Immunity is the ability to resist damage from foreign substances such as microorganisms, chemicals and toxins.
The human body has the ability to resist most of all the microorganisms and toxins that continuously interfere with it. The immunity system protects the host from invading pathogens and keeps the self-tissue damage minimized (1). It consists of an interconnected network of cells, proteins and lymphoid organs. Immune response is divided in to 2 categories (2,3). They are,
Acquired immunity / adaptive immunity
Innate immunity is present at birth and provides the immediately active, first line, non- specific protection against an invading pathogen (2). The antigen recognition ability is innate and develops without exposure to the antigen. The innate immune response to a specific pathogen is same in 2 healthy persons and the system responds in the same way for any pathogen (1).
IT consists of physical and chemical as well as immune mechanisms.
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anatomical barriers - physical, mechanical and chemical
phagocytic cells - neutrophils, monocytes
soluble molecules - complement, acute phase proteins, prostaglandins, interferon and histamine
natural killer cells
eosinophil, mast cells
These cells are directly activated by infectious agents, tissue damage or tumours via surface receptors (2). Innate immunity makes body immune to some paralytic viral infections of animals, hog cholera, cattle plague, and distemper (4).
Acquired immunity / Adaptive immunity
If the innate immune system fails to provide effective protection against an invading pathogen, the adaptive immune system gets activated. This mechanism does not develop until after the body is first attacked by an antigen. Often requires some time to develop the immunity. There are 3 characteristic features of adaptive immunity.
It is highly adaptive
It possesses immunological memory. It is the ability to recall previous encounter with an antigen so that subsequent exposure leads to a more rapid response (1).
These characteristic of this response is due to the use of antigen specific receptors on T lymphocytes (T- cell receptor, TCR) and B lymphocytes (surface and secreted antibody) to direct the response (2). Specificity is achieved by multiple rearrangements of DNA in T and B lymphocytes. The new DNA direct to production of proteins with hyper variable regions and creates the specific antigen-binding T-cell receptor and antibody sites. This diversity allows the production, for example, of over 108 different antibodies and 107 distinct TCRs (2). This increases the ability of the immune system to recognize a wider range of antigens. Even though adaptive immunity has benefit of specificity it cannot produce immediate protection on 1st meeting the antigen.
There are 2 categories to adaptive immunity. They are,
Cell mediated immunity
Humoral / antibody mediated immunity
These 2 systems closely interact with each other and with innate immunity.
Cell mediated immunity
It consists of T lymphocytes which produce and release cytokines which affect other cells. Protect against intracellular antigens such as viruses and intracellular bacteria and tumors. When an antigen enters the body it is recognized by antigen presenting cells such as macrophages, dendritic cells and B lymphocytes. Antigen is partially digested and coupled with MHC2 complex. Antigen bound to MHC2 gets associated with T helper (CD4) cells. This activated T helper cells produce interleukin 2 that promote the activation and proliferation of cytotoxic T cells. Some of these remain as memory cells and the rest become effector cytotoxic T cells. Cytotoxic T cells perform cell lysis by inserting Pore-forming proteins perforins and by initiating apoptosis with proteolytic enzymes (1). Cell mediated immunity is responsible for graft rejection and delayed allergic reactions. Cellular immunity constitutes a major defense against infections due to viruses, fungi, and a few bacteria.
The cytokines released by T helper cells also activate NK cells which play a major role in defense against tumours and viruses. So NK cells perform actions in both innate and adaptive immunity.
Humoral / antibody mediated immunity
This immune response is characterized by immunological memory. Humoral immunity is mediated by circulating immunoglobulin antibodies. It is the Î³-globulin fraction of the plasma proteins(3). It protects against extra cellular antigens such as bacteria, toxins and extracellular viruses.
When an antigen enters the body, it is taken up by an antigen presenting cell and partially digested. The products are coupled with MHC2. CD4 T helper cells recognize the antigen, get activated and produce interleukin 4. This causes activation of B lymphocytes cell development and proliferation occurs cells differentiate into plasma cells and memory cells. Plasma cells produce antibodies. Antibodies enhance the innate response by opsonizing foreign particles, neutralizing viruses and toxins, and plays a part in antigen presentation .There are 5 kinds of antibodies (2). They are IgA, IgG, IgM, IgD, and IgE.
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Antibodies can prevent infection in 3 main pathways. They are,
Complement system - chemotaxis, opsonization and cell lysis.
Basophil or mast cell bound antigen antibody complex activate inflammatory response
Infected cell uptake by macrophages
In primary exposure to antigen humoral immunity needs input from T helper cells. But as memory cells are produced in primary exposure, there is no need of involvement of T helper cells on subsequent exposures to the same antigen (1).
Immune impairment is partial or total inability to perform immune response. This can be congenital or acquired. Acquired reasons can be infection, drug therapy, malignancy and aging. The consequences of impairment of the immune system include recurrent infections, autoimmunity and susceptibility to malignancy (1). Humans are repeatedly exposed to various pathogens, including viruses and bacteria. Whether these organisms invade and cause disease is determined by the balance of the pathogenicity of the organism and the integrity of the host defense mechanisms.
AIDS - Acquired immunodeficiency syndrome
The acquired immunodeficiency syndrome (AIDS) was first recognized in 1981, although the earliest documented case has been traced to a blood sample from 1959 (1). In 1986, the first person with AIDs in Sri Lanka was reported. In 2006, 815 persons were diagnosed with the virus over 3500 persons are estimated to be infected with the virus (5).AIDS is caused by the human immunodeficiency virus (HIV-1). The origin of HIV is a non-human primate simian virus which probably passed from chimpanzees to humans via bush hunters (1). AIDS is the second leading cause of death worldwide. AIDS is the final stage of HIV infection. It can take years for a person infected with HIV, even without treatment, to reach this stage. CDC estimates that about 1 million people in the United States are living with HIV or AIDS. About one quarter of these people do not know that they are infected.
HIV - Human Immunodeficiency Virus
HIV is in retrovirus family and lentivirus group (1).Retrovirus is an RNA containing virus that can convert its genetic material in to DNA by means of the enzyme reverse transcriptase which enables it to become integrated into the DNA of its host's cells (6). The virus has two exact copies of single-stranded RNA in its genome.
There are 2 sub types to HIV. They are,
HIV-2 also causes an illness similar to HIV -1 but it is less severe and it is restricted to West Africa.
HIV -1 is further subdivided into 3 groups. They are
But these do not differ clinically in humans. Group N and O are restricted to West Africa (1).
HIV is present in body fluids such as blood, semen, breast milk and saliva. Exposure to contaminated fluid leads to infection. Routs of transmission of the virus are,
Mother to child by transplacentally, perinatally and breast feeding
Contaminated blood, blood products, organ donations
Contaminated needles - intravenous drug misuse, injections, needle stickinjuries
But acquiring infection depends on at least 3 factors. They are,
integrity of the exposed site
the type and volume of body fluid
the viral load (1)
Even though innate immunity is widely considered to be critical in shaping the body's immune response to HIV, this type of response is much more difficult to study. Innate immune responses are only active for about six to seven days following HIV transmission, and so newly HIV-infected individuals would have to be identified very soon after they become infected for researchers to study innate responses (7).
The adaptive immune responses produced following HIV infection have been well studied and are still being fully characterized. HIV targets CD4 T cells, which are required for the induction of high-affinity antibody responses and the formation of long-lived B cell memory. Monocytes, macrophages, follicular dendritic cells and microglial cells in the central nervous system also express the CD4 cell receptor and are permissive to infection (1). CD4 is a specific receptor for HIV.
When HIV enters the body it is transported to lymph nodes to CD4 cells, virus infects CD4 cells by engagement of a glycoprotein in the lipid membrane of HIV, gp120 with CD4 cell receptor (1). DNA copy is transcribed from the RNA genome by the reverse transcriptase (RT) enzyme. Reverse transcription is an error-prone process and multiple mutations arise with replication. This increases the genetic diversity.
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Increased HIV diversity has implications for diagnostic tests, treatments and vaccine development. It may also influence transmission, disease progression, co-receptor usage and emergent resistance patterns.
HIV infection promotes CD4+cell cycle disruption, cell death, and ultimately, CD4+ lymphocyte depletion.
DNA damage is a universal inducer of cell cycle arrest at the G2 phase. HIV-1 also blocks cellular proliferation at the G2 phase (8). This is done by activation of the ATR-initiated DNA damage-signaling pathway by a viral gene product.
A human gene named ATR normally protects people by preventing the replication of cells damaged by radiation or toxic chemicals. The ATR gene's normal job is to detect genetic damage to cells caused by radiation, toxic chemicals and chemotherapy, and to stop the damaged cells from replicating until they can repair themselves. The vpr gene - one of nine genes in the AIDS virus - encodes a conserved 96-amino acid protein (Vpr) that is necessary and sufficient for the HIV-1-induced block of cellular proliferation and exploits this normal repair process to stop vital white blood cells from replicating, thus disabling the immune system. Vpr does that by activating the ATR gene, which is found in white blood cells and all human cells (9).
It has been calculated that each day more than 1010 virions are produced and 109 CD4 cells destroyed. This represents a daily turnover of 30% of the total viral burden and 6-7% of the total body CD4 cells (1).
To convert the findings into a clinically and commercially useful AIDS treatment, scientists must find a drug that interferes with the ATR gene only in white blood cells and without causing serious side effects.
HIV specifically infects the very cells necessary to activate both B-cell and cytotoxic T-cell immune responses. Consequently the virus multiplies and CD4 cell count declines dramatically. The number of CD4+ white blood cells in healthy people is about 1,000 cells per microliter of blood, but drops below 200 cells per microliter in untreated AIDS patients and climbs to 500 to 1,000 cells per microliter in AIDS patients receiving antiretroviral treatment (9).
Virus-specific CD8 cytotoxic T lymphocytes develop rapidly after infection and are crucial in recognizing, binding and lysing infected CD4 cells, thus controlling HIV replication after infection and the subsequent rate of disease progression.
Any decrease in CD4 cell count in the body susceptible to opportunistic infections and oncogenic (describing a substance, organism, or environment that is known to be casual factor in the production of tumour.) virus-related tumors.
Opportunistic infection: denoting a disease that occurs when the patient's immune system is impaired by for example, an infection, another disease or drugs. The infecting organism rarely causes the disease in healthy persons (6).
The predominant opportunist infections seen in HIV disease are intracellular parasites or pathogens susceptible to cell-mediated rather than antibody-mediated immune responses (1).
Another immunologic abnormality caused by HIV infection is abnormal B-lymphocyte activation.
A small percentage of T cells (< 0.01%) enter a post-integration latent phase and represent the main reservoir of HIV (1). they can renew the infection if host defenses fail or HAART is discontinued. Even though there are not enough virus particles in blood to be detected by tests, the virus replication is still going on inside cells.
HIV Infection categorization
HIV infection is categorized into A, B and C, according to the Center for Disease Control (CDC) classification based broadly on the clinical evolution of the immunodeficiency state that leads to the development of the acquired immune deficiency syndrome (AIDS), on average some 8-15 years after infection if untreated (10).
Category A: Asymptomatic
Persistent generalized lymphadenopathy: enlargement of the lymph nodes. This is usually due to viral or bacterial infection, but may be causedby malignancy, autoimmune disease or advance drug reactions (6).
Category B: Symptomatic infection excluding category A
Candidiasis - oropharyngeal, vulvovaginal 1 episode or >1 dermatome)
Oral hairy leukoplakia
Pelvic inflammatory disease (10).
Category C: AIDS-defining illness
People infected with HIV progress to AIDS when their CD4 count falls below 200 or they experience an AIDS-defining complication.
Clinical consequences of HIV related immune dysfunction will depend on at least 3 factors.
Microbial exposure of patient throughout life
Pathology of organisms encountered
Degree of immunosuppression of the host
Acute Primary infection.
Is symptomatic in 70%- 80% patients (1).
Usually occurs 2-6 weeks after exposure
Increased plasma HIV-RNA levels and decreased CD4 count to about 300-400cells / mm3
Diagnosis is made by detecting HIV RNA in serum by immunoblast assay
Clinical features are Fever with rash, Pharyngitis with cervical lymphadenopathy, Night sweats, weight loss, diarrhoea, meningism, Myalgia/arthralgia, Headache and Mucosal ulceration (1, 10).
This is category A of CDC classification
Lasts for a variable period.
There is no evidence of illness in the patient except there may be persistent generalized lymphadenopathy (10).
Mildly symptomatic infection.
This is the category B of CDC classification.
There is some impairment of cellular immunity but which is not AIDS-defining
AIDS defining illness.
This is the CDC classification category C. This is defined by the development of specified opportunistic infections, tumors and presentations as mentioned earlier.
Chronic cryptosporidial Diarrhea
CMV retinitis or colitis
Chronic mucocutaneous herpes simplex
Pulmonary or extra pulmonary tuberculosis
Progressive multifocal Leucoencephalopathy
Extra pulmonary Coccidioidomycosis
Invasive cervical cancer
Primary cerebral lymphoma
As mentioned above the presenting problems are mucocutaneous diseases, gastrointestinal diseases, liver diseases, respiratory diseases, neurological and eye diseases, miscellaneous conditions and HIV related cancers. Patients present with few or more pathologies combined and are harder to manage than in an HIV-negative patient (1).
There's no cure for HIV/AIDS, but a variety of drugs can be used in combination to control the virus. Treatments are aimed to achieve the following goals.
Reduce the viral load
improve the CD4 count to > 200 cells/mL
improve the quantity and quality of life without serious side-effects or lifestyle alteration
reduce transmission (1).
Anti-HIV drugs block the virus in different ways. It is recommended to combine at least three drugs from two different classes to avoid creating strains of HIV that are immune to single drugs. There are more than 20 different drugs in use. The classes of anti-HIV drugs include:
Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
NNRTIs disable a protein needed by HIV to make copies of itself.
Nucleoside reverse transcriptase inhibitors (NRTIs).
NRTIs are faulty versions of building blocks that HIV needs to make copies of itself.
Protease inhibitors (PIs). PIs disable protease, another protein that HIV needs to make copies of itself.
Entry or fusion inhibitors.
These drugs block HIV's entry into CD4 cells
Integrase inhibitors works by disabling integrase, a protein that HIV uses to insert its genetic material into CD4 cells (11).
The most important among new findings is that early initiation of antiretroviral therapy can both improve individual patient outcomes and reduce the risk of HIV transmission to sexual partners by 96% (12).
A report reveals that in 2011, only an estimated 28% of people living with HIV in the United States has suppression of HIV RNA been achieved (12). Such suppression is a marker treatment success and a gauge of the risk of transmission. But this low percentage exposes a challenge shared by many countries affected by HIV.
But many successes have been achieved in HIV care in low- and middle-income countries (LMIC): increased number of HIV-infected individuals receiving antiretroviral treatment (ART), wide decentralization, reduction in morbidity and mortality and accessibility to cheapest drugs (13).
Side effects of ART
Adherence to antiretroviral therapy (ART) has been correlated strongly with HIV viral suppression, reduced rates of resistance, an increase in survival, and improved quality of life.
Nausea, vomiting or diarrhea
Shortness of breath
Bone death, particularly in the hip joints
HAART - highly active antiretroviral therapy
A combination of several antiretroviral drugs, called highly active antiretroviral therapy (HAART), has been very effective in reducing the number of HIV particles in the bloodstream. The principle of combining drugs serves to provide additive antiviral activity with a reduction in the emergence of viral resistance. But the suppression of viral replication is not associated with reconstitution of the immune function.
Highly active retroviral therapy (HAART) with three or more drugs has improved life expectancy to near normal in the majority of patients receiving it, with an 80% reduction of mortality since its introduction. When to start therapy depends on several factors, but mainly the CD4 cell count. Initial HAART is introduced when the CD4 count falls below 350 cells/mm3 or an AIDS-defining illness develops (1).
HAART is not a cure for HIV, but it has been very effective for the past 12 years. People on HAART with suppressed levels of HIV can still transmit the virus to others through sex or by sharing needles. There is good evidence that if the levels of HIV remain suppressed and the CD4 count remains high (above 200 cells / mm3), life can be significantly prolonged and improved.
HIV may become resistant to one combination of HAART, especially in patients who do not take their medications on schedule every day.
Treatment with HAART has complications. HAART is a collection of different medications, each with its own side effects. Some common side effects are:
Collection of fat on the back ("buffalo hump") and abdomen
General sick feeling (malaise)
When used for a long time, these medications increase the risk of heart attack, perhaps by increasing the levels of cholesterol and glucose (sugar) in the blood. Adherence to ART can be influenced by characteristics of the patient, the regimen, the clinical setting, and the provider/patient relationship (14).
A vaccine for HIV
During the 30 years since the discovery of HIV as the cause of AIDS, efforts to develop a vaccine have faced immense challenges. Increased the extensive subtype and sequence diversity of HIV has implications for diagnostic tests, treatments and vaccine development. And also there is the inability of a vaccine to generate protection across different viral strains. Yet with these complications, the experiments for developing a vaccine are carried on.
So far only three candidate HIV vaccines have completed clinical efficacy trials. The first of these was a recombinant protein of the HIV-1 envelope (AIDSVAX). The second was a non-replicating adenovirus serotype 5 vector expressing an internal HIV-1 protein. The third vaccine was a combination of a canary pox vector expressing HIV-1 immunogens (ALVAC) and the previously studied recombinant HIV-1 envelope protein (AIDSVAX) (15).
It is recommended for all pregnant women to be tested for HIV routinely. If they turn out to be HIV positive the treatments include,
Ritonavir-boosted PI (e.g. lopinavir) with zidovudine and lamivudine from 20 weeks
ZDV i.v. infusion at onset of labour (1).
Mother should avoid breast feeding and strictly formula feed the infants.
HIV in children
Over 2 million children have HIV infection all over the world (16).and the major route of transmission is vertical transmission. This is usually intrapartum, intrauterine or via breast feeding. Although a large number of infants are born to HIV positive mothers, only a few get infection due to vertical transmission prevention methods.
Vertical transmission prevention methods
Avoiding breast feeding
Use of antenatal, perinatal and postnatal antiretroviral drugs to prevent viral replication
Avoidance of labour and contact with birth canal by elective caesarean section delivery (16).
Diagnosis of HIV infected children
In children over 18 months HIV infection is diagnosed by detecting antibodies to the virus. The most sensitive test for HIV infected infants is by detecting the viral genome by PCR (polymerase chain reaction). Other less sensitive tests in infants include HIV culture, p24 antigen, elevated immunoglobulin, low CD4 T helper cell count for age and clinical features of infection (1, 16).
Treatments for HIV infected children
Prophylaxis against primary pneumocystis pneumonia (PCP) with co-trimoxazole is prescribed for HIV infected infants. They are immunized according to the normal immunization schedule. Infants born to infected mothers are at increased risk of exposure to TB, but BCG should be given only after confirming the infant is not HIV infected since it is a live mycobacterial vaccine. So BCG should not be given to immunosuppressed infants. A child who has symptomatic HIV disease is likely to have reduced CD4 count for age and a high viral load. Asymptomatic or mildly symptomatic children require regular monitoring of viral load and CD4 count. As with HIV infected adults, combination anti-retroviral therapy is most effective children. There are 3 families of antiretroviral therapy used for children.
As vaccine development for HIV is slow alternative measures to prevent HIV should be taken.
Prevention of sexual transmission
Sex education to school children
HIV awareness programs to public
Easily accessible/discreet testing centers
Safe sex practices
Targeting safe sex methods to high-risk groups
Effective treatment for HIV infected people
Post-sexual exposure prophylaxis
Pre exposure prophylaxis
Prevention of occupational transmission
Education/training: universal precautions, avoiding needle stick injuries
Prevention of perinatal transmission
Means to reduce vertical transmission from mother to child
Family planning for HIV seropositive
Male Circumcision is effective in reducing HIV infection rates in men without increasing high-risk behavior.
The use of antiretroviral agents by HIV-uninfected persons before potential sexual exposure to HIV-infected partners, known as pre-exposure prophylaxis, is a new approach to HIV prevention (17).
Post exposure prophylaxis (any means to prevent disease) is recommended if risk of infection is significant after a careful risk assessment, in occupational and non- occupational settings. First dose should be given as soon as possible (within 6-8 hours).4 weeks of therapy is recommended but only half of them complete it due to presentation of side effects.
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U of Utah Biologist Finds HIV Gene Makes a Human Gene Turn Bad
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