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S3 L18: Human Immunodeficiency Virus by Dr. Bunyi DDDeeeccceeemmmbbbeeerrr 111,,, 222000111000

Human Immunodeficiency Virus

Acquired Immunodeficiency syndrome first described in 1981

HIV-1 isolated in 1984, and HIV-2 in 1986

Belong to the Lentivirus subfamily of the Retroviridae

Enveloped RNA virus, 120nm in diameter

HIV-2 shares 40% nucleotide homology with HIV-1

Genome consists of 9200 nucleotides (HIV-1):

gag core proteins - p15, p17 and p24

pol - p16 (protease), p31 (integrase/endonuclease)

env - gp160 (gp120:outer membrane part, gp41: transmembrane part)

Other regulatory genes ex. tat, rev, vif, nef, vpr and vpu

HIV particles

HIV Genome

Replication

The first step of infection is the binding of gp120 to the CD4 receptorof the cell, which is followed by penetration and uncoating.

The RNA genome is then reverse transcribed into a DNA proviruswhich is integrated into the cell genome.

This is followed by the synthesis and maturation of virus progeny.

Clinical Features

1. Seroconversion illness - seen in 10% of individuals a few weeks afterexposure and coincides with seroconversion. Presents with an infectiousmononucleosis like illness.

2. Incubation period - this is the period when the patient is completelyasymptomatic and may vary from a few months to a more than 10 years.The median incubation period is 8-10 years.

3. AIDS-related complex or persistent generalized lymphadenopathy.4. Full-blown AIDS.

Schematic of HIV Replication

Stages of Infection

Group I Seroconversion illnessGroup II AsymptomaticGroup III Persistent Generalized Lymphadenopathy

Group IVA Constitutional diseaseB Neurological diseaseC Two infectious diseaseD Two cancersE Other conditions

Acute seroconversion illnesso resembles glandular fever adenopathyo flu-like symptomso 5-10%

Persistent generalized lymphadenopathy (PGL)o (+) 25-30%o enlarge LN : painlesso symmetrical

y

y

g

py

y

g

g

p

g

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Opportunistic Infections

Protozoal Pneumocystis carinii(now thought to be a fungus),toxoplasmosis, crytosporidosis

Fungal candidiasis, crytococcosishistoplasmosis, coccidiodomycosis

Bacterial Mycobacterium avium complexatypical Mycobacterial diseaseSalmonella septicaemia

multiple or recurrent pyogenic bacterial infection

Viral CMV, HSV, VZV, JCV

Opportunistic Tumours

The most frequent opportunistic tumour, Kaposi's sarcoma, isobserved in 20% of patients with AIDS.KS is observed mostly in homosexuals and its relative incidence isdeclining. It is now associated with a human herpes virus 8 (HHV-8).

Malignant lymphomas are also frequently seen in AIDS patients.

Kaposis sarcoma (HHV-8)

one of the earliest diseases

arises in many sites: skin, mouth, gut, eyearise from endothelial cells of blood vessels

bluish purple, raised irregular lesion

Other Manifestations

It is now recognised that HIV-infected patients may develop anumber of manifestations that are not explained by opportunisticinfections or tumours.

The most frequent neurological disorder is AIDS encephalopathywhich is seen in two thirds of cases.

Other manifestations include characteristic skin eruptions andpersistent diarrhoea.

Oral hairy leukoplakia

unique to HIV-infected patients

margins of tongue: white ridges of fronds on the epithelium

(+) assoc with EBV and papilloma virus

Pneumocystis carinii pneumonia

leading cause of morbidity and mortality

cause infections in immunocompromised

diagnosis in young men with no explanation for theirimmunosuppressionwas the 1st clue to the recognition of AIDS

Toxoplasma gondii

always associated with compromised patients

brain important site

HIV dementia

25% of patients with AIDS

gradual loss of cognition, progressing to overt dementia

CT Scan: loss of tissue

widening of sulci and ventricles

Developing countries:local problems

o MDRTB

o MAI BM, liver, spleen, LNPediatric AIDS

recurrent bacterial infections

lymphoid interstitial pneumonia

pulmonary lymphoid hyperplasia

Epidemiology

1. Sexual transmission - male homosexuals and constitute the largest riskgroup in N. America and Western Europe. In developing countriesheterosexual spread constitutes the most important means of transmission.

2. Blood/blood products - IV drug abusers represent the second largest AIDSpatient groups in the US and Europe. Haemophiliacs were one of the firsrisk groups to be identified: they were infected through contaminated factoVIII.

3. Vertical transmission - the transmission rate from mother to the newbornvaries from around 15% in Western Europe to up to 50% in Africa. Verticatransmission may occur via transplacental route, perinatal during the birthprocess, or postnatal through breast milk.

5 Million people infected with HIV globallyo Due to the rampant epidemics seen in sub-Saharan Africao Spikes in Soviet Union and Eastern Europe, Central Asia

and East Asiao

3.1 M deaths including 570,000 children

Disease Progression

Untreated from initial infection 5% within 3 years 20-25% by 6-7 years 5-10% each year < 5% asymptomatic for > 10 years 2% asymptomatic for > 12 years 13% of patient with viral RNA copy number of < 1500/ml will

develop AIDS within 9 years 93% progression in 9 years with RNA copy number >55,000/m

Pathogenesis

The profound immunosuppression seen in AIDS is due to thedepletion of T4 helper lymphocytes.

In the immediate period following exposure, HIV is present at a highlevel in the blood (as detected by HIV Antigen and HIV-RNA assays).It then settles down to a certain low level (set-point) during theincubation period. During the incubation period, there is a massiveturnover of CD4 cells, whereby CD4 cells killed by HIV are replacedefficiently.Eventually, the immune system succumbs and AIDS develop whenkilled CD4 cells can no longer be replaced (witnessed by high HIVRNA, HIV-antigen, and low CD4 counts).

HIV half-lives

Activated cells that become infected with HIV produce viruimmediately and die within one to two days.

Production of virus by short-lived, activated cells accounts for thevast majority of virus present in the plasma.

The time required to complete a single HIV life-cycle is approximately1.5 days.Resting cells that become infected produce virus only after immunestimulation; these cells have a half-life of at least 5-6 months.

Some cells are infected with defective virus that cannot complete thevirus life-cycle. Such cells are very long lived, and have an estimatedhalf-life of approximately three to six months.

Such long-lived cell populations present a major challenge for antiretroviral therapy.

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Laboratory Diagnosis

Serology is the usual method for diagnosing HIV infection.Serological tests can be divided into screening and confirmatoryassays. Screening assays should be as sensitive whereasconfirmatory assays should be as specific as possible.Screening assays - EIAs are the most frequently used screeningassays. The sensitivity and specificity of the presently availablecommercial systems now approaches 100% but false positive andnegative reactions occur. Some assays have problems in detectingHIV-1 subtype O.

Confirmatory assays - Western blot is regarded as the goldstandard for serological diagnosis. However, its sensitivity is lower

than screening EIAs. Line immunoassays incorporate various HIVantigens on nitrocellulose strips. The interpretation of results issimilar to Western blot it is more sensitive and specific.

ELISA for HIV Antibody

Microplate ELISA for HIV antibody: colored wells indicate reactivity

Western blot for HIV antibody

There are different criteria for the interpretation of HIV Western bloresults e.g. CDC, WHO, American Red Cross.

The most important antibodies are those against the envelopeglycoproteins gp120, gp160, and gp41

p24 antibody is usually present but may be absent in the later stagesof HIV infection

Other diagnostic assays

It normally takes 4-6 weeks before HIV-antibody appears followingexposure.

A diagnosis of HIV infection made be made earlier by the detection oHIV antigen, pro-DNA, and RNA.

However, there are very few circumstances when this is justified e.gdiagnosis of HIV infection in babies born to HIV-infected mothers.

Prognostic tests

Once a diagnosis of HIV infection had been made, it is important tomonitor the patient at regularly for signs of disease progression andresponse to antiviral chemotherapy.

HIV Antigen tests - they were widely used as prognostic assays. Iwas soon apparent that detection of HIV p24 antigen was not asgood as serial CD4 counts. The use of HIV p24 antigen assays foprognosis has now been superseded by HIV-RNA assays.

HIV viral load - HIV viral load in serum may be measured by assayswhich detect HIV-RNA e.g. RT-PCR, NASBA, or bDNA. HIV viraload has now been established as having good prognostic value, andin monitoring response to antiviral chemotherapy.

Treatment Aim

- produce the maximum lasting reduction in viral load- preserve or improve immune function- reduce clinical problems- prolong life- reduce infectivity

Basis for Selection clinical state deteriorating plasma viral load high or rising CD4 count falling or < 200 acute stage of initial infection to reduce early viral replication, achieve

a lower stable RNA load, preserve immune function and reduce riskof viral mutation

Zidovudine (AZT) was the first anti-viral agent shown to havebeneficial effect against HIV infection. However, after prolonged use

AZT-resistant strains rapidly appear which limits the effect of AZT. Combination therapy has now been shown to be effective, especially

for trials involving multiple agents including protease inhibitors(HAART - highly active anti-retroviral therapy)

The rationale for this approach is that by combining drugs that aresynergistic, non-cross-resistant and no overlapping toxicity, it may bepossible to reduce toxicity, improve efficacy and prevent resistancefrom arising.

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Anti-Retroviral Agents

Nucleoside analogue reverse transcriptase inhibitors e.g. AZT, ddI,lamivudineNon-nucleoside analoque reverse transcriptase, inhibitors e.g.Nevirapine

Protease Inhibitors e.g. Indinavir, Ritonavir

HAART (highly active anti-retroviral therapy) regimens normallycomprise 2 nucleoside reverse transcriptase inhibitors and aprotease inhibitor. e.g. AZT, lamivudine and indinavir. Since the useof HAART, mortality from HIV has declined dramatically in thedeveloped world.

HIV Treatment Assess effectiveness :

measure plasma viral load+

CD4 count(estimate state of immune system)

Start of treatment, 1 month, 3-4 months interval (+) response :

in RNA load within a few days by 1 log 10 at 2-8 wks

< 50% by 4-6 months

Continue prophylaxis and prompt treatment of opportunisticinfections

Pneumocystis carinii Toxoplasma gondii

Prevention

The risk of contracting HIV increases with the number of sexualpartners. A change in the lifestyle would obviously reduce the risk.The spread of HIV through blood transfusion and blood products hadvirtually been eliminated since the introduction of blood donorscreening in many countries.

AZT had been shown to be effective in preventing transmission ofHIV from the mother to the fetus. The incidence of HIV infection in

the baby was reduced by two-thirds.The management of health care workers exposed to HIV throughinoculation accidents is controversial. Anti-viral prophylaxis had beenshown to be of some benefit but it is uncertain what the optimalregimen is.

Vaccines are being developed at present but progress is hamperedby the high variability of HIV. Clinical trials for several vaccines are inprogress.

Control

There is no short cut, no vaccines, no magic bullet, because sexualtransmission remains the main route of infection and the focus must therefore

be on empowering people to AVOID UNSAFE SEX.Dr. Mevron

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