HHS Public Access

Author manuscript
J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
Author Manuscript

Published in final edited form as:

J Allergy Clin Immunol. 2010 February ; 125(2 Suppl 2): S195–S203. doi:10.1016/[Link].2009.08.040.

Secondary immunodeficiencies, including HIV infection

Javier Chinen, MD, PhD and William T. Shearer, MD, PhD
Department of Pediatrics, Allergy and Immunology Section, Baylor College of Medicine, Houston,
Tex

Abstract
Extrinsic factors can adversely affect immune responses, producing states of secondary
Author Manuscript

immunodeficiency and consequent increased risk of infections. These immunodeficiencies, which

can be encountered in routine clinical practice, arise from a number of conditions, such as
treatment with glucocorticoids and immunomodulatory drugs, surgery and trauma, extreme
environmental conditions, and chronic infections, such as those caused by HIV. The most common
cause of immunodeficiency is malnutrition, affecting many communities around the world with
restricted access to food resources. Protein-calorie deficiency and micronutrient deficiencies have
been shown to alter immune responses; of note, recent progress has been made in the influence of
vitamin D deficiency in causing failure of immune activation. Other categories of disease that
might present with secondary immunodeficiency include metabolic diseases and genetic
multisystemic syndromes. The immune defects observed in secondary immunodeficiency are
usually heterogeneous in their clinical presentation, and their prognosis depends on the severity of
the immune defect. Management of the primary condition often results in improvement of the
Author Manuscript

immunodeficiency; however, this is sometimes not possible, and the risk of infections can be
reduced with prompt antimicrobial treatment and prophylaxis.

Keywords
Secondary immunodeficiency; immunosuppression; lymphopenia; AIDS

Secondary immunodeficiencies are far more common than primary immunodeficiencies,

which are, by definition, caused by genetic defects affecting cells of the immune system.1
Secondary immunodeficiencies result from a variety of factors that can affect a host with an
intrinsically normal immune system, including infectious agents, drugs, metabolic diseases,
and environmental conditions. These deficiencies of immunity are clinically manifested by
Author Manuscript

an increased frequency or unusual complications of common infections and occasionally by

the occurrence of opportunistic infections (Fig 1). The secondary immunodeficiencies have a
wide spectrum of presentation, depending on the magnitude of the offending external
condition and on the host susceptibility. For example, the immunodeficiency induced by the
use of corticosteroids and other immunosuppressive drugs depends on the dose used2,3 and,
to a lesser degree, on concomitant disease processes of the host, such as the presence of

Reprint requests: Javier Chinen, MD, PhD, Department of Pediatrics, Allergy and Immunology Section, Baylor College of Medicine,
Texas Children’s Hospital, 1102 Bates St FC 330.01, Houston, TX 77030. jxchinen@[Link].
Disclosure of potential conflict of interest: J. Chinen and W. T. Shearer have declared that they have no conflict of interest.
 Chinen and Shearer Page 2

sepsis. AIDS, resulting from infection by HIV, is the best known secondary
Author Manuscript

immunodeficiency largely because of its prevalence and its high mortality rate if not treated.
However, the most common immunodeficiency worldwide results from severe malnutrition,
affecting both innate and adaptive immunity.4 The restoration of immunity in secondary
immunodeficiencies is generally achieved with the management of the primary condition or
the removal of the offending agent. We summarize reports of immune defects occurring in a
variety of clinical scenarios (Table I), with special emphasis on HIV infection. We selected
diseases and conditions based on their frequent presentation in general medical practice and
their relevance for allergists and immunologists. We do not discuss immunomodulating
mAbs and fusion proteins, which are covered in Chapter 28 of this primer.5

EXTREMES OF AGE: NEWBORN PERIOD AND ADVANCED AGE

Newborn period
Author Manuscript

Neonates have an increased susceptibility to common and opportunistic infections and sepsis
compared with older children.6 There is an inverse association of infection susceptibility and
the age of prematurity. In early life there are fewer marginal-zone B cells in lymphoid tissue
and a decreased expression of CD21 on B cells, thus limiting the ability of B cells to develop
specific responses.7 Although they can develop humoral responses to some antigens after
exposure in utero, impaired immunity in newborns can be attributed to the relative lack of
maturity of secondary lymphoid organs, including the lymphoid tissue associated to mucosa
in the gastrointestinal and respiratory tracts. This immaturity is related to the absence of
memory cell development because of the relative isolation provided by the maternal
environment. In addition, premature infants are more vulnerable to infections because of the
absence of maternal IgG transfer before 32 weeks of gestational age. Other significant recent
observations described at this early age are related to innate immunity mechanisms, such as
Author Manuscript

a decreased neutrophil storage pool, as defined by the ability of neutrophilia to develop in

response to an infection; decreased in vitro neutrophil functions (ie, phagocytosis, oxidative
burst, chemotaxis, and adhesion); capacity to develop a neutrophil extracellular trap8;
decreased natural killer cell activity; decreased Toll-like receptor signaling; decreased
production of cytokines; and reduced complement components.

Advanced age
Among the elderly, some subjects experience malignancies and an excessive number of
infections caused by viruses and bacteria, reflecting a decrease in the immune defenses,
particularly in the cellular compartment. Decreased delayed-type hypersensitivity skin
reactions and decreased lymphocyte proliferative responses to mitogens can be demonstrated
in this patient population. This relative impairment of the immune response has been linked
Author Manuscript

to the development of T-cell oligoclonality together with a limited capacity of the thymus to
generate naive T cells and therefore reduced responses to new antigens. Oligoclonal
expansion of CD8+ T cells begins in the seventh decade of life, which results in the skewing
of the T-cell repertoire and an increased number of differentiated memory CD8+ T cells.9
Advanced age is similarly associated with a restricted B-cell diversity repertoire and a
limited response to vaccines; however, there is also an increased number of total memory B
cells and increased total IgG levels. The innate immunity might be compromised in the

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 3

elderly, with increased breakdown of skin and mucosal barriers and slow healing processes
Author Manuscript

caused by metabolic and endocrinologic changes associated with aging. A diminished

production of hematopoietic growth factors has been postulated to occur in the elderly,
resulting in decreased ability to upregulate the production and function of macrophages and
neutrophils.10 Some subjects are at higher risk of infections when these immunologic
defects are combined with other environmental factors, such as malnutrition or the
concomitant presence of chronic inflammation caused by autoimmunity or persistent
infections.11 Progress in understanding the aging-associated immune defect is of importance
to optimize protective immunity against preventable infectious diseases.12

MALNUTRITION
Worldwide, protein-calorie malnutrition is the most common cause of immunodeficiency.13
Malnutrition can result from limited access to food sources and chronic diseases that induce
Author Manuscript

cachexia, such as neoplastic diseases. Diarrhea caused by infections and respiratory tract
infections are common. T-cell production and function decrease in proportion to the severity
of hypoproteinemia; however, specific antibody titers and immune responses to vaccines can
be detected in a malnourished subject for a relatively prolonged period. Eventually, these
immune responses decrease if malnutrition persists. The deficiency of micronutrients (eg,
zinc and ascorbic acid) contributes to increased susceptibility to infections through the
weakening of barrier mucosa, therefore facilitating a pathogen’s invasiveness.14,15 Other
essential molecules have been shown to have specific roles in the immune system; for
example, vitamin D appears to be necessary in the macrophage activity against intracellular
pathogens, remarkably Mycobacterium tuberculosis (Fig 2).16 Correction of the nutritional
deficiencies often results in the resolution of these immunologic defects.
Author Manuscript

METABOLIC DISEASES: DIABETES MELLITUS AND UREMIA

Many disease processes originating from dysfunctional metabolic pathways significantly
affect the cells involved in the immune response. Diabetes mellitus and uremia resulting
from kidney or liver disease are 2 common metabolic disorders with known deleterious
effects on immunity. Optimal control of the metabolic abnormality usually leads to improved
immune function. The defective immune functions reported in patients with diabetes
mellitus include defective phagocytosis and macrophage chemotaxis in vitro, T-cell anergy
demonstrated by delayed hypersensitivity skin tests, and poor lymphoproliferative response
to mitogens caused by chronic exposure to hyperglycemia.17 Impaired glucose metabolism,
insufficient blood supply, and denervation are other factors that contribute to the increased
susceptibility to infection in patients with diabetes, who present most commonly with skin
Author Manuscript

sores, bacterial and fungal respiratory tract infections, and systemic viral diseases.

Uremic patients experience increased incidence and severity of infections compared with the
general population. Even when disparities in age, sex, race, and diabetes mellitus were taken
into account, mortality rates in patients undergoing dialysis attributed to sepsis were higher
by a factor of 100 to 300.18 The need for dialysis procedures and use of vascular devices are
independent risk factors for invasive infections. Multiple defects of the innate and adaptive
immunity have been described to have a role in the increased frequency of infections,

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 4

summarized as immune hyporesponsiveness and a state of chronic activation. The

Author Manuscript

diminished capacity to generate memory antibody responses, regardless of repeated

vaccination, and defective phagocyte chemotaxis and microbicidal activity in vitro are
examples of the immune defects present in uremic patients.19,20

INHERITED DEFECTS OTHER THAN PRIMARY IMMUNODEFICIENCIES

Diseases caused by genetic defects might not primarily affect the immune system, but they
can present with impaired immunity to infections resulting from metabolic and cellular
dysfunction, such as poor expression of adhesion molecules or defects in the DNA repair
machinery. The molecular mechanisms leading to immunologic defects remain not well
defined. Genetic syndromes are relatively rare, and usually only a subset of patients present
with an immune defect of clinical severity that increases their risk of infections or
malignancies. The disease processes caused by chromosomal number abnormalities are the
Author Manuscript

most common within the genetic disorders. As an example, patients with Down syndrome or
trisomy of chromosome 21 present with increased incidence of infections, although they are
usually not severe, including skin abscesses, periodontitis, and upper respiratory tract
infections. T- and B-cell number and function are variably affected.21 Neutrophils isolated
from patients with Down syndrome have shown defects in chemotaxis and phagocytosis in
vitro. Most recent studies have focused on the overexpression of the gene Down syndrome
critical region 1 (DSCR1) and its role in contributing to phagocyte dysfunction.22 Patients
with Turner syndrome (complete or partial absence of the second X chromosome) also have
an increased number of respiratory tract infections, and hypogammaglobulinemia can be
identified, although this immune defect is not consistently demonstrated in these patients.
The gene defects involved in the decrease of immunoglobulin production are not known.
Author Manuscript

In other genetic diseases, such as cystic fibrosis, caused by deleterious mutations in the
cystic fibrosis transmembrane conductance regulator, the increased susceptibility to sinusitis
and pneumonia is explained by defective mechanisms of innate immunity.23 Patients with
cystic fibrosis have an impaired airway mucous clearance caused by the thickness of the
mucous secretions, which favors the development of respiratory infections caused by
Pseudomonas species. It is recommended that patients receive prompt antibiotic therapy
when infection is suspected, and antibiotic prophylaxis should be prescribed to those
patients with recurrent infections to reduce the number of infectious episodes.

ANTI-INFLAMMATORY, IMMUNOMODULATORY, AND

IMMUNOSUPPRESSIVE DRUG THERAPY
Author Manuscript

The use of drugs to ameliorate undesirable immune responses is common in clinical practice
as a consequence of the increasing prevalence of inflammatory conditions. These diseases
include the categories of autoimmune disorders, allergic disorders, transplant rejection, and
graft-versus-host disease (GvHD). Broadly, we can study these drugs by dividing them into
biologic, physical, and chemical categories. The chemical agents are the most available
clinically and have in common their ability to inhibit lymphocyte proliferation and their lack
of specificity for the immune response causing the particular illness of interest. Biologic
immunosuppressive drugs have been developed to increase the immune specificity by

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 5

targeting specific components of the immune response, such as cytokines or a particular

Author Manuscript

lymphocyte subset. Physical agents (ie, UV light and ionizing radiation) can also be used to
ablate immune responses.

In addition, there are drugs that might have an immunosuppressive effect that is not clearly
related to the pharmacologic activity of the molecule. Its occurrence is not predictable and
varies within different patient populations. Well-known examples of this drug mechanism
are the development of hypogammaglobulinemia in patients receiving antiepileptic drugs
and the leukopenia seen in patients taking trimethoprim-sulfamethoxazole.

Based on their structure and mechanism of action, most molecules with immunosuppressive
activity can be grouped into corticosteroids, calcineurin inhibitors, and cytotoxic drugs. The
adverse side effect of these drugs is that they tend to weaken the cellular immune response,
rendering patients more susceptible to fungal and viral infections (acute, chronic, and
Author Manuscript

reactivated).

Corticosteroids
The corticosteroids include both glucocorticoid and mineral-ocorticoid molecules. Only the
glucocorticoids have significant anti-inflammatory activity. Glucocorticoids are well known
for their variety of applications in both general and subspecialty medicine to reduce tissue
damage caused by an excessive inflammatory response. The range of potency of the
different molecules of this group and their routes of administration is diverse, each designed
to different applications. For example, betamethasone is 25 times more potent than cortisol
and can be used in topical, oral, and injectable preparations. Glucocorticoids bind a cytosolic
receptor, which then translocates to the nucleus to act as a transcription factor affecting the
expression of a number of genes, resulting in an anti-inflammatory effect (Fig 3).24 The
Author Manuscript

bound complex-glucocorticoid receptor modulates signal transduction pathways, resulting in

the activation of the transcription factors nuclear factor κB, nuclear factor of activated T
cells, and activator protein 1. It has been suggested that glucocorticoids might also cause an
effect on cell function by interacting with the cell membranes, which could explain observed
clinical benefits when used as “pulse therapy,” with doses higher than required for receptor
saturation. The overall results are decreased cytokine production (IL-1, IL-6, and TNF-α)
and impaired leukocyte chemotaxis, cell adhesion, phagocytosis, and lymphocyte anergy.
Lymphopenia occurs as a result of the proapoptotic activity and inhibition of IL-2–mediated
proliferative responses. When used at large doses, antibody responses and delayed-type
hypersensitivity responses are reversibly suppressed. This wide range of immune defects
renders the patient susceptible to viral, bacterial, and fungal infections, according to the
degree of immunosuppression and the administration route. Examples of these are oral
Author Manuscript

candidiasis, a frequent complication of the use of inhaled steroids, and herpes zoster disease,
which often presents with chronic use of systemic corticosteroids.

Calcineurin inhibitors
Calcineurin inhibitors bind cytoplasmic proteins from the immunophilin family and inhibit
their interaction with calcineurin, which is essential for the activation of IL-2 transcription
and T-cell function (Fig 4). The advantage of these drugs over corticosteroids and cytotoxic

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 6

drugs is to spare macrophage and neutrophil functions, reducing the spectrum of

Author Manuscript

susceptibilities to infections. However, these drugs cause respiratory tract and skin
infections, usually of viral cause, to occur with increased frequency. The most common
adverse effects of calcineurin inhibitors are hypertension and renal dysfunction; less
common but more serious is the increased frequency of lymphoproliferative disorders and
skin neoplasias. The first drug in this category was cyclosporine, which has been extensively
used to prevent organ transplant rejection,25 GvHD, and corticosteroid-resistant autoimmune
disorders. Other agents with a similar mechanism of action and immune selectivity are
tacrolimus and pimecrolimus. The latter is the most recent member of this group, and it was
developed for topical use in the treatment of severe atopic dermatitis. An agent with a
similar name, sirolimus or rapamycin, also binds an immunophilin but does not inhibit
calcineurin. Instead, sirolimus inhibits the IL-2–induced response by inhibiting the
mammalian target of rapamycin, a protein essential for cell activation and proliferation.
Author Manuscript

Cytotoxic agents
Cytotoxic agents were conceived to control neoplastic cell growth and ablate the bone
marrow for transplantation. They have progressively found their niche in the
immunosuppressive drugs category because of the selectivity conferred by the proliferative
nature of the immune response, and their application has extended to autoimmune and
inflammatory disorders, including GvHD and the prevention of graft rejection.26 The most
common drugs used for these applications are the alkylating agent cyclophosphamide and
the antimetabolites methotrexate, mycophenolate, azathioprine, and 6-mercaptopurine. Other
drugs with predominant use in autoimmune disorders are sulfasalazine, hydroxychloroquine,
and leflunomide.26 These compounds interfere with the synthesis of DNA, arresting the cell
cycle and inducing apoptosis. Generally, they inhibit both T- and B-cell proliferation and
Author Manuscript

therefore any new immune responses. In addition, depending on the dose used, they inhibit
cellular and antibody responses resulting from previous sensitizations. The major limitation
of the use of these agents is their toxicity to other hematopoietic and nonhematopoietic cells,
with development of cytopenias, gastrointestinal mucosa, and skin deterioration. These
cytopenias contribute to the state of secondary immunodeficiency and susceptibility to
infections.

SURGERY AND TRAUMA

Surgery and trauma cause disruption of epithelial barriers and cell destruction that triggers
an inflammatory response to promote healing and local microbicidal activity.27,28
Microorganisms contain surface pathogen–derived molecules that activate pattern-
recognition receptors expressed on antigen-presenting cells and other immune cells to
Author Manuscript

induce cytokine and chemokine release and recruitment of the adaptive immune system.29
Massive tissue injury further increases activation of proinflammatory mechanisms in
response to the presence of toxic byproducts of cell death.30 In this inflammatory response
Toll-like receptors play a central role in activating immune cells, resulting in the release of
inflammatory cytokines, such as IL-6 and TNF-α. If this response is severe, trauma patients
might experience the adult inflammatory respiratory syndrome in the lung or the systemic
inflammatory response syndrome when there is multiorgan failure. The inflammatory

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 7

response observed in patients with severe trauma develops gradually: loss of epithelial
Author Manuscript

barriers, vasodilatation and increased vascular permeability, cellular activation and increased
adhesion to endothelia, and a neuroendocrine stress response. At the same time, injured
patients are relatively immunosuppressed because of nonspecific cell activation leading to an
anergic immune state and because of increased levels of cortisol induced by stress in
addition to the loss of containment provided by epithelial barriers. This process occurs
within the context of a delicate balance of inflammatory and counterinflammatory
mechanisms.31

Patients who have undergone splenectomy deserve special consideration because they are
particularly susceptible to infections by encapsulated bacteria, such as Streptococcus
pneumoniae. The mortality for sepsis in splenectomized patients is between 50% and 70%,
emphasizing the need to avoid splenectomy when possible. Patients who are scheduled for
elective splenectomy should receive antipneumococcal, anti–Haemophilus influenzae, and
Author Manuscript

antimeningococcal immunizations at least 2 weeks before surgical intervention.32

ENVIRONMENTAL CONDITIONS: UV LIGHT, IONIZING RADIATION, HIGH

ALTITUDE, CHRONIC HYPOXIA, AND SPACE FLIGHTS
There is increased awareness of potential adverse effects caused by chronic exposure to
inhospitable environmental conditions, such as extreme cold or high altitude. It has been
recommended to avoid exposure to sunlight because of increased risk of malignancies;
however, beneficial effects of sunlight have also been observed, particularly in patients with
skin inflammatory conditions, such as psoriasis.33 The biologic effect of sunlight in
inflammation is mediated by UV light, which induces T-cell apoptosis, nonspecific release
of tolerogenic cytokines from antigen-presenting cells in the epidermis, and differentiation
Author Manuscript

of regulatory T cells; hence UV light is used in the treatment of eczema and the skin
manifestations of autoimmune disorders.

The immunosuppressive effect of ionizing radiation affects all blood cell lineages by
depleting the bone marrow and inducing cytopenias, whereas the humoral response and
phagocytosis are considered radioresistant.34 However, continuous exposure to radiation
eventually weakens all immune functions. Animal experiments of space radiation similar to
that human subjects would experience during long-duration space flights have demonstrated
a weakness of T cell–mediated immunity and reactivation of latent viral infections.35 Other
adverse conditions, such as chronic hypoxia at high-altitude locations and long-duration
space flights, might affect immunity by causing physical and mental stress. Confinement,
isolation, and sleep-cycle alterations induce chronic stress, which disturbs the corticoadrenal
Author Manuscript

regulation and increases cortisol levels. In human subjects space flight–equivalent models,
including acute sleep deprivation, have been shown to increase blood levels of inflammatory
cytokines and suppression of IL-10 secretion.36 Prolonged bedrest (ie, 60 days) with head-
down tilt, a model of microgravity in space, has produced a significant increase of serum
TNF-α soluble receptor levels in female volunteers (Fig 5).37 Interestingly, vigorous
exercise served as an effective countermeasure in negating this effect.

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 8

INFECTIOUS DISEASES
Author Manuscript

Transient periods of immunosuppression have been associated with viral infections since the
1900s, when it was observed that tuberculin skin test results became negative in patients
with measles during the acute phase of the infection. Some infectious agents or their toxins
and metabolites might be present in excess amounts to activate the immune system, leading
to a nonresponsive state, such as the T-cell anergy observed after toxic shock syndrome
induced by staphylococcal superantigen. Tissue destruction caused by microbial-induced
damage or inflammatory reaction to a particular infection facilitates access for other
microbes to develop secondary infections. Infections with measles virus, CMV, and
influenza virus can induce lymphopenia and also T-cell anergy; however, these are transient
and usually less severe than the immunodeficiency seen in AIDS. One additional mechanism
of immune compromise is infection of the bone marrow by viral and bacterial organisms
producing neutropenia or pancytopenia, particularly in immunocompromised hosts.38
Author Manuscript

HIV INFECTION: AIDS

Background
Without antiretroviral drug treatment, HIV infection almost always progresses to the
advanced stage of the disease called AIDS that is characterized by profound lymphopenia
and susceptibility to infections with opportunistic pathogens. HIV is transmitted sexually,
for the most part, but it is also transmitted parenterally among intravenous drug users and
vertically from mothers to their infants.39 Initially recognized during the early 1980s in a
handful of cases, it is currently estimated that more than 30 million persons are infected with
HIV worldwide. Two thirds of these subjects are living in the sub-Saharan region of Africa,
and approximately half of them are women and children (Fig 6).40 The HIV epidemics in
Author Manuscript

North America and Europe have shown decreasing trends in the last decade, thanks to
massive education campaigns and the use of potent anti-HIV drugs. However, more than
56,000 new cases of HIV infection were reported in the United States in the last HIV
infection survey by the Centers for Disease Control and Prevention, and approximately half
of these were in subjects younger than 25 years.41 There is an increasing number of reports
of viral multidrug resistance and clinical complications caused by the chronic use of
antiretroviral drugs.42

Virology
HIV is a double-stranded, enveloped RNA retrovirus from the group lentiviruses, with a
tropism for human CD4+ expressing cells, including T cells and macrophages.41 Two HIV
types have been identified, HIV-1 and HIV-2, and both cause human disease. HIV-2 is more
Author Manuscript

prevalent in West Africa and might take more time from infection to the development of
immunodeficiency than HIV-1. The HIV genome contains 3 structural genes (gag, pol, and
env) and 6 regulatory genes (tat, rev, nef, vif, vpr, and vpu). Gag protein is split by the HIV
protease into the proteins named capsid (p24), matrix, nucleocapsid, p6, and p2, all of which
form the viral particle and stabilize the viral genome. Pol protein is also split to produce 3
enzymes: integrase, reverse transcriptase, and the protease that cleaves the viral proteins.
After the viral genomic RNA is converted into DNA by the reverse transcriptase, the

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 9

integrase facilitates the incorporation of the viral DNA into the host genome and uses the
Author Manuscript

host cell’s replication mechanisms to produce more virions. The Env protein is also cleaved
to produce 2 envelope proteins named gp120 and gp41, which are involved in the binding to
CD4 and the chemokine receptors CXCR4 and CCR5 on the cell surface. Tat protein
increases the transcription of HIV genes by 100-fold, whereas Rev protein allows the
expression of the different HIV genes by regulating mRNA splicing.

The roles of the other regulatory genes have only been clarified in the last few years. Nef
protein downregulates CD4 and MHC class I surface expression on the membranes of
infected cells, probably facilitating escape from immune surveillance. Vif is a protein that
induces the degradation of APOBEC3 G, a cytosine deaminase that causes mutations during
viral transcription. Vpr and Vpu proteins seem to facilitate the intracellular transport of viral
proteins for viral particle formation.
Author Manuscript

Immunopathogenesis
HIV infection begins with the binding of the HIV gp120 protein to the CD4 molecule and
the chemokine receptor CCR5 on target cells. Infected cells migrate to the lymph nodes,
where initial replication and infection of nearby CD4+ T cells occur.43 During acute HIV
infection, the gut-associated lymphoid tissue is severely depleted, with predominant loss of
memory CD4+ T cells and with high viremia and immune activation.44,45 HIV induces T-
cell lymphopenia through several mechanisms: HIV-induced apoptosis, viral cytopathic
effect, apoptosis caused by nonspecific immune activation, and cytotoxicity to HIV-infected
cells. An additional form of cell death named autophagy, in which organelles are sequestered
and directed toward lysosomal pathways, has been shown to be induced by HIV Env protein
in uninfected T cells.46 The acute phase of HIV infection occurs 1 to 6 weeks after infection,
with nonspecific symptoms, such as fever, fatigue, myalgia, and headaches. The period of
Author Manuscript

clinical latency that follows is characterized by a virtual absence of signs or symptoms until
symptomatic disease occurs and can last as long as 10 years. Levels of several cytokines are
increased and contribute to determine the degree of control of HIV viremia. Higher viral
loads at the initial stage predict shorter clinical latency. Without anti-HIV drug treatment,
CD4+ T-cell counts progressively decrease, and the host usually succumbs to infections with
opportunistic organisms that take place because of the immune deficiency. Investigators have
been able to demonstrate the production of specific anti-HIV CD4+ T cells and CD8+ T
cells, as well as neutralizing anti-HIV antibodies; however, these immune responses are
eventually overcome by viral escape strategies. At this stage, patients present with fever,
weight loss, diarrhea, lymphadenopathy, and fungal and viral skin infections, indicating
compromise of the immune system. When the peripheral CD4+ T-cell count is less than 200
cells/mL, the patient can present with any of a number of infections that define AIDS, such
Author Manuscript

as Pseudomonas jiroveci–induced pneumonia, histoplasmosis, toxoplasmosis, and

coccidioidomycosis.47 If the patient does not receive antiretroviral treatment, repeated
infections that are difficult to manage lead to the patient’s death. A small proportion of HIV-
infected patients remain asymptomatic and do not have AIDS. These patients are called
long-term nonprogressors and have been the focus of multiple studies to understand the
basis of their protection. Those who maintain low levels of HIV (ie, <50 RNA copies/mL)
without treatment are called elite controllers.48 This immunity appears to be explained by

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 10

different viral and host factors. The best known of these factors is the inherited defect in the
Author Manuscript

gene encoding the CCR5 receptor, a T-cell surface molecule that is necessary for HIV cell
entry. CCR5 gene mutations have been found with significant prevalence in persons of
Northern European ancestry. Other factors identified in long-term nonprogressors include a
low number of activated CD8+ T cells,49 the presence of particular HLA haplotypes, and
viral mutations that result in low virulence. The diagnosis of HIV infection is made by using
a sensitive ELISA to detect antibodies against the HIV protein p24. A positive HIV ELISA
result is confirmed by using the more specific Western blot, which detects antibodies to
several HIV proteins, or the detection of HIV DNA sequences by PCR. Rapid diagnostic
tests to rule out HIV infection use serum, saliva, or urine with similar sensitivity and
specificity to the ELISA and can be performed in the office or at home. Infants and children
up to 18 months of age born to HIV-infected mothers should be evaluated with an HIV DNA
PCR test because the presence of passively acquired maternal antibodies in the serum of the
Author Manuscript

child can result in a positive HIV ELISA test result, even if the child is not infected with
HIV. Other useful laboratory tests are genotyping and phenotyping assays. Genotyping
identifies HIV mutations that confer viral resistance to antiretroviral drugs. Phenotyping
measures the inhibitory action of anti-HIV drugs on the isolated HIV strain, which is similar
to a bacterial susceptibility assay. These assays define anti-HIV drug susceptibility profiles
of viral strains isolated from infected patients and help in the design of the combination of
drugs with the most probability to have a therapeutic effect in a particular patient.

Treatment
In adults specific anti-HIV therapy is recommended when the patient has an AIDS-defining
illness, the CD4+ T-cell count is less than 350 cells/mm3, or the HIV viral load is greater
than 100,000 copies/mL. Caution should be exercised in other clinical situations because of
Author Manuscript

the development of viral resistance to the antiretroviral agents and significant drug-induced
adverse effects, including allergic and metabolic syndromes.50,51 In children treatment is
considered for any HIV-infected infant because disease progresses faster than in older
children. For children older than 12 months, the criteria are similar to those in adults:
presence of an AIDS-defining illness, CD4+ T-cell count of less than 15% of PBMCs, or
viral load greater than 100,000 copies/mL.52 Anti-HIV drug classes are defined according to
their mechanism of action: nucleoside reverse transcriptase inhibitor, nonnucleoside reverse
transcriptase inhibitor, protease inhibitor, and cell fusion inhibitor. In the last 2 years, CCR5
inhibitors and integrase inhibitors have been added to the arsenal of anti-HIV medications.
53,54 Combinations of 3 synergistic anti-HIV drugs from 2 different classes are known as

highly active antiretroviral therapy (HAART). HAART protocols have been effective in
reducing viremia and restoring normal T-cell counts, with drastic reduction of mortality and
Author Manuscript

number of infections; however, they do not eradicate HIV and need to be administered
continuously for life. As an adjuvant treatment to improve baseline immunity, the
administrations of IL-7 and IL-2 have been independently tested to increase CD4+ T-cell
counts, with promising results.55,56

Immunologic reactions associated with anti-HIV treatment

The immune reconstitution inflammatory syndrome (IRIS) is a severe inflammatory
response to existing opportunistic infections that can be observed in 15% to 25% of patients

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 11

with AIDS 2 to 3 weeks after starting HAART treatment.57 The management of IRIS
Author Manuscript

consists of corticosteroid therapy and simultaneous treatment of the opportunistic infections;

however, IRIS might not occur if these infections are recognized and treated before starting
the HAART therapy. A similar clinical observation is the increased incidence of asthma in
HIV-infected patients receiving HAART, up to 3 times the rate of HIV-negative control
subjects.58

Drug-allergic reactions have an increased prevalence in this patient population. Urticarial or

maculopapular rashes, which occasionally present as the Steven-Johnson syndrome, occur in
as many as 60% of patients with HIV receiving trimethoprim-sulfamethoxazole and in 17%
of those receiving the antiretroviral nevirapine.59 Abacavir is a nucleoside reverse
transcriptase inhibitor that causes a multiorgan hypersensitivity syndrome characterized by
fever, rash, diarrhea, myalgia, and arthralgia in as many as 14% of patients who take this
drug. This has a strong association with the presence of HLA B5701. This syndrome
Author Manuscript

presents within the first weeks of treatment and can be fatal; however, it usually resolves
after 72 hours of discontinuing the drug.

HIV vaccine
The failure of current antiretroviral therapy to eliminate the HIV virus emphasizes the need
of preventive measures to control the HIV pandemic. Research for an effective anti-HIV
vaccine has yielded several lessons; perhaps the most important is the need to demonstrate
the development of specific cellular immunity and humoral responses and include mucosal
protective immunity.60 The first vaccine candidates were based on strategies that had worked
for other infectious diseases, such as inactivated virus and HIV proteins conjugated to
adjuvants. These were able to induce only weak neutralizing antibody activity and did not
provide significant protection against HIV infection in clinical trials. Live attenuated simian
Author Manuscript

immunodeficiency virus strains have been demonstrated to protect macaques from simian
immunodeficiency virus challenge; however, there are safety concerns related to the
extraordinary capacity of HIV for recombination, which might lead to wild-type revertant
strains. A novel approach using an adenovirus-based vaccine expressing HIV proteins
elicited strong anti-HIV immunity; however, it was unable to demonstrate a protective effect
over placebo in a phase I/II clinical trial with more than 3,000 subjects.61

Prevention measures
Considerable resources have been placed on educational campaigns to control the HIV
epidemics. Preventive interventions that have been useful are using condoms, providing
intravenous drug users with free sterile needles, screening blood products, and administering
antiretroviral agents to HIV-infected pregnant women and their infants. Avoidance of breast-
Author Manuscript

feeding has been recommended on the basis of the increased risk of transmitting the virus
through breast milk; however, this might be revised in communities with poor resources,
where it has been demonstrated that breast-feeding up to 1 month in combination with
antiretroviral therapy does not increase early transmission and provides immune and
nutritional support to the newborn.62 Other preventative interventions are male circumcision,
with a reduction of the risk of HIV infection in heterosexual males by 50% to 60%,63 and
topical anti-HIV microbicidals as an alternative to the use of condoms.64 The control of this

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 12

deadly disease will only result from a combined effort of researchers and physicians
Author Manuscript

developing and using anti-HIV drugs effectively and educators working in the promotion of
safe behavioral practices in communities at risk.

CONCLUSION
There is an increased awareness of the variety of factors that can affect the immune
response. When evaluating a patient with increased frequency or severity of infections
suggesting immunodeficiency, physicians should consider that secondary
immunodeficiencies are far more common than primary immune defects of genetic cause. A
detailed clinical history might uncover the condition affecting the immune system, such as
infection, malnutrition, age extremes, concomitant metabolic or neoplastic diseases, use of
immunosuppressive drugs, surgery and trauma, and exposure to harsh environmental
conditions. Because of its prevalence and clinical progression, HIV infection should be
Author Manuscript

considered and ruled out. The specific immune defects and clinical presentation in other
secondary immunodeficiencies are usually heterogeneous, affecting both the innate and the
adaptive immunity. The immune impairment improves with the resolution of the primary
condition.

Acknowledgments
Supported by National Institutes of Health grants AI27551, AI36211, AI6944I, HD41983, RR0188, HD79533,
HL72705, and HD78522 and the David Fund, the Pediatrics AIDS Fund, and the Immunology Research Fund,
Texas Children’s Hospital.

Abbreviations used
GvHD: Graft-versus-host disease
Author Manuscript

HAART: Highly active antiretroviral therapy

IRIS: Immune reconstitution inflammatory syndrome

REFERENCES
1. Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol 2010;125: S182–94.
[PubMed: 20042228]
2. Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De Gaudio R, et al. Corticosteroids
in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA
2009;301:2362–75. [PubMed: 19509383]
3. Tan HP, Smaldone MC, Shapiro R. Immunosuppressive preconditioning or induction regimens,
evidence to date. Drugs 2006;66:1535–45. [PubMed: 16956302]
Author Manuscript

4. Black RE, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M, et al. Maternal and Child
Undernutrition Study Group. Maternal and child undernutrition: global and regional exposures and
health consequences. Lancet 2008;371:243–60. [PubMed: 18207566]
5. Lee SJ, Chinen J, Kavanaugh A. Immunomodulator therapy: Monoclonal antibodies, fusion
proteins, cytokines, and immunoglobulins. J Allergy Clin Immunol 2010;125:S314–23. [PubMed:
20036416]
6. Lewis DB. Development of the fetal and neonatal immune system In: Rich RR, editor. Clinical
immunology. Principles and practice. 3th ed. Philadelphia: Elsevier Saunders; 2008 p. 493–502.

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 13

7. Siegrist CA, Aspinalli R. B cell responses to vaccination at the extremes of age. Nat Rev Immunol
2009;9:185–94. [PubMed: 19240757]
Author Manuscript

8. Yost CC, Cody MJ, Harris ES, Thornton NL, McInturff AM, Martinez ML, et al. Impaired
neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human
neonates. Blood 2009;113:6419–27. [PubMed: 19221037]
9. Dorshkind K, Montecino-Rodriguez E, Signer RA. The ageing immune system: is it ever too old to
become young again? Nat Rev Immunol 2009;9:57–62. [PubMed: 19104499]
10. Gomez CR, Nomellini V, Faunce DE, Kovacs EJ. Innate immunity and aging. Exp Gerontol
2008;43:718–28. [PubMed: 18586079]
11. Castle SC, Uyemura K, Fulop T, Makinodan T. Host resistance and immune responses in advanced
age. Clin Geriatr Med 2007;23:463–79. [PubMed: 17631228]
12. Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf D, Grubeck-Loebenstein B.
Biology of immune responses to vaccines in elderly persons. Clin Infect Dis 2008;46:1078–84.
[PubMed: 18444828]
13. Roth DE, Caulfield LE, Ezzati M, Black RE. Acute lower respiratory infections in childhood:
opportunities for reducing the global burden through nutritional interventions. Bull World Health
Author Manuscript

Organ 2008;86:356–64. [PubMed: 18545738]

14. Hamer DH, Sempértegui F, Estrella B, Tucker KL, Rodríguez A, Egas J, et al. Micronutrient
deficiencies are associated with impaired immune response and higher burden of respiratory
infections in elderly Ecuadorians. J Nutr 2009;139:113–9. [PubMed: 19056665]
15. Cunningham-Rundles S, McNeeley DF, Moon A. Mechanisms of nutrient modulation of the
immune response. J Allergy Clin Immunol 2005;115:1119–28. [PubMed: 15940121]
16. Adams JS, Liu PT, Chun R, Modlin RL, Hewison M. Vitamin D in defense of the human immune
response. Ann N Y Acad Sci 2007;1117:94–105. [PubMed: 17656563]
17. Daoud AK, Tayyar MA, Fouda IM, Harfeil NA. Effects of diabetes mellitus vs. in vitro
hyperglycemia on select immune cell functions. J Immunotoxicol 2009;6:36–41. [PubMed:
19519161]
18. Foley RN. Infectious complications in chronic dialysis patients. Perit Dial Int 2008; 28(suppl
3):S167–71. [PubMed: 18552250]
19. Lim WH, Kireta S, Leedham E, Russ GR, Coates PT. Uremia impairs monocyte and monocyte-
Author Manuscript

derived dendritic cell function in hemodialysis patients. Kidney Int 2007;72:1138–48. [PubMed:
17728708]
20. Raff AC, Meyer TW, Hostetter TH. New insights into uremic toxicity. Curr Opin Nephrol
Hypertens 2008;17:560–5. [PubMed: 18941347]
21. De Hingh YCM, van der Vossen VW, Gemen EFB, Mulder AB, Hop WCJ, Brus F, et al. Intrinsic
abnormalities of lymphocyte counts in children with Down syndrome. J Pediatr 2005;147:744–7.
[PubMed: 16356423]
22. Douglas SD. Down syndrome: immunologic and epidemiologic association enigmas remain. J
Pediatr 2005;147:723–5. [PubMed: 16356417]
23. Brennan S Innate immune activation and cystic fibrosis. Paediatr Respir Rev 2008; 9:271–9.
[PubMed: 19026368]
24. Stahn C, Buttgereit F. Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract
Rheumatol 2008;4:525–33. [PubMed: 18762788]
25. Opelz G, Döhler B. Collaborative Transplant Study. Influence of immunosuppressive regimens on
graft survival and secondary outcomes after kidney transplantation. Transplantation 2009;87:795–
Author Manuscript

802. [PubMed: 19300179]

26. Sagg KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American College of
Rheumatology. American College of Rheumatology 2008 recommendations for the use of
nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis
Rheum 2008;59:762–4. [PubMed: 18512708]
27. Flohé SB, Flohé S, Schade FU. Deterioration of the immune system after trauma: signals and
cellular mechanisms. Innate Immun 2008;14:333–44. [PubMed: 19039057]
28. Heizmann O, Koeller M, Muhr G, Oertli D, Schinkel C. Th1- and Th2-type cytokines in plasma
after major trauma. J Trauma 2008;65:1374–8. [PubMed: 19077629]

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 14

29. Joffre O, Nolte MA, Sporri R, Reis e Sousa C. Inflammatory signals in dendritic cell activation and
the induction of adaptive immunity. Immunol Rev 2009;227:234–47. [PubMed: 19120488]
Author Manuscript

30. Lenz A, Franklin GA, Cheadle WG. Systemic inflammation after trauma. Injury 2007;38:1336–45.
[PubMed: 18048040]
31. Tschoeke SK, Ertel W. Immunoparalysis after multiple trauma. Injury 2007;38: 1346–57.
[PubMed: 18048039]
32. American Academy of Pediatrics. Pneumococcal infections In: Pickering LK, editor. RedBook.
2009 Report of the Committee of Infections Diseases. 28th ed. Elk Grove Village (IL): American
Academy of Pediatrics; 2009 p. 534–5.
33. Patel RV, Clark LN, Lebwohl M, Weinberg JM. Treatments for psoriasis and the risk of
malignancy. J Am Acad Dermatol 2009;60:1001–17. [PubMed: 19344980]
34. Kusunoki Y, Hayashi T. Long-lasting alterations of the immune system by ionizing radiation
exposure: implications for disease development among atomic bomb survivors. Int J Radiat Biol
2008;84:1–14. [PubMed: 17852558]
35. Shearer WT, Zhang S, Reuben JM, Lee BM, Butel JS. Effects of radiation and latent virus on
immune responses in a space flight model. J Allergy Clin Immunol 2005;115:1297–303. [PubMed:
Author Manuscript

15940150]
36. Shearer WT, Lee BN, Cron SG, Rosenblatt HM, Smith EO, Lugg DJ, et al. Suppression of human
anti-inflammatory plasma cytokines IL-10 and IL-1RA with elevation of proinflammatory
cytokine IFN-gamma during the isolation of the Antarctic winter. J Allergy Clin Immunol
2002;109:854–7. [PubMed: 11994711]
37. Shearer WT, Ochs HD, Lee BN, Cohen EN, Reuben JM, Cheng I, et al. Immune responses in adult
female volunteers during the bed-rest model of spaceflight: antibodies and cytokines. J Allergy
Clin Immunol 2009;123:900–5. [PubMed: 19232702]
38. Lindblom A, Heyman M, Gustafsson I, Norbeck O, Kaldensjö T, Vernby A, et al. Parvovirus B19
infection in children with acute lymphoblastic leukemia is associated with cytopenia resulting in
prolonged interruptions of chemotherapy. Clin Infect Dis 2008;46:528–36. [PubMed: 18194100]
39. Baliga CS, Paul ME, Chine J, Shearer WT. HIV infection and the acquired immunodeficiency
syndrome In: Rich RR, editor. Clinical immunology. Principles and practice. 3th ed. Philadelphia:
Elsevier Saunders; 2008 p. 553–60.
Author Manuscript

40. UNAIDS. 2008 Report on the global AIDS epidemic. Geneva, Switzerland: United Nations
Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO); 2008.
41. Centers for Disease Control and Prevention. HIV/AIDS surveillance report. Vol 19 Department of
Health and Human Services; 2007.
42. Hammer SM, Eron JJ, Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, et al. Antiretroviral
treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA
panel. JAMA 2008;300:555–70. [PubMed: 18677028]
43. Shen L, Siliciano RF. Viral reservoirs, residual viremia, and the potential of highly active
antiretroviral therapy to eradicate HIV infection. J Allergy Clin Immunol 2008;122:22–8.
[PubMed: 18602567]
44. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, et al. CD4 T cell
depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp
Med 2004;200:749–59. [PubMed: 15365096]
45. Norris PJ, Pappalardo BL, Custer B, Spotts G, Hecht FM, Busch MP, et al. Elevations in IL-10,
TNF-alpha, and IFN-gamma from the earliest point of HIV Type 1 infection. AIDS Res Hum
Author Manuscript

Retroviruses 2006;22:757–62. [PubMed: 16910831]

46. Espert L, Denizot M, Grimaldi M, Robert-Hebmann V, Gay B, Varbanov M, et al. Autophagy is
involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J Clin Invest
2006;116:2161–72. [PubMed: 16886061]
47. Rodriguez B, Sethi AK, Cheruvu VK, Mackay W, Bosch RJ, Kitahata M, et al. Predictive value of
plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA
2006;296:1498–506. [PubMed: 17003398]
48. Baker BM, Block BL, Rothchild AC, Walker BD. Elite control of HIV infection: implications for
vaccine design. Expert Opin Biol Ther 2009;9:55–69. [PubMed: 19063693]

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 15

49. Paul ME, Mao C, Charurat M, Serchuck L, Foca M, Hayani K, et al. Predictors of immunologic
long-term non progression in HIV-infected children: implications for initiating therapy. J Allergy
Author Manuscript

Clin Immunol 2005;115:848–55. [PubMed: 15806009]

50. Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice AC, et al. Effect of early
versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009;360:1815–26.
[PubMed: 19339714]
51. Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human
Services 11 3, 2008 Available at: [Link]
[Link] Accessed May 30, 2009.
52. Working Group on Antiretroviral Therapy and Medical Management of HIV Infected Children.
Guidelines for the use of antiretroviral agents in pediatric HIV infection. 2 23, 2009 Available at:
[Link] Accessed May 30, 2009.
53. MacArthur RD, Novak RM. Reviews of anti-infective agents: maraviroc: the first of a new class of
antiretroviral agents. Clin Infect Dis 2008;47:236–41. [PubMed: 18532888]
54. Hicks C, Gulick RM. Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis
Author Manuscript

2009;48:931–9. [PubMed: 19231980]

55. Pahwa S, Muresan P, Sleasman J, Fenton T, Moye J, Deveikis A, et al. Phase I/II trial of
intermittent subcutaneous IL-2 administration in pediatric patients with moderate immune
suppression: results of Pediatric AIDS Clinical Trials Study 402. J Allergy Clin Immunol
2007;119:1538–41. [PubMed: 17418382]
56. Camargo JF, Kulkarni H, Agan BK, Gaitan AA, Beachy LA, Srinivas S, et al. Responsiveness of T
cells to interleukin-7 is associated with higher CD4 + T cell counts in HIV-1-positive individuals
with highly active antiretroviral therapy-induced viral load suppression. J Infect Dis
2009;199:1872–82. [PubMed: 19432535]
57. French MA. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. Clin Infect
Dis 2009;48:101–7. [PubMed: 19025493]
58. Foster SB, McIntosh K, Thompson B, Lu M, Yin W, Rich KC, et al. Increased incidence of asthma
in HIV-infected children treated with highly active antiretroviral therapy in the National Institutes
of Health Women and Infants Transmission Study. J Allergy Clin Immunol 2008;122:159–65.
[PubMed: 18547627]
Author Manuscript

59. Davis CM, Shearer WT. Diagnosis and management of HIV drug hypersensitivity. J Allergy Clin
Immunol 2008;121:826–32. [PubMed: 18190954]
60. Haynes BF, Shattock RJ. Critical issues in mucosal immunity for HIV-1 vaccine development. J
Allergy Clin Immunol 2008;122:3–9. [PubMed: 18468671]
61. McElrath MJ, De Rosa SC, Moodie Z, Dubey S, Kierstead L, Janes H, et al. HIV-1 vaccine-
induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet
2008;372:1894–905. [PubMed: 19012957]
62. Shapiro RL, Smeaton L, Lockman S, Thior I, Rossenkhan R, Wester C, et al. Risk factors for early
and late transmission of HIV via breast-feeding among infants born to HIV-infected women in a
randomized clinical trial in Botswana. J Infect Dis 2009;199:414–8. [PubMed: 19090775]
63. Newell ML, Barninghausen T. Male circumcision to cut HIV risk in the general population. Lancet
2007;369:617–8. [PubMed: 17321292]
64. Cutler B, Justman J. Vaginal microbicides and the prevention of HIV transmission. Lancet Infect
Dis 2008;8:685–97. [PubMed: 18992405]
Author Manuscript

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 16
Author Manuscript
Author Manuscript
Author Manuscript

FIG 1.
Extrinsic factors leading to defects of immune function.
Author Manuscript

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 17
Author Manuscript
Author Manuscript
Author Manuscript

FIG 2.
Role of vitamin D (VitD) in macrophage activation. Toll-like receptor 2 (TLR2) activation
increases expression of CYP21B1, a mitochondrial enzyme that converts vitamin D into its
active form, 1,25OH vitamin D, and vitamin D nuclear receptor (VDR) expression, which
when bound to 1,25OH vitamin D promotes cathelicidin synthesis. Cathelicidins are
intracellular bactericidal proteins.
Author Manuscript

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 18
Author Manuscript
Author Manuscript
Author Manuscript

FIG 3.
Molecular mechanism of action of glucocorticoids. A cytosolic receptor binds
glucocorticoids and translocates them to the nucleus, where they either activate anti-
inflammatory genes or inhibit proinflammatory genes. At high doses, corticosteroids can
also affect cell function by non–receptor-dependent mechanisms.
Author Manuscript

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 19
Author Manuscript
Author Manuscript
Author Manuscript

FIG 4.
Author Manuscript

Effect of cyclosporine on T cells. Inhibition of calcineurin activity by cyclosporine results in

decreased activation of IL-2 transcription. TCR, T-cell receptor; NFAT, nuclear factor of
activated T cells; NFATc, cytoplasmic monomer; NFATn, nuclear monomer.

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 20
Author Manuscript
Author Manuscript

FIG 5.
Human model to test the effects of microgravity. Volunteers are maintained in bedrest
position for 60 days to mimic the affects of microgravity in space. Exercise is used as a
Author Manuscript

countermeasure.
Author Manuscript

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 21
Author Manuscript
Author Manuscript
Author Manuscript

FIG 6.
Worldwide prevalence of HIV infection. Adapted from the United Nations Programme on
HIV/AIDS.40
Author Manuscript

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.
 Chinen and Shearer Page 22

TABLE I.

Selected causes of secondary immunodeficiencies

Author Manuscript

Condition Effect on immune function

Extremes of age

Newborn period Immature lymphoid organs

Absent memory immunity
Low maternal IgG levels in premature infants
Decreased neutrophil storage pool
Decreased neutrophil function
Decreased natural killer activity

Advanced age Decreased antigen-specific cellular immunity

T-cell oligoclonality
Restricted B-cell repertoire

Malnutrition Decreased cellular immune response

Weakened mucosal barriers

Metabolic diseases
Author Manuscript

Diabetes mellitus Decreased mitogen-induced lymphoproliferation

Defective phagocytosis
Decreased chemotaxis

Chronic uremia Decreased cellular immune response

Decreased generation of memory antibody responses
Decreased chemotaxis

Genetic syndromes: trisomy 21 Defective phagocytosis

Defective chemotaxis
Variable defects of antigen-specific immune responses

Anti-inflammatory, immunomodulatory, and immunosuppressive drug therapy: Lymphopenia

corticosteroids, calcineurin inhibitors, cytotoxic agents Decreased cellular immune response and anergy
Decreased proinflammatory cytokines
Decreased phagocytosis
Decreased chemotaxis
Neutropenia (cytotoxic agents)
Weakened mucosal barriers (cytotoxic agents)

Surgery and trauma Disruption of epithelial and mucosal barriers

T-cell anergy caused by nonspecific immune activation
Author Manuscript

Environmental conditions UV light, radiation, hypoxia, space Flight Increased lymphocyte apoptosis
Increased secretion of tolerogenic cytokines
Cytopenias
Decreased cellular immunity and anergy
Stress-induced nonspecific immune activation

Infectious diseases: HIV infection T-cell lymphopenia

Decreased cellular immune response and anergy
Defective antigen-specific antibody responses
Author Manuscript

J Allergy Clin Immunol. Author manuscript; available in PMC 2018 September 24.