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Open Access to Dental and Medical Research

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Viral-Host Interactions and Immune Responses in HIV-Infected Infants: A Review

^*Emmanuel Ifeanyi Obeagu ¹ and Getrude Uzoma Obeagu ²

¹ Department of Medical Laboratory Science, Kampala International University, Ishaka, Uganda.

² School of Nursing Science, Kampala International University, Ishaka, Uganda.

 

 

Introduction

Human Immunodeficiency Virus (HIV) infection continues to be a global health challenge, particularly affecting vulnerable populations such as infants. Unlike adults, infants exhibit unique immunological characteristics that influence the course of HIV disease progression, treatment outcomes, and long-term health.¹ Infants acquire HIV primarily through vertical transmission from infected mothers during pregnancy, childbirth, or breastfeeding. This mode of transmission results in a high burden of infection among newborns, particularly in regions with limited access to antiretroviral therapy (ART) and maternal healthcare. Early diagnosis and timely initiation of ART are essential to suppress viral replication, reduce morbidity and mortality, and preserve immune function in HIV-infected infants.^2-3 The immune system of infants undergoes rapid development and maturation during the early stages of life. Key developmental milestones include the establishment of T-cell and B-cell repertoires, thymic output of naïve T cells, and the acquisition of immune memory. These processes are critical for mounting effective immune responses against pathogens, including HIV. However, the immaturity of the infant immune system also renders them more susceptible to severe infections and challenges in achieving sustained viral suppression with ART.^4-5 Viral dynamics in HIV-infected infants differ significantly from those observed in adults. Infants often present with high viral loads during acute infection, driven by rapid viral replication and diversification. The establishment of viral reservoirs within CD4+ T cells, macrophages, and other immune cells occurs early in life, contributing to persistent viremia and potential viral persistence despite ART. These reservoirs, particularly in anatomical sanctuaries like the central nervous system and lymphoid tissues, pose obstacles to achieving viral eradication and functional cure.^6-7

Immune responses in HIV-infected infants are characterized by distinct patterns of T-cell activation, cytokine production, and immune regulation. CD4+ T cells play a central role in orchestrating immune responses, while CD8+ T cells contribute to cytotoxic activity against infected cells. However, HIV employs various immune evasion strategies to evade host immune surveillance, including rapid mutation rates, shielding of viral epitopes, and modulation of host immune responses. These mechanisms contribute to the establishment of chronic infection and challenges in achieving durable immune control.^8-9 Effective management of HIV infection in infants requires a multidisciplinary approach encompassing early diagnosis, initiation of ART, monitoring of immune function, and management of opportunistic infections. While ART suppresses viral replication and preserves immune function, challenges such as drug resistance, treatment adherence, and long-term effects on immune reconstitution persist. Strategies to enhance immune responses, mitigate viral reservoirs, and optimize therapeutic interventions are critical for improving clinical outcomes and reducing the global burden of pediatric HIV infection.^10-11 Advances in diagnostic technologies, including early infant diagnosis (EID) and viral load monitoring, have revolutionized HIV care by enabling early detection and prompt initiation of ART. However, gaps in access to healthcare services, particularly in resource-limited settings, continue to hinder efforts to achieve universal ART coverage and optimal treatment outcomes for HIV-infected infants. Addressing these challenges requires innovative approaches to healthcare delivery, capacity building, and international collaboration to support comprehensive HIV care programs tailored to the needs of infants and their families.^12-13

Immune Development in Infants

Immune development in infants is a dynamic process crucial for establishing effective host defense mechanisms against pathogens, including Human Immunodeficiency Virus (HIV).  The immune system in infants undergoes a series of developmental stages that begin during gestation and continue through early childhood. During fetal development, hematopoiesis occurs primarily in the fetal liver and then transitions to the bone marrow. The thymus, a critical organ for T-cell maturation, develops early in gestation and plays a pivotal role in shaping cellular immunity. The production of diverse T-cell receptor (TCR) repertoires and the selection of functional T cells in the thymus are crucial for establishing a competent adaptive immune system.^14-16 Innate immune responses in infants are essential for immediate defense against pathogens before the adaptive immune system fully matures. Innate immune cells, such as neutrophils, macrophages, and dendritic cells, exhibit functional capabilities early in life but may have reduced capacity for pathogen recognition and response compared to adults. Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) play key roles in innate immune activation, influencing cytokine production and inflammatory responses critical for immune defense.^17-19

Adaptive Immune Responses

Adaptive immunity in infants evolves gradually during the first years of life, characterized by the development of antigen-specific immune responses mediated by T cells and B cells. Naïve T cells generated in the thymus undergo maturation and differentiation into effector T cells upon encountering antigens. This process is essential for mounting cellular immune responses against viral infections like HIV. B cells mature in the bone marrow and secondary lymphoid organs, producing antibodies that contribute to humoral immunity and long-term immune memory.^20-21 Immune tolerance mechanisms in infants are crucial for maintaining self-tolerance and preventing autoimmunity. Regulatory T cells (Tregs) play a pivotal role in immune homeostasis by suppressing excessive immune activation and inflammation. The balance between effector T cells and Tregs influences immune responses to pathogens and vaccines, impacting the efficacy of immune interventions in early life. Dysregulation of immune tolerance mechanisms may contribute to immune-mediated disorders and susceptibility to infections, including HIV.^22-25 Several factors influence immune development and responses in infants, including genetic predisposition, environmental exposures, maternal health status, and nutritional factors. Maternal antibodies transferred across the placenta and through breast milk provide passive immunity to newborns, offering protection against infections during early life. Breastfeeding, in particular, supports immune development by providing essential nutrients and immunomodulatory factors that enhance immune function and protect against pathogens.^26-28 HIV infection profoundly impacts immune development in infants by disrupting T-cell maturation, impairing thymic function, and depleting CD4+ T cells critical for adaptive immunity. Early HIV acquisition during gestation or infancy results in high viral replication rates, rapid establishment of viral reservoirs, and immune dysregulation. The virus's ability to infect and replicate within immune cells, including CD4+ T cells and macrophages, undermines immune responses and compromises host defense mechanisms.^29-30

Viral Dynamics and Establishment of Reservoirs

Viral dynamics and the establishment of reservoirs are critical aspects of HIV infection in infants, significantly influencing disease progression, treatment outcomes, and the potential for viral eradication.  HIV infection in infants is characterized by rapid viral replication and high viral loads during early stages of infection. Infants often acquire the virus perinatally, either in utero, during childbirth, or through breastfeeding, leading to a rapid dissemination of the virus throughout the body. This rapid replication contributes to the establishment of diverse viral populations, known as quasispecies, which evolve dynamically within individual hosts. Viral diversity and mutation rates are influenced by factors such as viral replication dynamics, host immune responses, and selective pressures exerted by antiretroviral therapy (ART). Early in HIV infection, particularly during the neonatal period and infancy, viral reservoirs are established within CD4+ T cells, macrophages, and other immune cells. These reservoirs represent anatomical sites where HIV can persist in a latent or low-level replicating state, evading immune surveillance and antiretroviral drugs. The central nervous system (CNS), gut-associated lymphoid tissue (GALT), and lymphoid organs are known sanctuary sites where viral reservoirs can persist despite effective ART. The establishment of these reservoirs early in life poses significant challenges for achieving viral eradication or functional cure.^31-40

Factors Influencing Reservoir Establishment

Several factors contribute to the establishment and maintenance of viral reservoirs in HIV-infected infants:

• Early Initiation of ART: Timely initiation of ART in infants can suppress viral replication and reduce the size of viral reservoirs. However, the effectiveness of ART in preventing reservoir establishment may vary depending on the timing of infection and the level of viral exposure.⁴¹
• Immune Activation: Persistent immune activation, even in the presence of ART, may contribute to ongoing viral replication and the seeding of viral reservoirs. Immune activation markers such as CD38 and HLA-DR on T cells are associated with higher viral reservoir size and poorer treatment outcomes.⁴²
• Anatomical and Cellular Factors: Sanctuary sites within the body, such as the CNS and GALT, provide protected environments where HIV-infected cells can evade immune responses and antiretroviral drugs. Cellular factors, including differential expression of viral entry receptors and immune activation markers, also influence the establishment and persistence of viral reservoirs.⁴³

Challenges in Targeting Viral Reservoirs

HIV can persist in a latent state within long-lived memory CD4+ T cells, macrophages, and other reservoir cells. Latently infected cells can evade immune surveillance and remain undetectable by current diagnostic tests, complicating efforts to eradicate the virus. High mutation rates and viral diversity contribute to the emergence of viral escape mutants that evade immune recognition and antiretroviral drugs. This viral diversity complicates treatment strategies aimed at achieving durable viral suppression and cure. Sanctuary sites such as the CNS have limited penetration of antiretroviral drugs and reduced immune surveillance, allowing HIV to persist and potentially rebound after cessation of therapy.^44-45

Immune Responses and Immune Evasion Strategies

Immune responses and immune evasion strategies are central to the interplay between Human Immunodeficiency Virus (HIV) and the immune system in infected infants. Understanding these dynamics is crucial for developing effective therapeutic interventions and improving clinical outcomes.  Upon HIV exposure, innate immune cells such as dendritic cells, macrophages, and natural killer (NK) cells recognize viral components through pattern recognition receptors (PRRs). This recognition triggers the production of pro-inflammatory cytokines and chemokines, recruiting other immune cells to the site of infection and initiating an early antiviral response. The adaptive immune response involves the activation and differentiation of antigen-specific T cells (CD4+ and CD8+ T cells) and B cells. CD4+ T cells play a crucial role in orchestrating immune responses by providing help to B cells for antibody production and activating CD8+ cytotoxic T cells to eliminate HIV-infected cells. B cells produce antibodies that can neutralize free virus particles and facilitate antibody-dependent cellular cytotoxicity (ADCC).^46-48

Immune Evasion Strategies of HIV

HIV has evolved multiple strategies to evade host immune responses and establish persistent infection:

• Antigenic Variation: HIV exhibits high genetic variability due to its error-prone reverse transcriptase enzyme. This high mutation rate results in the rapid generation of diverse viral quasispecies within an infected individual. The ability of HIV to continuously evolve and escape immune recognition contributes to difficulties in developing effective vaccines and antiviral therapies.⁴⁹
• T-cell Depletion and Dysfunction: HIV preferentially infects CD4+ T cells, leading to their progressive depletion and functional impairment. This depletion compromises the adaptive immune response and impairs the host's ability to mount effective antiviral immunity. Additionally, HIV infection induces chronic immune activation, which further exacerbates T-cell dysfunction and exhaustion.⁵⁰
• Immune Evasion at Mucosal Sites: HIV transmission often occurs at mucosal surfaces, where the virus encounters local immune defenses. HIV exploits mucosal immune tolerance mechanisms to evade detection and establish a foothold within the host. This includes downregulating major histocompatibility complex (MHC) class I molecules on infected cells, thereby evading recognition by CD8+ cytotoxic T cells.⁵¹
• Escape from Antibody Responses: HIV can evade neutralizing antibodies by shielding its envelope glycoprotein (gp120/gp41) through glycosylation and conformational masking. Additionally, HIV may infect CD4+ T cells and macrophages within anatomical reservoirs, such as lymphoid tissues and the central nervous system, where they are less accessible to neutralizing antibodies and immune surveillance.⁵²

Clinical Implications and Challenges

The extensive genetic diversity of HIV poses challenges for developing broadly effective vaccines and antiviral therapies that can target diverse viral strains and prevent immune escape. Latently infected cells persist in HIV-infected individuals despite effective antiretroviral therapy (ART). These reservoirs remain a barrier to viral eradication and necessitate novel strategies, such as latency-reversing agents, to expose and eliminate latent HIV. Maintaining strict adherence to ART regimens is essential to suppress viral replication and prevent the emergence of drug-resistant HIV strains. However, challenges in treatment adherence among infants and caregivers can compromise treatment efficacy and contribute to virologic failure.^53-54 Clinical management and therapeutic interventions for HIV-infected infants require a comprehensive approach that addresses the unique challenges posed by early-life infection, including immune system immaturity, rapid disease progression, and potential long-term complications. Effective management aims to suppress viral replication, preserve immune function, prevent opportunistic infections, and promote overall health and development.^55-56  Early diagnosis of HIV infection in infants is critical for timely initiation of ART, which is essential for achieving viral suppression and preserving immune function. Early infant diagnosis (EID) techniques, such as polymerase chain reaction (PCR) testing of dried blood spots, enable prompt identification of HIV-exposed infants. Initiating ART as soon as possible after diagnosis reduces viral replication, limits the establishment of viral reservoirs, and improves long-term clinical outcomes. However, challenges in accessing healthcare services, particularly in resource-limited settings, can delay diagnosis and hinder early treatment initiation.⁵⁷ Regular monitoring of viral load and immune function is essential for assessing treatment efficacy, disease progression, and the need for treatment adjustments in HIV-infected infants. Viral load testing helps clinicians evaluate the effectiveness of ART in suppressing viral replication and detect early signs of virologic failure or drug resistance. Immune function assessments, including CD4+ T-cell counts and immune activation markers, provide insights into immune reconstitution and potential risks of opportunistic infections. Close monitoring allows for timely interventions to optimize ART regimens and mitigate complications associated with HIV infection.⁵⁸

HIV-infected infants are at increased risk of opportunistic infections due to immune suppression and impaired immune responses. Prophylactic measures, such as cotrimoxazole prophylaxis and vaccinations against common childhood infections (e.g., pneumococcus, influenza), are recommended to prevent opportunistic infections and reduce morbidity and mortality. Prompt recognition and management of infections, including bacterial, viral, and fungal pathogens, are crucial for maintaining overall health and preventing disease progression in HIV-infected infants.⁵⁹ Comprehensive clinical management of HIV-infected infants includes providing supportive care to optimize growth, development, and quality of life. Nutritional support is essential to meet the increased energy and nutrient requirements associated with HIV infection and ART. Adequate nutrition supports immune function, enhances medication adherence, and reduces the risk of complications such as wasting and stunting. Multidisciplinary care teams, including pediatricians, nurses, nutritionists, and social workers, collaborate to address the holistic needs of HIV-infected infants and their families.⁵⁷ Achieving and maintaining optimal adherence to ART regimens pose significant challenges in the management of HIV-infected infants. Factors such as caregiver understanding, socioeconomic factors, stigma, and medication tolerability can affect treatment adherence and virologic suppression. Long-term outcomes in HIV-infected infants depend on sustained viral suppression, immune reconstitution, and management of coexisting conditions. Challenges in maintaining adherence underscore the need for ongoing support, education, and counseling for caregivers to ensure effective treatment outcomes.⁵⁸

Conclusion

The management of HIV infection in infants remains a dynamic and evolving field, marked by significant progress in diagnosis, treatment, and understanding of the virus-host interactions. Infants infected with HIV face unique challenges due to their developing immune systems, rapid disease progression, and vulnerability to opportunistic infections. Effective clinical management requires a multifaceted approach that encompasses early diagnosis, prompt initiation of antiretroviral therapy (ART), monitoring of viral load and immune function, prevention of opportunistic infections, nutritional support, and adherence to treatment regimens. Early diagnosis through effective screening programs and early infant diagnosis (EID) techniques has revolutionized the ability to identify HIV-infected infants promptly, enabling timely initiation of ART. Initiating ART early in infancy not only suppresses viral replication but also helps preserve immune function and reduce the establishment of viral reservoirs, which are critical for long-term management.

Monitoring of viral load and immune function plays a crucial role in assessing treatment efficacy and guiding clinical decisions. Regular monitoring allows healthcare providers to tailor ART regimens, identify treatment failures early, and intervene promptly to prevent disease progression and drug resistance. Prevention and management of opportunistic infections are essential components of pediatric HIV care. Prophylactic measures and vaccinations are employed to prevent common childhood infections and reduce morbidity and mortality associated with HIV. Integrated, multidisciplinary care teams are vital in addressing the holistic needs of HIV-infected infants, including nutritional support, developmental screening, and psychosocial support for caregivers.

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