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IMMUNITY TO MICROBES
Most infectious diseases are caused by pathogens much smaller than a human cell. For
these microbes, the human body constitutes a vast resource-rich environment in which to live
and reproduce. Without a functional immune system, people would quickly succumb to the
countless infectious microorganisms in the environment. The development of an infectious
disease in an individual involves complex interactions between the microbe and the host. The
key events during infection include entry of the microbe, invasion and colonization of host
tissues, evasion of host immunity, and tissue injury or functional impairment. Many features
of microorganisms determine their virulence, and many diverse mechanisms contribute to the
pathogenesis of infectious diseases. Although anti-microbial host defense reactions are
numerous and varied, there are important general features of immunity to microbes. Defense
against microbes is mediated by the effector mechanisms of innate and adaptive immunity.
The innate immune system provides early defense, and its mechanisms can get rid of most of
the microbes without activating adaptive immunity. However, many pathogenic microbes
have evolved to resist innate immunity, and protection against such infections is critically
dependent on adaptive immune responses. In adaptive responses, large numbers of effector
cells and antibody molecules are generated that function to eliminate the microbes and
memory cells that protect the individual from repeated infections. In this chapter, we will
consider the main features of immunity to three major categories of pathogenic
microorganisms: extracellular bacteria, intracellular bacteria as well as viruses. The way that
the immune system responds to parasitic worm (helminth) infections is very similar to the
way it responds to allergens. These mechanism are described and discussed in the next
chapter.
Immune responses to extracellular bacteria
Many different species of extracellular bacteria are pathogenic, and induce diseases in
humans by two principal mechanisms. First, these bacteria induce inflammation, which results
in tissue destruction at the site of infection. Second, pathogenic bacteria produce toxins,
which have diverse pathologic effects. The toxins may be endotoxins, which are components
of cell walls and released by dying Gram-negative bacteria, or exotoxins, which are secreted
by living bacteria. The endotoxin of Gram-negative bacteria, also called lipopolysaccharide
(LPS), is a potent activator of macrophages, dendritic cells, and endothelial cells. Many
exotoxins are cytotoxic, and others cause disease by various mechanisms. For instance,
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diphtheria toxin shuts down protein synthesis in infected cells, cholera toxin interferes with
ion and water transport, tetanus toxin inhibits neuromuscular transmission, and anthrax toxin
disrupts several critical biochemical signaling pathways in infected cells. Other exotoxins
interfere with normal cellular functions without killing cells, and yet other exotoxins stimulate
the production of cytokines that cause disease.
The principal mechanisms of innate immunity to extracellular bacteria are activation of
the complement cascade, phagocytosis, and inflammatory responses. Peptidoglycans in the
cell walls of Gram-positive bacteria and LPS in Gram-negative bacteria are able to activate
the complement system by the alternative pathway. Bacteria that express mannose on their
surface may bind mannose-binding lectin (MBL), which activates complement by the lectin
pathway. C-reactive protein, an acute phase protein of the innate immune response, binds to
phosphorylcholine on bacterial surfaces and activates complement by the classical pathway.
One result of complement activation is opsonization and enhanced phagocytosis of the
bacteria. The membrane attack complex generated by complement activation lyses bacteria,
especially Neisseria species that are particularly susceptible to lysis because of their thin cell
walls. In addition, complement byproducts (C3a and C5a) stimulate inflammatory responses
by recruiting and activating leukocytes. Phagocytes (neutrophils and macrophages) use
surface receptors, including mannose receptors and scavenger receptors, to recognize
extracellular bacteria, and they use Fc receptors and complement receptors to recognize
bacteria opsonized with antibodies and complement proteins, respectively. Microbial products
activate cell surface and endosomal Toll-like receptors (TLRs) and various cytoplasmic
sensors in phagocytes and other cells. Some of these receptors function mainly to promote the
phagocytosis of the microbes (e.g., mannose receptors, scavenger receptors); others stimulate
the microbicidal activities of the phagocytes (mainly TLRs); and yet others promote both
phagocytosis and activation of the phagocytes (Fc and complement receptors). In addition to
killing of engulfed microbes by phagocytosis, neutrophils use another mechanism of
destruction that is directed at extracellular pathogens. During infection, some activated
neutrophils undergo an unique form of cell death in which the nuclear chromatin is released
into the extracellular space and forms a fibril matrix known as neutrophil extracellular trap
(NET). NETs are composed of nuclear components (such as DNA and histones) and are
decorated by proteins from granules (such as myeloperoxidase, neutrophil elastase, and
lactoferrin). Mitochondria can also serve as a source of DNA for NET formation. NETs have
been shown to capture microorganisms and promote the interaction of these pathogens with
granule-derived proteins and their subsequent disposal. Captured microorganisms can also be
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more efficiently phagocytosed by other neutrophils or macrophages. Dendritic cells and
phagocytes that are activated by the microbes secrete chemokines and cytokines, which
induce local inflammation. The recruited leukocytes ingest and destroy the bacteria.
The major mechanisms of innate immunity in the oral cavity are inactivation and
clearance of microbes from the oral mucosal epithelium and enamel surfaces as well as
inflammation. The oral mucosa is an anatomical barrier that prevents entry of microbes. Oral
health depends on the integrity of the mucosal barrier, which also provides a habitat for
normal oral flora. Continuous desquamation of the oral mucosal epithelium continuously
removes bacteria and fungi that try to colonize the mucosa, and this minimizes the microbial
biomass in the oral cavity. Stable colonization therefore requires a continual process of
microbial attachment, growth and reattachment to exposed epithelial cells, or growth of
microbes in saliva at a rate exceeding the salivary flow or dilution rate. When the oral mucosa
is compromised (e.g. Sjogren’s syndrome or chemotherapy), infections frequently develop.
Saliva has multiple antimicrobial actions. Salivary flow combined with the continuous
swallowing that cleanses the mouth removes debris and unattached microbes. Saliva also
replenishes fluids in the oral cavity, which dilutes and clears microbes and acid from plaque.
Saliva contains neutrophils as wells as several defence chemicals that promote innate immune
responses in the oral cavity. The mucus layer on intraoral surfaces exists as a sticky, slippery
gel-like barrier composed of mucin glycoproteins, which prevent entry of microbes into
underlying tissues. Mucous traps microbes and removes them from the oral cavity by
sloughing. Secretory immunoglobulins also become attached to the mucin polypeptides,
where they stand ready to bind commensal and pathogenic microorganisms. Lysozyme can
break the glycosidic bonds in the peptidoglycan and hydrolyze the bacterial cell wall.
Lactoferrin and apolactoferrin sequester iron from bacteria. Peroxidases are indirectly
involved in the oxidation of bacterial enzymes in glycolytic pathways, and this inhibit the
growth of oral microbes. Histidine-rich proteins are cationic proteins, which display various
functions including fungicidal and bactericidal activity. Defensins are a class of pore-forming
cationic peptides that insert into the phospholipid bilayer of bacterial membranes causing
osmotic instability and cell lysis.
The systemic and mucosal immune systems use different strategies for coping with
infections. As the systemic immune system cannot anticipate infection, it is necessary for
macrophages to be activated by the invading bacteria and then to secrete cytokines that recruit
effector cells to the infected tissue. This creates a state of inflammation in which the bacteria
are killed, but at a cost to the structural integrity of the tissue. Infection is followed by an
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extensive period for repair and recovery of the damaged tissue. In contrast, the mucosal
immune system anticipates potential infections by continually making adaptive immune
responses against the microbiota, which places secretory IgA on mucosal surfaces and the
lamina propria, and effector cells in the lamina propria and the epithelium. When bacteria
invade the mucosal tissue, effector molecules and cells are ready and waiting to contain the
infection. In the absence of inflammation, a further adaptive immune response to the invading
organism is made in the draining mesenteric lymphoid which augments that in the local
lymphoid tissue. Little damage is done to the tissue, and repair occurs as part of the normal
process by which mucosal epithelial cells are frequently turned over and replaced.
Humoral immunity is a major protective adaptive immune response against
extracellular bacteria, and it functions to block infection, to eliminate the microbes, and to
neutralize their toxins. Adaptive defense mechanisms to extracellular bacteria in the oral
cavity are also mediated by humoral factors that involve gingival crevicular fluid Igs (IgM,
IgG and IgA) derived from plasma cells in the gingivae, and, principally, secretory IgA.
Antibody responses against extracellular bacteria are directed against cell wall antigens and
secreted and cell-associated toxins, which may be polysaccharides or proteins. The
polysaccharides are prototypic T-independent antigens, and humoral immunity is the principal
mechanism of defense against polysaccharide-rich encapsulated bacteria. The effector
mechanisms used by antibodies to combat these infections include neutralization,
opsonization and phagocytosis, and activation of complement by the classical pathway. The
protein antigens of extracellular bacteria also activate TH1 and TH17 cells, which produce
cytokines that induce local inflammation, enhance the phagocytic and microbicidal activities
of macrophages and neutrophils, and stimulate antibody production. The same reactions of
neutrophils and macrophages that function to eradicate the infection also cause tissue damage
by local production of reactive oxygen species and lysosomal enzymes. These inflammatory
reactions are usually self-limited and controlled. Cytokines secreted by leukocytes in response
to bacterial products also stimulate the production of acute-phase proteins and cause the
systemic manifestations of the infection. Septic shock is a severe pathologic consequence of
disseminated infection by some Gram-negative and Gram-positive bacteria. It is a syndrome
characterized by circulatory collapse and disseminated intravascular coagulation. The early
phase of septic shock is caused by cytokines produced by macrophages that are activated by
bacterial cell wall components, including LPS and peptidoglycans. TNF-α, IL-6, and IL-1 are
the principal cytokine mediators of septic shock. This early burst of large amounts of
cytokines is sometimes called a cytokine storm. There is some evidence that the progression
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of septic shock is associated with defective immune responses, perhaps related to depletion or
suppression of T cells, resulting in unchecked microbial spread. Certain bacterial toxins,
called superantigens, stimulate all T cells in an individual that express a particular family of
Vβ T cell receptor (TCR) genes. The superantigen first binds MHC class II molecules and
then engages the Vβ chain and CD28. Signals from the T-cell receptor, CD4 co-receptor, and
CD28 combine to activate the T cell. Their importance lies in their ability to activate many T
cells, with the subsequent production of large amounts of cytokines that can also cause a
systemic inflammatory syndrome.
The virulence of extracellular bacteria has been linked to a number of mechanisms that
enable the microbes to resist innate immunity. Bacteria with polysaccharide-rich capsules
resist phagocytosis and are therefore much more virulent than homologous strains lacking a
capsule. The capsules of many pathogenic Gram-positive and Gram-negative bacteria contain
sialic acid residues that inhibit activation of the complement system by the alternative
pathway. Coagulase enzyme, which enables the conversion of fibrinogen to fibrin, is tightly
bound to the surface of Staphylococcus aureus and can coat its surface with fibrin upon
contact with blood. The fibrin clot may protect the bacterium from phagocytosis and isolate it
from other defenses of the host. Some surface antigens of Neisseria gonorrhoeae are
contained in their pili, which are the structures responsible for bacterial adhesion to host cells.
The major antigen of the pili is a protein called pilin. The pilin genes of gonococci undergo
extensive gene conversion, because of which the progeny of one organism can produce up to
106 antigenically distinct pilin molecules. This ability to alter antigens helps the bacteria
evade attack by pilin-specific antibodies. Changes in the production of glycosidases lead to
chemical alterations in surface LPS and other polysaccharides, which enable the bacteria to
evade humoral immune responses against these antigens. Most staphylococci possess catalase
enzyme that is used in the detoxification of reactive oxygen intermediates. Some bacteria
(e.g., Haemophilus influenzae and Neisseria meningitidis) secrete a protease that specifically
cleaves the hinge region of IgA.
Immune responses to intracellular bacteria
Some of the human pathogenic bacteria have evolved mechanisms to survive and
replicate in phagocytic host cells. Macrophages are good targets for such bacteria (e.g.
Mycobacterium, Listeria, Legionella), because they are mobile cells allowing wide
dissemination of the pathogen throughout the body. The innate immune responses to
intracellular bacteria are mediated mainly by activated macrophages and NK cells. At the
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site of entry, neutrophils and later macrophages, engulf and try to kill these microbes, but
pathogenic intracellular bacteria are resistant to degradation within phagosomes. Intracellular
bacteria stimulate dendritic cell and macrophage to produce IL-12, which activates NK cells.
IL-12-exposed NK cells produce IFN-γ, which in turn activates macrophages and promotes
killing of the phagocytosed bacteria. Thus, NK cells can provide an early defense against
these microbes, before the development of adaptive immunity. Innate immunity may control
bacterial growth, but elimination of these bacteria requires adaptive cell-mediated immunity.
The major protective immune response against intracellular bacteria is T cell–mediated
recruitment and activation of phagocytes. Individuals with deficient cell-mediated immunity,
such as patients with AIDS, are extremely susceptible to infections with intracellular bacteria.
T cells can provide defense against infections by two mechanisms. TH1 cells activate
phagocytes through the actions of CD40 ligand and IFN-γ, resulting in an increase in their
capacity to destroy the microbes in phagosomes. Activated macrophages produce higher
levels of microbicidal substances, including reactive oxygen species, nitric oxide, and
lysosomal enzymes. CD8+ cytotoxic T lymphocytes kill infected cells, eliminating microbes
that escape the killing mechanisms of phagocytes. Naive CD4+ T cells differentiate into TH1
effector cells under the influence of IL-12 produced by macrophages and dendritic cells.
CD8+ cytotoxic T cells also respond to the IL-12, and they also produce IFN-γ, which may
activate phagocytes taking up debris of killed infected cells. In immunodeficient patients
lacking the IL-12 receptor or the IFN-γ receptor, this cycle of mutual activation cannot
proceed, so they are highly susceptible to infections with intracellular bacteria, such as
atypical mycobacteria.
Phagocytosed bacteria trigger CD8+ T cell responses if bacterial antigens are
transported from phagosomes into the cytosol or if the bacteria escape from phagosomes and
enter the cytoplasm of infected cells. In these cases bacterial antigens can be presented by
MHC-I molecules to cytotoxic T cells. In the cytosol, the bacteria are no longer susceptible to
the microbicidal mechanisms of phagocytes, and for eradication of the infection, the infected
cells have to be killed by CD8+ cytotoxic T cells. Thus, the effectors of cell-mediated
immunity, namely, TH1 cells that activate macrophages and CD8+ cytotoxic T cells, act
cooperatively in defense against intracellular bacteria.
Intracellular bacteria resist killing within phagocytes; therefore, they often persist in
these cells for long periods and cause chronic antigenic stimulation. Chronic activation of
macrophages and T cells may result in the formation of granulomas surrounding the
microbes. This type of inflammatory reaction may serve to localize and prevent spread of the
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microbes, but it is also associated with severe functional impairment caused by tissue necrosis
and fibrosis. Tuberculosis is an example of an infection with an intracellular bacterium in
which immune responses may lead to granuloma formation. In a primary infection with
Mycobacterium tuberculosis, bacteria multiply slowly in the lungs and cause only mild
inflammation. More than 90% of infected patients remain asymptomatic, but bacteria survive
in the lungs, mainly in macrophages and dendritic cells. By 6 to 8 weeks after infection,
mycobacterium-specific TH1 cells and CD8+ T cells have been activated. These T cells
produce IFN-γ, which activates macrophages and enhances their ability to kill phagocytosed
bacteria. Although T cell reaction is adequate to control bacterial spread, M. tuberculosis is
capable of surviving within macrophages because components of its cell wall inhibit the
fusion of phagocytic vacuoles with lysosomes. As a result, infected cells continuously provide
signals for prolonged T cell activation leading to the formation of granulomas. This consists
of a central core of infected macrophages. The core may include multinucleated giant cells,
which are fused macrophages, surrounded by large macrophages often called epithelioid cells.
Granulomas induced by mycobacteria are often associated with central caseous necrosis,
which is caused by lysosomal enzymes and reactive oxygen species from macrophages. The
central core is surrounded by T cells, many of which are TH1 cells. Necrotizing granulomas
and the fibrosis that accompanies granulomatous inflammation are important causes of tissue
injury and clinical disease in tuberculosis.
The TH1- and TH2-derived cytokines are able to determine the outcome of infection
caused by intracellular bacteria. An example of this relationship between the type of T cell
response and disease outcome in humans is leprosy, which is caused by Mycobacterium
leprae. There are two polar forms of leprosy, the lepromatous and tuberculoid forms, although
many patients fall into less clear intermediate groups. In lepromatous leprosy, patients have
high specific antibody titers but weak cell-mediated responses to M. leprae antigens.
Mycobacteria proliferate within macrophages and are detectable in large numbers. The
bacterial growth results in destructive lesions in the skin and underlying tissue. In contrast,
patients with tuberculoid leprosy have strong cell-mediated immunity but low antibody levels.
This type of immunity is reflected in granulomas that form around nerves and induce
peripheral sensory nerve defects and secondary skin lesions but with a paucity of bacteria in
the lesions. One possible reason for the differences in these two forms of leprosy may be that
there are different patterns of T cell differentiation and cytokine production in individuals.
Some studies indicate that patients with the tuberculoid form of the disease produce IFN-γ
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and IL-2 in lesions indicating TH1 cell activation, whereas patients with the lepromatous form
may exhibit TH2 cell-mediated immunity and failure to control bacterial spread.
Intracellular bacteria have developed various strategies to resist elimination by
phagocytes. These include inhibiting phagolysosome fusion (Mycobacterium and Legionella
pneumophila) or escaping into the cytosol (Listeria monocytogenes), thus hiding from the
microbicidal mechanisms of lysosomes, and directly scavenging or inactivating microbicidal
substances (Mycobacterium leprae) such as reactive oxygen species. The outcome of
infection by these organisms often depends on whether the T cell-stimulated anti-microbial
mechanisms of macrophages or bacterial resistance to killing dominate the infection.
Resistance of these bacteria to phagocyte-mediated elimination is also the reason that they
tend to cause chronic infections that may last for years, and are difficult to eradicate.
The immunity to viruses
Viruses are obligatory intracellular pathogens that use components of the nucleic acid
and protein synthetic machinery of the host cells to replicate. Viruses are able to infect
various cell types by using normal cell surface molecules as receptors to enter the cells. Viral
replication interferes with normal cellular protein synthesis and function and may lead to
injury and ultimately death of the infected cell. This result is one type of cytopathic effect of
viruses, and the infection is said to be lytic because the infected cell is lysed. Viruses may also
cause latent infections, in which the virus persists in infected cells, sometimes for the life of
the individual. Innate and adaptive immune responses to viruses are aimed at blocking
infection and eliminating infected cells. The principal mechanisms of innate immunity against
viruses are inhibition of infection by type I interferons (IFN-α and IFN-β) and NK cell mediated killing of infected cells. Infection by many viruses is associated with production of
type I interferons by infected cells. Recognition of viral RNA and DNA by endosomal TLRs
and cytoplasmic RIG-like receptors activates the IRF transcription factors that stimulate
interferon gene transcription. Type I interferons function to inhibit viral replication in both
infected and uninfected cells. Type I interferons prevent viral replication by activating host
genes that destroy viral mRNA and inhibit translation of viral proteins. They also increase the
expression of ligands for NK-cell receptors and activate NK cells to kill virus-infected cells.
Expression of MHC-I molecules is often decreased on virally infected cells as an escape
mechanism from cytotoxic T cells. This enables NK cells to kill the infected cells because the
absence of MHC-I releases NK cells from a normal state of inhibition. During the innate
immune response to a primary viral infection, activation of an NK cell requires intracellular
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signals to come from two or more of the activating receptors. This strategy, in which two
receptors confirm the occurrence of infection, decreases the likelihood that NK cells will
become activated inadvertently in the absence of infection. During the adaptive immune
response to a virus, when pathogen-specific IgG becomes available, NK cells can be activated
by a single Fcγ receptor. When the antibodies bind to the antigen on virus infected cells, the
FcγRIII receptors on the NK cell bind to the Fc regions of the cell-bound IgG. Signals from
FcγRIII activate the NK cell to form a conjugate pair and a synapse with the target cell. By
secreting the contents of its lytic granules onto the surface of the target cell, the NK cell
instructs the virus infected target cell to die by apoptosis. This NK cell-mediated killing of
infected cell is called antibody-dependent cellular cytotoxicity (ADCC).
During cross-presentation, debris of viral infected cells is ingested by APCs and viral
antigens are processed and presented in association with MHC-I molecules to CD8+ T cells.
However, the same APCs also display MHC-II-associated antigens from the virus for
recognition by CD4+ helper T cells. Adaptive immunity against viral infections is mediated by
antibodies, which block virus binding and entry into host cells, and by cytotoxic T cells,
which eliminate the infection by killing infected cells. Antibodies are effective against viruses
only during the extracellular stage of the viral replication. Viruses may be extracellular early
in the course of infection, before they infect host cells, or when they are released from
infected cells. Antiviral antibodies bind to viral envelope or capsid antigens and function
mainly as neutralizing antibodies to prevent virus attachment and entry into host cells. In
addition to neutralization, antibodies can opsonize viral particles and promote their clearance
by phagocytes. Complement activation may also participate in antibody-mediated viral
immunity, mainly by promoting phagocytosis and possibly by direct lysis of viruses with lipid
envelopes. Elimination of viruses that reside within cells is mediated by cytotoxic T cells,
which kill the infected cells. Cytotoxic T cells also produce cytokines such as IFN-γ, which
activates phagocytes and may have some antiviral activity.
Viruses have evolved numerous mechanisms for evading host immunity. One of the
strategies than viruses can alter their antigens and are thus no longer targets of immune
responses. Surface glycoproteins are most commonly affected, which are recognized by
antibodies, but T cell epitopes may also undergo variation. The principal mechanisms of
antigenic variation are point mutations and reassortment of segmented RNA genomes (in
some RNA viruses). Both of these mechanisms are used by influenza virus, a common
seasonal viral pathogen that causes acute infections and has been responsible for several
major pandemics. The two major antigens of the influenza virus are the hemagglutinin (H)
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and neuraminidase (N). Changes in the antigenicity of these major viral surface glycoproteins,
caused by point mutations in the genes, is called antigenic drift. Every 2–3 years a variant
influenza virus arises with mutations that allow it to evade neutralization by the antibodies
present in the population. Antigenic changes in influenza virus that result from reassortment
of the segmented RNA genome are known as antigenic shift. This mechanism results in
major changes in the viral antigens. Antigenic shifts cause global pandemics of severe
disease, often with substantial mortality, because the new antigens are recognized poorly, if at
all, by antibodies and T cells directed against the previous variant. Antigenic shift is due to
reassortment of the segmented RNA genome of the human influenza virus and animal
influenza viruses in an animal host, in which some genes from the animal virus replace genes
in the human virus. Some viruses are able to inhibit MHC-I-mediated presentation of
cytosolic protein antigens. These viruses make a variety of proteins that block different steps
in antigen processing, transport, and presentation. Cells infected by such viruses cannot be
recognized or killed by cytotoxic T cells. NK cells can be activated by infected cells,
especially in the absence of MHC-I molecules; therefore, some viruses produce proteins that
act as ligands for NK cell inhibitory receptors and thus inhibit NK cell activation. Some
viruses produce molecules that inhibit the immune response. Poxviruses encode molecules
that are secreted by infected cells and bind to several cytokines, including IFN-γ, TNF, and
IL-1. The secreted cytokine-binding proteins may function as competitive antagonists of the
cytokines. Epstein- Barr virus produces a protein that is homologous to the cytokine IL-10,
which inhibits activation of macrophages and dendritic cells and may thus suppress cellmediated immunity. Some viruses also can infect and either kill or inactivate
immunocompetent cells. The obvious example is human immunodeficiency virus (HIV),
which survives by infecting and eliminating CD4+ T cells, the major organizers of immune
responses to protein antigens.
The immunopathogenesis of HIV infection
Acquired immune deficiency syndrome (AIDS) caused by HIV is a special example of
immune subversion by a pathogen. HIV is a retrovirus that infects cells of the immune
system, mainly CD4+ T lymphocytes, and causes progressive depletion of these cells. Once
inside the host cell, the virus uses its own reverse transcriptase enzyme to produce DNA from
its RNA genome, the reverse of the usual pattern of transcription, thus retro (backwards). An
infectious HIV particle consists of two RNA strands, as well as reverse transcriptase,
integrase, and protease enzymes within a protein core, surrounded by a lipid envelope derived
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from infected host cells but containing viral proteins. The viral RNA encodes structural
proteins, enzymes, and proteins that regulate transcription of viral genes and the viral life
cycle. HIV infection is a global health problem, because despite a great improvement in
treatment and prevention of the disease during the last years, 1.5 million people died of AIDSrelated causes in 2013 and an estimated 35 million are infected by HIV worldwide. The life
cycle of HIV consists of the following sequential steps: infection of cells, production of viral
DNA and its integration into the host genome, expression of viral genes, and production of
viral particles. HIV infects cells by virtue of its major envelope glycoprotein, called gp120,
which binds to CD4 and to particular chemokine receptors on human cells (mainly CXCR4 on
naive and central memory T cells; and CCR5 on macrophages, dendritic cells and effector
memory T cells). The major cell types that may be infected by HIV are CD4+ T lymphocytes,
macrophages, and dendritic cells. HIV can complete its replication cycle in the host cell to
produce progeny virus, or, like other retroviruses and herpesviruses, establish a latent
infection in which the provirus (viral DNA integrated into the cell genom) is remains
quiescent. The viruses typically enter the body through mucosal epithelia and infect
macrophages, dendritic cells and CCR5-expressing effector memory CD4+ T cells. This is the
start point of the acute phase of HIV infection, which lasts for several weeks and is
characterized by a rapid replication of the virus, primarily in CCR5-expressing CD4+ T cells.
This period is marked by an abundance of virus circulating in the blood (viremia) and a rapid
decline of CCR5-expressing CD4+ T cells. The reason behind this phenomenon is that CCR5expressing CD4+ T cells are killed by viral cytopathic effects (macrophages and dendritic
cells appear more resistant to lysis by replicating virus). Because of the high viral titers during
the acute phase of infection, the risk of viral transmission to uninfected contacts at this time is
especially high. Some people may experience a flu-like illness during this early period of HIV
infection, but some people may not feel sick during this stage. The acute viremia during acute
phase is accompanied by activation of an HIV-specific adaptive immune responses, in which
anti-HIV antibodies are produced and cytotoxic T cells become activated. These responses
reduce the load of virus carried by the infected person and cause a corresponding increase in
the number of circulating CD4+ T cells. When infected persons first exhibit detectable levels
of anti-HIV antibodies in their blood serum, they are said to have undergone seroconversion.
Seroconversion is preceded by a „window” period, which is between the onset of the HIV
infection and the appearance of detectable antibodies to the virus. The second phase of HIV
infection is a latent asymptomatic or silent phase, which is marked by low viremia and
slowly declining CD4+ T-cell numbers, typically over several years. During this time the virus
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continues to actively replicate, but it is kept under controll, principally by HIV-specific CD8+
T cells and antibodies. Infected individuals are often not even aware that they are carrying the
virus, and may therefore unwittingly infect new sex partners. A positive HIV test is often the
only indication of HIV infection during this latent phase. Under strong selective pressure
brought by the antiviral immune response, there is selection for HIV escape mutants that are
no longer detected by adaptive immune cells. This gives rise to many different viral variants
in a single infected person and to even broader variation within the population as a whole.
Development of viral variants leads to a rapid decline in CD4+ T-cell count. Eventually, the
number of CD4+ T cells drops below that required to mount effective immune responses
against other infectious microbes. That transition marks the end of clinical latency, the
beginning of the period of increasing immunodeficiency, and the onset of AIDS. AIDS is
defined as less than 200 CD4+ T cells per microliter in peripheral blood. Patients with AIDS
become susceptible to a range of opportunistic infections and some cancers, and it is from the
effects of these that they die.
HIV can be by transmitted by sexual contact, blood-borne exposure (e.g. blood
transfusion, shared needles), and from mother to child during pregnancy, delivery, or
breastfeeding. HIV infected persons are treated using a combination of medicines. This is
called antiretroviral therapy (ART). ART is not a cure, it does not eliminate the integrated
virus, but it can control the viral replication so that the infected person can live a longer,
healthier life and reduce the risk of transmitting HIV to others. HIV medicines are grouped
into six drug classes according to how they fight HIV. The six drug classes are: nonnucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors,
protease inhibitors, fusion inhibitors, CCR5 antagonists (also called entry inhibitors), and
integrase inhibitors. The development of resistance to ART has been recognized as an
important cause of treatment failure in HIV-infected patients. The high rate of viral
replication, together with the lack of proof reading activity of HIV reverse transcriptase,
accounts for the rapid establishment of extensive genotypic variation, resulting in the
emergence of viral mutants showing resistance to ART. A recent discovery of highly potent,
broadly neutralizing antibodies provides a novel class of potential therapeutic agents.
Current research on these antibodies is exploring two complementary clinical applications.
The first is to design vaccines that will favor the production of this kind of antibodies; the
second is to infuse infected people, or people at risk of exposure to HIV, with the antibodies
in a passive immunization.
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