SECONDARY

IMMUNODEFICENCY
 ON
•Immunodeficiency disorders result in partial or full impairment of the immune system, leaving the patient
unable to effectively resolve infections or disease.
•Immunodeficiency disorders can either be primary or secondary in nature. There are over 300 forms of primary
immunodeficiency and, although rare, the condition can be life threatening.  
•Secondary immunodeficiencies are the result of disease or other environmental factors weakening the immune
system.
•Although affecting fewer patients than other classes of immune illness, immunodeficiency patients may require
expensive definitive therapy (e.g. bone marrow transplant), or may remain lifelong patients with complex care
needs, and the cost-burden on the NHS is significant.
•Immunological research provides hope of improved curative therapies through the development of new
technologies. Continued and increased investment is critical to ensure these potential advances are realised. 
• Primary immunodeficiencies are the result of genetic defects
• Secondary immunodeficiencies are caused by environmental
factors, such as HIV/AIDS or malnutrition
 HYPOGAMMOGLOBULINEMA
 A condition that shows genetic predisposition symptoms include recurrent infection,
 And the condition typically manifests in young adults who have very low but
detectable levels of total immunoglobulin with normal T-cell numbers and function.
 However, some cases do involve T-cell defects, which may grow more severe as the
disease progresses.
 The disease is generally treated by immunoglobulin therapy
 Unlike the similar primary deficiencies , there is no evidence for genetic
transmission of this disease.
 Mothers with acquired hypogammaglobulinemia deliver normal infants.
 However, at birth these infants will be defi cient in circulating
immunoglobulin due to the lack of IgG in maternal circulation that can be
passively transferred to the infant
 Humoral immunological defects are frequent and important causes of
hypogammaglobulinemia, leading to recurrent infections, autoimmunity,
allergies, and neoplasias.
 AGENT INDUCED

IMMUNODEFICENCY
• Results from exposure to any of a number of environmental agents that induce an
immunosuppressed state.
• These could be :
1. Immunesupressive drugs
2. Corticosteroids
3. Cytotoxic drugs
4. Radiation treatment given to treat various forms of cancer.
5. Accidental radiation exposure.
•Frequently damage rapidly dividing cells in the body, including those of
the immune system, inducing a state of temporary immunodefi ciency as
an unwanted consequence
•The mechanism of action of these immunosuppressive agents varies, as do
the defects in immune function, although T cells are a common target
•Th e very young and elderly suff er from impairments to immune function
not typically seen during the remainder of the life span.
• Neonates, and especially premature babies, can be very susceptible to
infection, with degree of prematurity linked to the degree of immune
dysfunction.
•Although all the basic immune components are in place in full-term,
healthy newborns, the complete range of innate and adaptiveimmune
• Along with presence of passive maternal antibody for about the first 6 months of
life, this is part of the reason for a gradual vaccination program against the
common childhood infectious diseases that peak around 1 year of age
• In later life, individuals again experience an increasing risk of infection, especially
by bacteria and viruses, as well as more malignancies.
 ACQUIRED IMMUNODEFICIENCY
• The single most common cause of acquired immunodeficiency is severe malnutrition,
aff ecting both innate and adaptive immunity.
• Hypoproteinemia are associated with depression in T-cell numbers and function,
although deleterious B cell eff ects may take longer to appear.
• Th e reason for this is unclear, although some evidence suggests a bias toward anti-
inflammatory immune pathways (e.g., IL-10 and TREG cells) when protein is scarce.
• In addition to protein, an insuffi ciency in micronutrients, such as zinc and ascorbic
acid, likely contributes to the general immunodefi ciency and increased susceptibility
to opportunistic infection that occurs with malnutrition.
• Th is can be further complicated by stress and infection, both of which may contribute
to diarrhea, further reducing nutrient absorption in the gut.
• Deficiency in vitamin D, required for calcium uptake and bone health,
has also been linked to an inhibition in the ability of macrophages to act
against intracellular pathogens, such as M.tuberculosis, endemic in many
regions of the world where people are at greatest risk of malnutrition.
 THE RETROVIRUS HIV -1 IS THE
CAUSATIVE AGENT OF AIDS
• The causative agent of AIDS , now known as HIV-1, was discovered by Robert
Gallo and Mary Land.
• About 2 years later the infectious agent was found to be Retroviruse.
• Retrovirus carry genetic material in the form of RNA.
• When the virus enter the cell RNA is reverse transcribed in presence of enzyme
Reverse transcriptase.
• Viral DNA called provirus
• Pro virus integrated into the cell and is replicated along with cell DNA.
• When the provirus is expressed to new virion,the cell lysis
• Alternatively the pro-virus may remain latent in the cell until some regulating signal
start expression process.
• The discovery of a retrovirus as the cause of HIV was novel, since at the time only
one other human retrovirus, human T-cell lymphotropic virus I (HTLV-I), had been
identifi ed.
• Although comparisons of their genomic sequences revealed that HIV-1 is not a close
relative of HTLV-I, similarities in overall characteristics led to use of the name
HTLV-III for the AIDS virus in early reports.
• About 5 years aft er the discovery of HIV-1, a close retroviral cousin, HIV-2, was
isolated from some AIDS suff erers in Africa.
• Unlike HIV-1, its prevalence is mostly limited to areas of Western Africa, and disease
progresses much more slowly, if at all.
• Most of these individuals experience a nearly normal lifespan.
• There is some hope that scientists can gain a better understanding of HIV-1 from the
study of the more benign cohabitation of HIV-2 and its human host.
• Viruses related to HIV-1 have been found in nonhuman primates, and some of these
are believed to be the original source of HIV-1 and -2 in humans.
• These viruses, variants of simian immunodeficiency virus (SIV), can cause
immunodeficiency disease in certain infected monkeys.
• Typically, SIV strains cause no disease in their natural hosts but produce
immunodeficiency similar to AIDS when injected into another species.
• HIV-1 is believed to have evolved from a strain of SIV that jumped the species
barrier from African chimpanzees to humans, although HIV-2 is thought to have
arisen from a separate but similar transfer from SIVinfected sooty mangabeys.
• Both of these events are believed to have occurred some time during the twentieth
century, making this a relatively new pathogen for the human population.
• A number of other animal retroviruses more or less similar to HIV-1 have been
reported.
• These include the feline immunodefi ciency virus and bovine immunodefi ciency
virus (FIV and BIV, respectively) and the mouse leukemia virus.
• Study of these animal viruses has yielded information concerning the general
nature of retrovirus action and pathways to the induction of immunodefi ciency.
• Because HIV does not replicate in typical laboratory animals, model systems to
study it are few.
• Only the chimpanzee supports infection with HIV-1 at a level suffi cient to be
useful in vaccine trials, but infected chimpanzees rarely develop AIDS, which
limits the value of this model in the study of viral pathogenesis.
• In addition, the number of chimpanzees available for such studies is low, and both
the expense and the ethical issues
 SPREAD OF HIV-1 AND PRECAUTIONS
• Epidemiological data indicate that the most common means of transmission
include vaginal and anal intercourse,
• Receipt of infected blood or blood products.
• Passage from HIV infected mothers to their infants.
• Before routine tests for HIV-1 were in place, patients who received blood
transfusions and hemophiliacs who received blood products were at risk for
HIV-1 infection.
• Exposure to infected blood accounts for the high incidence of AIDS among
intravenous drug users, who oft en share hypodermic needles.
• Infants born to mothers who are infected with HIV-1 are at high risk of
infection; without prophylaxis, over 25% of these newborns may become
• However, elective Cesarean section delivery and antiretroviral treatment
programs for HIV pregnant women and their newborns are making a real dent in
these numbers .
• In the worldwide epidemic, it is estimated that approximately 75% of the cases
of HIV transmission are attributable to sexual contact.
• The presence of other sexually transmitted diseases (STDs) increases the
likelihood of transmission.
• The open lesions and activated inflammatory cells (some of which may express
receptors for HIV) associated with STDs favor the transfer and attachment of
the virus during intercourse.
• Estimates of transmission rates per exposure vary widely and depend on many
factors, such as the presence of STDs and number of virions.
•
• However, male-to-female transfer between discordant couples during vaginal
intercourse is approximately twice as risky to the female as to the male
• Based solely on anatomical considerations, and receptive partners in anal
intercourse are even more at risk.
• Data from studies in India and in Africa indicate that men who are circumcised
are at signifi cantly lower risk of acquiring HIV-1 via sexual contact, possibly
because foreskin provides a source of cells that can become infected or harbor
the virus.
• However, this did not work in reverse: circumcised males were equally likely to
transmit HIV-1 to their sexual partners.
• No similarly protective effect of circumcision was seen for other STDs,
including herpes simplex type 2, syphilis, or gonorrhea.
• Identifying the initial events that take place during HIV transmission is logistically
and ethically challenging,
• As we know that immediate antiviral treatment signifi cantly diminishes the odds
of infection.
• Nonetheless, hypotheses concerning the most likely sequence of events have been
pieced together based on observations in humans and animals, including in vitro
studies using explanted human tissue and in vivo studies in macaques, a nonhuman
primate.
• Based on these observations, we believe that free virus and virus-infected cells,
which can both be found in vaginal secretions and semen, contribute to infection.
• The female genital tract is a relatively robust barrier to most infectious agents
(with the adaptive immune response taking over from there), emerging evidence
based on viral sequence analysis suggests that a single HIV-1 virion may be
responsible for all or most of the systemic infection in many male-to-female
transfers.
• Because transmission of HIV-1 infection requires direct contact with infected
blood, milk, semen, or vaginal fluid.
• Preventive measures can be taken to block these events. Scientific researchers and
medical professionals who take reasonable precautions, which include avoiding
exposure of broken skin or mucosal membranes with fl uids from their patients,
signifi cantly decrease their chances of becoming infected.
• When exposure does occur, rapid administration of anti-HIV treatment can often
prevent systemic infection.
• The use of condoms when having sex with individuals of unknown infection
status also significantly reduces chances of infection.
• One factor contributing to the spread of HIV is the long period after infection
during which no clinical signs may appear but during which the infected
individual may infect others.
• Thus, universal use of precautionary measures is important whenever infection
status is uncertain
STRUCTURE OF HIV
 THE STRUCTURE OF HIV-1

• HIV-1 carries three structural genes (gag, pol, and env) and six regulatory or
accessory genes (tat, rev, nef, vif, vpr, and vpu).
• The structural genes and the proteins they encode were the first to be sequenced
and meticulously characterized.
• The gag gene encodes several proteins, including the capsid and matrix, which
enclose the viral genome and associated proteins.
• The pol gene codes for the three main enzymes (in addition to those supplied by
the host cell) that are required for the viral life cycle: protease, integrase, and
reverse transcriptase.
• As we will see shortly, these uniquely viral enzymes are some of the main
targets for therapeutic intervention.
• The final structural gene, env, is the source of the surface proteins gp120 and
gp41, involved in attachment of the virus to the CD4 viral receptor and its
coreceptor, either CXCR4 or CCR5.
• The regulatory genes expressed by HIV-1, which took longer to characterize,
encode functions such as modulating CD4 and class I MHC expression,
inactivating host proteins that interfere with viral transcription, and facilitating
intracellular viral transport.
 LIFE CYCLE OF HIV -1
• The life cycle of HIV-1 from in vitro studies, where cultured human T cells have
been used to map out virus attachment and post-attachment intracellular events.
• HIV-1 infects cells that carry the CD4 antigen on their surface; in addition to
Tcells, these can include monocytes and macrophages, as well as other cells
expressing CD4.
• This preference for CD4 cellsis due to a high-affi nity interaction between gp120
and the CD4 molecule on the host cell.
• However, this interaction alone is not suffi cient for viral entry and productive
infection.expression of another cell-surface molecule, called a coreceptor, is
required for HIV-1 access to the cell.
• Each of the two known coreceptors for HIV-1, CCR5 and CXCR4, belongs to a
separate class of molecule known as a chemokine receptor.
•The role of chemokine receptors in the body is to bind their natural ligands,
chemokines, which are chemotactic messengers driving the movement of
leukocytes .
•The infection of a T cell is assisted by the CXCR4 coreceptor, while the
analogous CCR5 seems to be the preferred coreceptor for viral entry into
monocytes and macro-phages, and is now a target for antiviral intervention.
•After HIV-1 has entered a cell, the RNA genome of the virus is reverse-
transcribed and a cDNA copy integrates into the host genome.
•The integrated provirus is transcribed, and the various viral RNA messages
are spliced and translated into proteins that, along with a complete new copy
of the RNA genome, are used to form new viral particles .
• These initial viral proteins are cleaved by the virally encoded protease into
• Virus expression leads to newly formed virions that bud from the surface of
the infected cell, often causing cell lysis .
• However, HIV-1 can also become latent, or remain unexpressed, for long
periods of time in an infected cell.
• This period of dormancy makes the task of finding these latently infected
cells especially diffi cult for the immune response to HIV-1
• Latent infection is believed to aid in the establishment of HIV reservoirs, or
safe havens, where both drug therapy and antiviral immunity can have little
impact.
• Studies of the viral envelope protein gp120 identified a region called the V3
loop, which plays a role in the choice of receptors used by the virus.
• It is clear from these studies that a single amino acid difference in this region
of gp120 may be sufficient to determine which receptor is used.
• Moreover, a mutation in the CCR5 gene that occurs with varying frequency, imparts
nearly total resistance to infection with the strains of HIV-1 that are most commonly
encountered in sexual exposure.
• Individuals who are homozygous for this mutation express no CCR5 on the surface
of their cells, making them impervious to viral strains that require this coreceptor.
• The discovery that CXCR4 and CCR5 serve as coreceptors for HIV-1 on T cells and
macrophages, respectively, explained why some strains of HIV-1 preferentially
infect T cells (T-tropic strains), whereas others prefer macrophages (M-tropic
strains). T-tropic strains use the CXCR4 coreceptor, whereas M-tropic strains use
CCR5
• This also helped to explain some observed roles of chemokines in virus replication.
• It was known from in vitro studies that certain chemokines, such as RANTES,
had a negative effect on virus replication.
• CCR5 and CXCR4 cannot bind simultaneously to HIV-1 and to their natural
chemokine ligands.
• Competition for the receptor between the virus and the natural chemokine ligand
can thus block viral entry into the host cell.
 GRADUAL
IMPAIRMENT OF IMMUNE FUNCTION
• Isolation of HIV-1 and its growth in culture allowed purification of viral proteins
and the development of tests for infection with the virus.
• The most commonly used test is an ELISA to detect the presence of antibodies
directed against proteins of HIV-1, especially the gag p24 protein, one of the most
immunogenic of the HIV proteins.
• These antibodies generally appear in the serum of infected individuals within 6 to
12 weeks after exposure, but can take up to 6 months to appear.
• When antibodies appear in the blood, the individual is said to have seroconverted
or to be seropositive for HIV-1.
• Positive p24 ELISA results are then confi rmed using the more specific Western
blot technique, which detects the presence of antibodies against several HIV-1
proteins.
• Although the precise course of HIV-1 infection and disease onset varies
considerably in different patients,
• PROGRESSION OF AIDS
• First, there is the acute, or primary, stage of infection. This is the period
immediately after infection.
• Where there are often no detectable anti-HIV-1 antibodies.
• Estimates vary, but some reports fi nd that more than half of the individuals
undergoing primary infection experience fl u-like symptoms, including fever,
lymphadenopathy , and malaise approximately 2 to 4 weeks after exposure.
• During this acute phase, HIV-1 infection is spreading and the viral load in the
blood as well as in other body fl uids can be quite high, elevating the risk of
transfer to others
• This stage is followed by an asymptomatic period during which there is a gradual
decline in CD4+T cells .
• Although the infected individual normally has no clinical signs of disease at this
stage, viral replication continues, CD4 cell levels gradually fall, and viral load in the
circulation can be measured by PCR assays for viral RNA.
• These measurements of viral load have assumed a major role in the determination
of the patient’s status and prognosis.
• Even when the level of virus in the circulation is stable, large amounts of virus are
produced in infected CD4 T cells; as many as 10^9 virions are released every day
and continually infect and destroy additional host T cells.
• Low levels of virus in this period correlate with a longer asymptomatic period and
opportunistic pathogen-free window.
•Without treatment, most HIV-1 infected patients eventually progress to AIDS, where
opportunistic infection is the hallmark
•Diagnosis of AIDS occurs only once four criteria have been met:
1.Evidence of infection with HIV-1 (presence of antibodies or viral RNA in blood)
2.Greatly diminished numbers of CD4 T cells
3.Impaired or absent delayed-type hypersensitivity reactions,
4.The occurrence of opportunistic infections
•
The first overt indication of AIDS is often opportunistic infection with the
.

fungus
Candida albicans, which causes the appearance of sores in the mouth (thrush) .
• In women, a vulvovaginal yeast infection that does not respond to treatment.
•A persistent hacking cough caused by P. carinii infection of the lungs is another
early indicator.
•A rise in the level of circulating HIV-1 in the plasma (viremia) and a
concomitant drop in the number of CD4T cells generally precedes this first
appearance of symptoms.
•Late-stage AIDS patients generally succumb to tuberculosis, pneumonia, severe
wasting diarrhea, or various malignancies.
•Without treatment, the time between acquisition of the virus and death from the
immunodeficiency averages 9 to 11 years.
THERAPEUTIC AGENTS INHIBIT
RETROVIRUS
REPLICATION
• Development of a vaccine to prevent the spread of AIDS is the highest priority
for immunologists.
• There are several strategies for the development of effective antiviral drugs that
take advantage of the life cycle of HIV.
• The key to success for such therapies is that they must bespecific for HIV-1 and
interfere minimally with normal cell processes.
• These anti retroviral drugs are classified into six classes:
• (1) nucleoside-analog reverse transcriptase inhibitors (NNRTIs)
• (2) non–nucleoside reverse transcriptase inhibitors (NNRTIs)
• (3) integrase inhibitors
• (4) protease inhibitors (PIs)
• (5) fusion inhibitors
• (6) coreceptor antagonists
THANK YOU