ImmunologyImmunology

1-1- decrease numbers of helper T ( CD4 positive ) decrease numbers of helper T ( CD4 positive ) lymphocytes lymphocytes

( leading to a decreased T- helper / T-suppressor ratio & to an ( leading to a decreased T- helper / T-suppressor ratio & to an absolute lymphppenia. absolute lymphppenia.

2- hypergammaglobulinaemia ( polyclonal rise in IgG 2- hypergammaglobulinaemia ( polyclonal rise in IgG

3- Impaired response to recall antigens on skin testing ( i.e. 3- Impaired response to recall antigens on skin testing ( i.e. impaired delayed type hypersensitivity “ DTH “impaired delayed type hypersensitivity “ DTH “

T4

T8

NK

B

M

T4

..…

....

..

Mixed lymphocyte reaction Response to soluble antigen

Lymphokine production

Specific cytotoxicity

NK activity

Polyclonal activity

Specific Ig production

Parasite killing

chemotaxis

T-helper test

RNA

Reversetranscriptase

T4 receptor

DNA

RNA

RNA

Diagrammatic representation of retrovirus replication.

5’ 3’tat

////

Trs/art

////

gag

pol

sorior

env

(P55)(P66) (gp 160)

gp 120

gp41p51p15

p24p17

o o gp 120 ( major envelope glycoproteingp 41 ( transmembrane glycoprotein)RNAP24 ( major core protein )

Schematic representation of genome of HIV

Two clinical findings of HIV infection , plus two Two clinical findings of HIV infection , plus two laboratory abnormalities suggestive of it laboratory abnormalities suggestive of it

Clinical findings: Lab. Clinical findings: Lab. abnormalitiesabnormalities

- Fatigue - Decrease T helper - Fatigue - Decrease T helper cell cell

- Night sweats count - Night sweats count - Lymphadinopathy - Increase serum - Lymphadinopathy - Increase serum > 3 months globulins> 3 months globulins- Weight loss - Anergy - Weight loss - Anergy 10% total body w. loss - Anemia 10% total body w. loss - Anemia - Fever > 3 months - Fever > 3 months - Diarrhea - Diarrhea

Persistent generalized lymphadinopathy Persistent generalized lymphadinopathy ( PGA ) ( PGA )

1- lymphadinopathy of at least three 1- lymphadinopathy of at least three months duration involving two or extra months duration involving two or extra inguinal sitesinguinal sites

2- absence of any current illness or drug 2- absence of any current illness or drug use known to cause lymphadenopathy use known to cause lymphadenopathy

3- presence of reactive hyperplasia in a 3- presence of reactive hyperplasia in a lymph if biopsy is performed lymph if biopsy is performed

CDC classification of HIV CDC classification of HIV diseasedisease

Group I Group I

Acute infection Acute infection

Group IIGroup II

Asymptomatic infection Asymptomatic infection

Group IIIGroup III

progressive generalized lymphadenopathyprogressive generalized lymphadenopathy

Group IV Group IV

Other diseases : Other diseases : a- Constitutional diseasea- Constitutional disease b- Neurological disease b- Neurological disease c- Secondary infectious diseasec- Secondary infectious disease i- Specified secondary infectious i- Specified secondary infectious

diseases listed in the CDC diseases listed in the CDC Surveillance definition for AIDS Surveillance definition for AIDS

ii- Other specified secondary ii- Other specified secondary infectious disease. infectious disease.

d- Secondary cancersd- Secondary cancers e- Other conditions e- Other conditions

StageStage

HIVHIV

Ab/AgAb/Ag

IsolatioIsolationn

ChroniChronicc

LymphLymph- -

adenoadenopathypathy

T- T- helperhelper

Cell/Cell/mmmm

DTHDTH ThrusThrushh

O.IO.I

WR0WR0 __ __ >400>400 NormalNormal __ __

WR1WR1 ++ __ >400>400 NormalNormal __ __

WR2WR2 ++ +/-+/- >400>400 NormalNormal __ __

WR3WR3 ++ +/-+/- <400<400 NormalNormal __ __

WR4WR4 ++ +/-+/- <400<400 partialpartial __ __

WR5WR5 ++ +/-+/- <400<400 Anergy/+Anergy/+ ++ __

WR6WR6 ++ +/-+/- <400<400 Anergy/Anergy/partialpartial +/-+/- ++

Oral cavity problems in HIV Oral cavity problems in HIV disease disease

Oral Thrush Oral Thrush

Hairy leukoplakia Hairy leukoplakia

Kaposi’s sarcoma Kaposi’s sarcoma

Gingivitis Gingivitis

Aphthous ulcerationAphthous ulceration

Dental abscess Dental abscess

Intra oral warts Intra oral warts

Skin diseaseSkin disease

1- Seborrheic dermatitis 1- Seborrheic dermatitis 2- Papuloprritic eruptions/ folliculitis2- Papuloprritic eruptions/ folliculitis3- Shingles 3- Shingles 4- Herpes simplex 4- Herpes simplex 5- Xeroderma ( dry skin )5- Xeroderma ( dry skin )6- Molluscum contagiosum6- Molluscum contagiosum7- Tineas (fungal skin and nail eruptions) 7- Tineas (fungal skin and nail eruptions)

ENT problemsENT problems

1.1. Catarrh/postnasal drip Catarrh/postnasal drip

2.2. Sinusitis Sinusitis

3.3. Otitis mediaOtitis media

4.4. Serous otitis media Serous otitis media

5.5. Otitis external Otitis external

6.6. Nerve deafnessNerve deafness

Gastrointestinal disease Gastrointestinal disease

1) Diarrhea 1) Diarrhea

1.1. cryptosporidium cryptosporidium

2.2. Cytomegalovirus Cytomegalovirus

3.3. A typical mycobacteriaA typical mycobacteria

4.4. GiardiasisGiardiasis

5.5. SalmonellaSalmonella

6.6. Campylobacter Campylobacter

2) Oesophagitis2) Oesophagitis

3) Anal herpes3) Anal herpes

4) Kaposi’s sarcoma of the 4) Kaposi’s sarcoma of the gastrointestinal tract gastrointestinal tract

Paediatric HIV diseasePaediatric HIV diseaseHIV infection for infants & HIV infection for infants & children under 15 months children under 15 months

1- Virus in blood or tissue 1- Virus in blood or tissue

2- HIV antibody plus evidence of both 2- HIV antibody plus evidence of both cellular & humeral immune deficiency cellular & humeral immune deficiency plus one or more categories in class P2 plus one or more categories in class P2

3- Symptoms & sign meeting the CDC 3- Symptoms & sign meeting the CDC case definition for AIDS case definition for AIDS

Precautions in the dental Precautions in the dental surgerysurgery

- Gloves should always be used when touching blood , saliva - Gloves should always be used when touching blood , saliva , mucous membranes. They should be changed between , mucous membranes. They should be changed between patients & hands should be washed. patients & hands should be washed.

- Surgical masks & protective eyewear should be worn if - Surgical masks & protective eyewear should be worn if blood or saliva could be spattered .blood or saliva could be spattered .

- Instruments which come into contact with oral tissue - Instruments which come into contact with oral tissue should be sterilized after use . Debris should be should be sterilized after use . Debris should be removed by scrubbing with soap & water before removed by scrubbing with soap & water before sterilized . Instruments should be sterilized by sterilized . Instruments should be sterilized by autoclaving for three minutes at 134C minimum. Dry autoclaving for three minutes at 134C minimum. Dry takes longer ( two hours at 150 C – 160 C . Heat takes longer ( two hours at 150 C – 160 C . Heat sensitive instruments may sterilized using sensitive instruments may sterilized using glutaraldehyde glutaraldehyde

- Disposable gowns or washable work overalls or shirts - Disposable gowns or washable work overalls or shirts should be worn . Gowns & work clothing should be should be worn . Gowns & work clothing should be changed daily or if they soiled with blood changed daily or if they soiled with blood

- Surface should be decontaminated by wiping down with - Surface should be decontaminated by wiping down with sodium hypochlorite or an iodophor. Surface difficult to sodium hypochlorite or an iodophor. Surface difficult to disinfect should be isolated with an impervious cover disinfect should be isolated with an impervious cover as plastic .as plastic .

- Droplet & aerosol production should be avoided where - Droplet & aerosol production should be avoided where posible by use of rubber dams and high speed posible by use of rubber dams and high speed evacuation evacuation

- Great care should be taken with hypodermic needles & - Great care should be taken with hypodermic needles & sharps containers are available for use with dental sharps containers are available for use with dental syringes which enable the needle to be unscrewed syringes which enable the needle to be unscrewed from the syringe without resheathing from the syringe without resheathing

Full definition of AIDSFull definition of AIDS

A case of AIDS is defined As:A case of AIDS is defined As:

An illness characterized by An illness characterized by one ore more of the following ‘ one ore more of the following ‘ indicator ‘ diseases, depending indicator ‘ diseases, depending on the status of laboratory on the status of laboratory evidence for HIV infection evidence for HIV infection

- Without laboratory evidence regarding HIV Without laboratory evidence regarding HIV infection:infection:

- Pneumocystis carinii pneumoniaPneumocystis carinii pneumonia- Toxoplasmosis of the brain in patient > month of Toxoplasmosis of the brain in patient > month of

ageage- Cryptosporidiosis with diarrhoea persisting for> Cryptosporidiosis with diarrhoea persisting for>

1month1month- Extrapulmonary creptococcosis Extrapulmonary creptococcosis - Mycobacterium avium complex or M. kansasii Mycobacterium avium complex or M. kansasii

disease at a site other than lungs or lymph nodesdisease at a site other than lungs or lymph nodes- Cytomegalovirus infection of an internal organ Cytomegalovirus infection of an internal organ

other than liver in a patient > 1 month of age other than liver in a patient > 1 month of age

- Herpes simplex virus infection causing a Herpes simplex virus infection causing a mucocutanneous ulcer that persist for mucocutanneous ulcer that persist for more than 1 month , or bronchitis , more than 1 month , or bronchitis , pneumonitis, or oesophagitis for any pneumonitis, or oesophagitis for any duration in a patient > 1 month of age duration in a patient > 1 month of age

- Progressive multifocal Progressive multifocal leucoencephalopathyleucoencephalopathy

- Primary lymphoma of the brain in patient < Primary lymphoma of the brain in patient < 60 years of age 60 years of age

- Kaposi’s sarcoma in a patient < 60 years of Kaposi’s sarcoma in a patient < 60 years of age age

- PLH/ LIP complex ( pulmonary lymphoid PLH/ LIP complex ( pulmonary lymphoid hyperplasia & /or lymphoid interstitial hyperplasia & /or lymphoid interstitial pneumonia ) in a child < 13 years of age pneumonia ) in a child < 13 years of age

With laboratory evidence for With laboratory evidence for HIV infectionHIV infection

Disease diagnosed definitively Disease diagnosed definitively - Isosporriasis with diarrhea persisting > 1 month Isosporriasis with diarrhea persisting > 1 month - Extrapulmonary or disseminated histoplasmosis Extrapulmonary or disseminated histoplasmosis - Extrapulmonary or disseminated Extrapulmonary or disseminated

coccidioidomycosis coccidioidomycosis - Extrapulmonary or disseminated tuberculosis Extrapulmonary or disseminated tuberculosis - Any noncutaneous extrapulmonary or Any noncutaneous extrapulmonary or

disseminated mycobacterial infection other than disseminated mycobacterial infection other than TB or leprosyTB or leprosy

- Recurrent non typhoid Salmonella - Recurrent non typhoid Salmonella septicaemiasepticaemia

- kaposi’s sacroma at any age kaposi’s sacroma at any age - Primary lymphoma of the brain at any Primary lymphoma of the brain at any

age age - Other non-Hodgkin’s lymphoma of B- cell Other non-Hodgkin’s lymphoma of B- cell

immunologic phenotype immunologic phenotype - HIV encephalopathy ( AIDS demential HIV encephalopathy ( AIDS demential

complex complex - HIV wasting syndrome HIV wasting syndrome

Diseases diagnosed Diseases diagnosed presumptively presumptively

- Pneumocystis carinii pneumonia Pneumocystis carinii pneumonia - Toxoplasmosis of the brain in patient > 1 Toxoplasmosis of the brain in patient > 1

month of age month of age - Oesophageal candidiasis Oesophageal candidiasis - Extrapulmonary or disseminated Extrapulmonary or disseminated

mycobacterial infectionmycobacterial infection- Kaposi’s sacromaKaposi’s sacroma- Lymphoid interstatial pneumonitis( LIP/PLH Lymphoid interstatial pneumonitis( LIP/PLH

complex ) in a child < 13 years of age complex ) in a child < 13 years of age

With evidence against HIV With evidence against HIV infection infection

Pneumocystis carinii pneumonia Pneumocystis carinii pneumonia diagnosed by a definitive diagnosed by a definitive

Any other disease indicative of AIDS Any other disease indicative of AIDS listed above listed above

T- helper T4 lymphocyte count <400 T- helper T4 lymphocyte count <400 /mm/mm

None of the other causes of None of the other causes of immunodeficiency listed above.immunodeficiency listed above.

Months Years

Antigen / Antibody response to HIV

Antigen Ab ( gp 41 )

Ab (p 24 )

Antigen

Cumulative of number of Cumulative of number of HIV/AIDS by mode of HIV/AIDS by mode of

transmission in Palestine 2003transmission in Palestine 2003 Sexually Blood Drug Vertical Unknown Total Transmission Addicts Transmission Hetro Bisex Homo Hemophilia Others

30 2 1 4 6 3 1 8 55

Maternal Factors Maternal Factors

1.1. Advanced immunosuppressantAdvanced immunosuppressant

2.2. Advanced clinical diseaseAdvanced clinical disease

3.3. High viral load High viral load

4.4. Recently acquired HIV infection & Recently acquired HIV infection & placental barrier distribution ( through placental barrier distribution ( through chronic amnionitis, placental malaria , chronic amnionitis, placental malaria , smoking ) smoking )

Delivery factorsDelivery factors

- Vaginal delivery or caesarian section- Vaginal delivery or caesarian section

- Invasive procedures- Invasive procedures

- Prolonged rupture of membrane - Prolonged rupture of membrane

Factors after delivery Factors after delivery

- Breast-feeding- Breast-feeding

Cracked nippleCracked nipple

Oral lesion in the infant Oral lesion in the infant

DiagnosisDiagnosis

1)1) Elisa 2) Western Blot ( W.B ) 3) P.C.R.Elisa 2) Western Blot ( W.B ) 3) P.C.R.

Elisa TestElisa Test Negative Positive Negative Positive RepeatRepeat Negative Positive Negative Positive

Repeat Repeat W.BW.B

Negative Indeterminate PositiveNegative Indeterminate Positive

Repeat Repeat

IndeterminateIndeterminate P.C.RP.C.R

Causes of false- Negative Causes of false- Negative ELISA reactions to HIV:-ELISA reactions to HIV:-

1.1. Incubation period or acute disease before Incubation period or acute disease before seroconversion (widow-period)seroconversion (widow-period)

2.2. MalignancyMalignancy3.3. Intensive or long-term Intensive or long-term

immunosuppressive therapy immunosuppressive therapy 4.4. Replacement transfusion Replacement transfusion 5.5. Bone-marrow transplantationBone-marrow transplantation6.6. Kits that detect antibody to p24 primarilyKits that detect antibody to p24 primarily7.7. B-cell dysfunction B-cell dysfunction

Cause of false positive ELISA Cause of false positive ELISA Reactions to HIV:-Reactions to HIV:-

Antibody against smooth muscle ,parietal cell, Antibody against smooth muscle ,parietal cell, mitochondria, nuclear , leukocyte, and T-cell mitochondria, nuclear , leukocyte, and T-cell antigen ; anti-HAV-IgM and anti HBc- IgMantigen ; anti-HAV-IgM and anti HBc- IgM

Antibodies against class II leukocyte Antibodies against class II leukocyte antigen( HLA-DR4,-DQw3) present on H-9 antigen( HLA-DR4,-DQw3) present on H-9 cell (more frequently observed in multiply cell (more frequently observed in multiply transfused patients)transfused patients)

Several alcoholic liver disease , primary biliary Several alcoholic liver disease , primary biliary cirrhosis, sclerosing cholangitis cirrhosis, sclerosing cholangitis

Heat inactivation or RPR positively of Heat inactivation or RPR positively of serum tested ( abott EIA only )serum tested ( abott EIA only )

Hematologic malignangies, lymphomaHematologic malignangies, lymphoma Acute DNA viral infections, HIV-2 Acute DNA viral infections, HIV-2

infectioninfection Renal transplants, chronic renal failureRenal transplants, chronic renal failure Stevens-johnson syndrom Stevens-johnson syndrom Passively acquired HIV-1 antibody Passively acquired HIV-1 antibody

( hepatitis B immunoglobulin)( hepatitis B immunoglobulin)

Causes of false-positive W.B. Causes of false-positive W.B. reactions to HIV-1 antigen reactions to HIV-1 antigen

( gag, env, and pol proteins ):-( gag, env, and pol proteins ):-Cross reactions with Cross reactions with

Normal human ribonucleoproteins Normal human ribonucleoproteins

Other human retroviruses Other human retroviruses

Antibody to mitochondrial, nuclear ,T-cell , and Antibody to mitochondrial, nuclear ,T-cell , and leukocyte antigen leukocyte antigen

Antibodies to HLA antigens (classes I and II)Antibodies to HLA antigens (classes I and II)

Globulins produced during polyclonal Globulins produced during polyclonal gammopathygammopathy

Recommendations for when to Recommendations for when to initiate treatment initiate treatment

Symptomatic HIV disease*Symptomatic HIV disease*Therapy recommended for all patients Therapy recommended for all patients

* Include symptoms as recurrent * Include symptoms as recurrent mucosal candidacies , oral hairy mucosal candidacies , oral hairy leukoplakia, chronic or other wise leukoplakia, chronic or other wise unexplained fatigue, night sweats or unexplained fatigue, night sweats or weight lossweight loss

Asymptomatic Asymptomatic

CD4 cell count <500/uL :therapy recommended+CD4 cell count <500/uL :therapy recommended+

CD4 cell count <500/uL : therapy recommended for CD4 cell count <500/uL : therapy recommended for patients with > 30,000-50,000 HIV RNA copies/ patients with > 30,000-50,000 HIV RNA copies/ mL or rapidly declining CD4 cell counts consider mL or rapidly declining CD4 cell counts consider therapy for patients > 5000- 10000 HIV RNA therapy for patients > 5000- 10000 HIV RNA copies.copies.

+ some would defer therapy in subset of patients + some would defer therapy in subset of patients with stable CD4 cell count between 350-500/uLwith stable CD4 cell count between 350-500/uL

And plasma HIV RNA consistently below 5000-And plasma HIV RNA consistently below 5000-10000 copies/ mL 10000 copies/ mL

LTR : long terminal report .promoter/enhancer LTR : long terminal report .promoter/enhancer for the HIV genes ( it interacts with the cell for the HIV genes ( it interacts with the cell proteins that undulate viral replication)proteins that undulate viral replication)

Pole gene: codes for construction of reverse Pole gene: codes for construction of reverse transcriptase ,protease & integrase enzyme transcriptase ,protease & integrase enzyme

nef gene : contributions to the virulence of HIV nef gene : contributions to the virulence of HIV rev. gene : the rev protein swiches the rev. gene : the rev protein swiches the

replication cycle to the production of whole replication cycle to the production of whole virus particles virus particles

tat gene : accelerate viral replication. tat gene : accelerate viral replication. vif gene : determines the infectivity of cell –free vif gene : determines the infectivity of cell –free

virusvirusvpr gene : facilitate the transport of HIV DNA vpr gene : facilitate the transport of HIV DNA

into the cell nucleus & regulates the cell cycle into the cell nucleus & regulates the cell cycle itselfitself

Transcriptase enzyme

Entry to the cell & HIV replication:Entry to the cell & HIV replication:

1.1. HIV bind to the CD4 protein on the cell HIV bind to the CD4 protein on the cell membrane membrane

2.2. After binding , the looped segment V3 of the After binding , the looped segment V3 of the gp 120 molecule interacts with chemokine gp 120 molecule interacts with chemokine receptor CKR5, CKR3, CKR2b, CXCR4 , to allow receptor CKR5, CKR3, CKR2b, CXCR4 , to allow fusion of the cell & viral membrane fusion of the cell & viral membrane

3.3. After penetration , the virus loses its envelopeAfter penetration , the virus loses its envelope

4.4. The reverse transcriptase enzyme of DNA The reverse transcriptase enzyme of DNA copies of viral RNA copies of viral RNA

5.5. Viral RNA is conveyed to the nucleus & Viral RNA is conveyed to the nucleus & inserted into cellular DNA . This integrated inserted into cellular DNA . This integrated DNA copy of the HIV genome is called provirus DNA copy of the HIV genome is called provirus

6- The HIV DNA provirus is transcribed into 6- The HIV DNA provirus is transcribed into RNA copies, which are either incorporated RNA copies, which are either incorporated into new virus particles as the genome or into new virus particles as the genome or function as messenger RNA and are function as messenger RNA and are translated into core, envelope or translated into core, envelope or accessory proteins.accessory proteins.

7- The core proteins and genomic RNA are 7- The core proteins and genomic RNA are assembled into viral cores in the assembled into viral cores in the cytoplasm beneath patches of the cell cytoplasm beneath patches of the cell membrane containing the envelope membrane containing the envelope proteins.proteins.

8- The virus particle buds out through the 8- The virus particle buds out through the altered cell membrane into infect other altered cell membrane into infect other cells.cells.