DIAGNOSTIC, IMMUNOLOGICAL, AND PATHOGENETIC ASPECTS IN HIV-INFECTED CHILDREN

Galzio R, Martinotti S. Diagnostic, immunological, and pathogenetic aspects in HIV-infected children. International Journal of Infection. 2025;9(1):29-33.

R. Galzio^1* and S. Martinotti²

¹ Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy;
² Department of anesthesiology, ASL Chieti-Lanciano-Vasto, Lanciano, Italy.

*Correspondence to:
Prof. Renato Galzio,
Neurosurgery Unit,
Department of Clinical-Surgical, Diagnostic and Pediatric Sciences,
University of Pavia,
Pavia, Italy.
e-mail: r.galzio@smatteo.pv.it

Received: 24 January, 2025 Accepted: 15 April, 2025

ISSN 1972-6945 [online] Copyright 2025 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Human immunodeficiency virus (HIV)-infected women have an approximately 30% increased risk of transmitting HIV infection perinatally. Positive screening tests such as enzyme immunoassay (EIA), immunofluorescence, and Western blot are essential for accurate diagnosis of HIV infection in infants. After infection, the first antibodies appear within a few weeks, while antibodies to other HIV antigens are produced later. Infants born to HIV-infected mothers have IgG antibodies to HIV from the placenta and may remain positive for about 18 months of age whether or not they are infected with HIV. Because IgA cannot cross the placenta, the presence of IgA antibodies to HIV is an experimental method in the evaluation of HIV infection. The measurement of p24 antigen in serum, a modified test that would consist of the dissociation of the immune complex, could be another valid diagnostic method although the polymerase chain reaction (PCR) method that reveals viral DNA has a higher sensitivity. Children infected with HIV have an inhibition of the immune system that facilitates the onset of opportunistic infections due to a decrease in the number of CD4+ cells  necessary for the activation of B cells to produce antibodies. Measurement of the absolute number and percentage of CD4+ lymphocytes remains an effective diagnostic method. In infected patients, the presence of gp120 antibodies is present in the serum. These antibodies damage CD4+ cells, prevent their binding to major histocompatibility complex (MHC), and cause immunodeficiency. Lymphocytes from HIV-infected patients undergo apoptosis or cell death with the participation of gp120-anti gp120 complexes, or by gp120 expressed on HIV-infected cells. Improved diagnosis and therapy of pediatric patients infected with HIV is necessary in the treatment of this infection.

KEYWORDS: HIV infection, children, human immunodeficiency virus, diagnosis, immune dysfunction

INTRODUCTION

A rise in the number of women infected with human immunodeficiency virus (HIV) has led to a parallel increase in perinatal HIV infection (1). Most studies indicate that approximately 30% of newborns born to HIV-infected mothers acquire the virus perinatally, and the World Health Organization (WHO) estimates that 10 million HIV-infected children will have been born by the end of the century (2).

Given this rapid increase in the number of infected children and the possibility of reducing the infection rate, it has become essential to define accurate, rapid, and definitive methods for diagnosing HIV infection as soon as possible after birth for early diagnosis (3).

The current routine standard requires a positive screening test performed twice with an enzyme immunoassay (EIA), or by immunofluorescence and a confirmatory test performed with a Western blot, immunofluorescence, or another reliable test (4).

The determination of seroconversion after HIV infection depends on the time required for measurable levels of antibodies to the various HIV antigens to occur. The shortest time interval between infection and the first antibodies is found between four and six weeks, while antibodies to other HIV antigens are produced later (5).

Results from a clinical trial with zidovudine (AZT) suggest that a potentially major reduction in this infection rate is possible provided this therapy is available worldwide (6).

DISCUSSION

Children born to HIV-infected mothers result HIV-positive at birth because anti-HIV IgG crosses the blood-placental barrier (7). This poses one of the major problems in the early detection of HIV infection in newborns using commonly accepted serological testing protocols, given that the newborn can result EIA and Western blot positive until approximately 18 months of age, whether infected or not with HIV, as a result of the transplacental passage of anti-HIV IgG (8). Clearly, it is necessary to obtain positive evidence of HIV infection as soon as possible after birth to accurately monitor the immune status, to establish therapy and prophylaxis, and to reassure the parents of uninfected newborns.

Consequently, several alternative methods have been examined that could serve to provide a diagnosis of HIV infection during the very early life of the newborn (9). Since IgA cannot cross the placenta, the detection of anti-HIV IgA antibodies is an experimental method that has proven reliable and technically practical in evaluating HIV infection (10). However, sensitivity in early childhood is not adequate, given that at 10 weeks of age only 10-30% of newborns infected with HIV test positive, and the positivity rate rises to 70-90% by six months.

Measurement of p24 antigen in serum has an even lower sensitivity with only 20-40% positivity at six months. Recent modifications of this test, which consist of the dissociation of the immune complex, have increased the sensitivity to 90-95%, at 6 months (11).

Much greater sensitivity has been achieved by testing for the presence of the virus in culture, by detecting the presence of viral DNA by the polymerase chain reaction (PCR) method, and by in vitro antibody production. These methods have a 70-90% positivity rate at two months and reach 95% between three and six months of life (12).

However, these last three methods are very demanding; they require considerable experience and specialized laboratory facilities which makes them very expensive and not optimal for the routine of a hospital laboratory. There is still a need for a reliable and easy-to-perform test to detect HIV infection shortly after birth.

HIV infection leads to a regular and progressive decline in immune function to the point where opportunistic infections occur due to a high degree of immunosuppression. The extent and precise nature of events affected by HIV are important for the integrity of the immune system and are unfortunately not yet fully established. However, it is clear that an important cause of the decline in immune function is the progressive reduction of the number of CD4+ lymphocytes, which are targeted by HIV. These cells are called T helper cells because they help B cells produce antibodies. They are a cellular subpopulation that plays a fundamental role in the regulation of immune functions (13).

It has been universally accepted that the method of choice for carefully evaluating the progression of HIV infection and for instituting therapy is the CD4+ lymphocyte count. For this purpose, the most commonly used method is flow cytometry with monoclonal antibodies labeled with fluorescent substances (14). Very precise quality control guidelines have been defined to ensure the validity of the results of this procedure. Subsequently, other methods for counting CD4+ lymphocytes have been proposed. Some of them are based on simplified flow cytometry methods, while others are based on the use of enzyme immunoassays. If the latter prove to be as reliable, sensitive, and as specific as flow cytometry, they will bring an undoubted benefit to the continuous control of HIV infection in underdeveloped areas.

In recent years, a series of studies have been launched to more accurately define the immune deficits resulting from HIV infection, to establish more precise methods in following the course of the disease and to improve therapy (15). While these studies improve our knowledge of the immune dysfunction caused by HIV, measurement of the absolute percentage number of CD4+ lymphocytes remains the method of choice for following patients (16).

Having clearly established that CD4+ lymphocytes are the main target of HIV, considerable efforts have been focused on understanding the mechanisms by which HIV infection causes a reduction in CD4+ lymphocytes. It is reasonable to believe that the explanation of these mechanisms would contribute to the understanding of the pathogenesis of HIV infection and, at the same time, provide more reliable methods for following the course of the infection. The results of studies in this area have suggested that many mechanisms may be involved in the destruction or depletion of helper T lymphocytes in HIV-infected patients (17).

The direct cytopathic effects of HIV may be responsible for the depletion of CD4+ lymphocytes. Furthermore, it has been shown that in vitro syncytia can form between HIV-infected cells and uninfected cells, leading to the formation of giant cells (18). However, this latter mechanism has not been found in vivo, and it is not easily understood how the formation of a syncytium can lead to the depletion of T lymphocytes.

The presence of antibodies for gp120, which is found in the envelope of HIV, has been found on CD4+ lymphocytes and in the serum of infected patients. This finding led to the suggestion of two other possible mechanisms for lymphocyte depletion. These antibodies cross-react with type II major histocompatibility complex (MHC) proteins and could block CD4-MHC interactions and interfere with the normal function of CD4 lymphocytes, similarly to a state of anergy (19). It could be induced by gp120 protein-anti-gp120 antibody immune complexes that bind to the CD4 antigen and damage the normal function of CD4 lymphocytes. It has also been proposed that CD4+ lymphocytes may become anergic and reduced in number due to the effect of superantigens. These retrovirus-associated antigens are recognized entirely by the Vb region of the T cell antigen receptor (TCR) and therefore, selectively activate and drive clonal proliferation of all Vb T cells (20). Since this leads to anergy and death of these lymphocyte clones, a state of immunosuppression would result due to the disappearance of a high number of CD4+ lymphocytes.

The finding that apoptosis is a very important mechanism in the elimination of self-reactive T lymphocyte clones during thymic maturation has stimulated interest in exploring the role played by apoptosis as a possible mechanism of lymphocyte elimination in viral infections (21).

Many studies have shown that lymphocytes from patients infected with HIV undergo apoptosis when stimulated by a series of antigens. Moreover, during HIV infection of cell lines, apoptosis is an important mechanism of cell death. It has also been demonstrated that the cross-binding of the CD4+ antigen on the membranes of lymphocytes by gp120 determines apoptosis following activation of the lymphocyte. Taken together, these observations suggest that uninfected cells may undergo apoptosis as a consequence of stimulation by gp120-anti gp120 complexes or by gp120 expressed on HIV-infected cells, followed by activation by a series of antigenic or other stimuli (22). This could explain the progressive depletion of CD4+ lymphocytes following HIV infection, since it appears that only small numbers of CD4+ lymphocytes are infected by HIV. The finding that in vitro mitogen stimulation induces T lymphocytes from HIV-infected patients to undergo apoptosis suggests that evaluation of pokeweed mitogen (PWM)-induced apoptosis may help identify HIV-infected infants (23).

Studies have shown that PWM-stimulated lymphocytes obtained from pediatric patients infected with HIV undergo apoptosis in a higher percentage than uninfected controls. Furthermore, the rapid progressive forms present a higher frequency of apoptosis than the slow progressive forms, although the difference is at the limit of statistical significance. These observations are interesting as they suggest that the evaluation of the frequency of apoptosis induced by PWM may be valid in defining the diagnosis of HIV infection shortly after birth, and even more importantly, it may help in distinguishing between rapid progressive forms and slow progressive forms (24). This would help in establishing therapy and monitoring pediatric patients infected with HIV over time.

CONCLUSIONS

Faced with the scale of the HIV pandemic, it is vitally important to diagnose the infection and follow the best treatment in a timely manner. Considering this situation, efforts must continue to accurately delineate the nature and extent of the immunological alterations that accompany HIV infection, realizing that a better understanding of the immune disorder induced by the virus would help to clarify the pathogenesis, the natural history of the infection, and would allow for the design of more effective therapy (25).

Similarly, success in preventing infection through an effective vaccine relies on a deeper understanding of the interactions between HIV and the immune system. The understanding that the immune system is the main target of HIV has stimulated numerous studies aimed at defining changes in the number and function of natural killer lymphocytes in different lymphocyte subpopulations and in cytokine concentrations, as well as delineating the mechanisms involved in the interaction between HIV and cells and in the depletion of CD4+ lymphocytes which causes immunosuppression (26).

As studies slowly advance our understanding of the natural history and pathogenesis of HIV infection, more effective treatment modalities will be developed to care for pediatric patients. However, only a complete clarification of the natural history of HIV will lead to a complete eradication of this infection.

Conflict of interest                                                                                                                      The authors declare that they have no conflict of interest.

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