion of additional immunological markers to increase the accuracy of the data. Moreover, the clinical information available for patients was limited, which may have impacted the comprehensiveness of the findings.

In this study, TCD4 cell counts were utilized as a key parameter to explore the complex interactions between immune and hematological cells in HIV infection. It has proven to be an essential indicator of immune and hematological cell dysfunction, particularly when levels are very low (<200 cells/mm³), which is synonymous with advanced HIV infection-related immunosuppression.

In addition to the relatively well-known consequences of T CD4 depletion on T CD8, B and NK cells, our findings highlighted significant changes, particularly declines in almost all the studied cells, including polymorphonuclear cell populations(PNN, PNB, PNE), monocytes, erythrocytes and platelets, with many relevant risks, such as susceptibility to diverse infections, anemia and bleeding.

This multiparametric analysis provides a global understanding of the dynamic interactions between different cell populations and HIV progression and highlights the importance of taking these interactions into account to define patient categories, which in turn makes it possible to indicate or even develop more effective therapeutic strategies and thus improve patient outcomes.

This study was reviewed and approved by the Ethics Committee of University Hospital Mohammed VI, Marrakech. All procedures involving human participants were conducted in accordance with institutional and national ethical standards and with the 1964 Helsinki Declaration and its later amendments. Written informed consent was obtained from all participants prior to their inclusion in the study.

Funding Statement: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

This study was conducted in accordance with the ethical standards of the institutional research committee and the Declaration of Helsinki. Informed consent was obtained from all participants. The data supporting the findings are available from the corresponding author upon reasonable request and are being securely stored and protected to ensure participant confidentiality. The authors declare no financial support for this work. All the authors contributed to the design, data collection, analysis, and writing of the manuscript. All the authors have completed the ICMJE disclosure form and declare that they have no competing interests. The authors would like to thank the Department of Immunology and Infectious Diseases for their support. The views expressed are those of the authors and do not necessarily reflect the official position of their affiliated institutions.

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No competing interests reported.

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A comprehensive analysis of immune and hematologic cells in HIV-infected moroccan population

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Abstract

Figures

Background

Methods

Results

Discussion

1. Impact of age and sex on CD4+ T-cell counts in HIV-infected individuals

2. Association between T CD4+ levels and polymorphonuclear neutrophils (PNNs) in HIV: Implications for innate immunity

3. Correlation between CD4+ depletion and eosinophil counts in HIV: implications for antiparasitic immunity

4. Impact of CD4+ depletion on basophil reduction in HIV: Consequences for allergic responses and immune regulation

5. Association between CD4+ levels and monocyte reduction in HIV: Implications for the immune response and inflammation

6. Increase in CD8+ T cells in HIV patients with CD4+ depletion: Adaptive immune response mechanisms

7. Decline in NK cells with CD4 depletion in HIV: Consequences for innate immunity and the antiviral response

8. Impact of T CD4 depletion on B cells and humoral immunity in HIV

9. Erythrocyte decline and CD4 depletion in HIV: Anemia risks in HIV-infected patients

10. Thrombocytopenia and T CD4 depletion in HIV: Effects on coagulation and hemorrhagic risks

Study Limitations

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1