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Human Immunodeficiency Virus

presented by Rughoobur chitra Group 2(a) Faculty of foreign students

Human Immunodeficiency Virus

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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 ie. tat, rev, vif, nef, vpr and vpu

Types of HIV
For human immunodeficiency virus characterized by a high frequency of genetic changes that occur during self-renewal. Error Rate for HIV is 10 -3 - 10 -4 errors / (* genome replication cycle), which is several orders of magnitude more similar in eukaryotes. The length of the HIV genome is approximately 10 4 nucleotides. From this it follows that almost every virus on at least one nucleotide different from its predecessor. In nature, HIV exists as a set of quasi-species, being a single taxonomic unit. In the study of HIV yet been discovered species that differed significantly from each other on several grounds, including different structure of the genome. Varieties of HIV identified in Arabic numerals. To date, known HIV-1, HIV-2, HIV-3 HIV-4.

•HIV-1 - the first representative of the group, which opened in 1983 . The most common form. •HIV-2 - the kind of human immunodeficiency virus identified in 1986 [28] . Compared with HIV1, HIV-2 was studied to a much lesser degree. HIV-2 differs from HIV-1 genome structure. It is known that HIV-2 is less pathogenic and is transmitted is less likely than HIV-1. It was noted that people infected with HIV-2 have low immunity to HIV-1. •HIV-3 - a rare species, the discovery of which was reported in 1988 [29] . Detected the virus did not react with antibodies of other known groups, and also had significant differences in genome structure. More common name for this species - HIV-1 subtype O [30] . •HIV-4 - a rare variant of the virus, discovered in 1986 [31] . The global epidemic of HIV infection is mainly caused by the spread of HIV-1. HIV-2 prevalent mainly in West Africa . HIV and HIV-3-4 does not play a significant role in the spread of the epidemic. In most cases, unless otherwise stated, under the assumed HIV HIV-1

HIV particles

HIV Genome .

vif. •pol .tat. p17 . VIF. vpr. However. The other six genes . HIV-1 genome has a length of 9. vpu (vpx in HIV-2) .000 nucleotides .a protein gp160 .encodes a polyprotein Gag/p55. ] . 9 genes of HIV-1 encodes at least 15 proteins [ . rev. which control the production of new viruses and can be activated and the proteins of the virus and infected cell proteins.encodes enzymes: reverse transcriptase (RT). nef. these proteins are required for full infection in vivo . •env . or (+)) RNA . •gag . Replication of HIV-1 in vitro is possible without gene NEF. vpu . integrase (IN) and protease (PR). vpr.HIV-1 genome and proteins encoded by them Genome of HIV-1 HIV's genetic material is presented in two unrelated strings of positive-sense (positivesense.The ends of the genome are long terminal repeats (LTR). viral protease fissionable (PR) to structural proteins P6 . p24 . P7 . fissionable endoproteazoy Furin at the cell structural proteins gp41 and gp120 .encode proteins that are responsible for the ability of HIV-1 to infect cells and produce new copies of the virus.

Replication  The first step of infection is the binding of gp120 to the CD4 receptor of the cell. which is followed by penetration and uncoating.  The RNA genome is then reverse transcribed into a DNA provirus which is integrated into the cell genome. This is followed by the synthesis and maturation of virus progeny.  .

However. AG.   . B. D. H. especially since there are so few N group isolates. G. M (Main). DF. O (Outlayer).HIV-1 Genotypes   There are 3 HIV-1 genotypes. F2. AB. BC. F1. CD  O and N group subtypes not clearly defined. and N (New) M group comprises of a large number subtypes and recombinant forms   Subtypes .AE. certain subgroups may be difficult to detect by certain commercial assays. C. different HIV-1 genotypes are not associated with different courses of disease nor response to antiviral therapy. A2. J and K) Recombinant forms . As yet.(A.

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Schematic of HIV Replication .

HIV-1 Replication Cycle Reverse Transcription Attachment CD4 Uncoating Integration Integrase Reverse Transcriptase Assembly Budding CCR5 Maturation Protease CXCR4 .

The genes of Retroviruses with clinical consequences Table 65-2 =genes common to all retroviruses .

2.Clinical stages classification 1. 4. Incubation period (stage 1) Stage of primary manifestations (stage 2) Latent stage (stage 3) Stage of secondary manifestations (stage 4) End stage (stage 5) . 5. 3.

Stage of primary manifestations (stage 2): 2 "A" .a regular. a response to the introduction of HIV is the antibody.an acute HIV infection without secondary diseases (various clinical manifestations.asymptomatic when clinical manifestations of HIV infection or opportunistic infections are not available. . herpes .angina. well-treatable). 2 “C" . 2 "B" . The duration of clinical manifestations of acute HIV infection is usually 2 .Incubation stage (stage 1): From the moment of infection until clinical signs of acute infection and / or antibody production (average of 3 weeks to 3 months). bacterial pneumonia. most of them similar to symptoms of other infections).an acute HIV infection with secondary disease (compared to a temporary decline of T-4 lymphocytes develop secondary diseases .3 weeks. candidiasis.

Symptoms at this stage are reversible.3 to 20 years or more.Latent stage (stage 3): Slow the progression of immunodeficiency.7 years. . inflammatory disease of the upper respiratory tract. 4 "B" . which can not be removed. The only clinical sign is swollen lymph nodes. meaning they can pass on their own or with treatment. Depending on the severity of secondary diseases are the following stage.a more severe and prolonged skin lesions. infectious and / or cancer. Stage of secondary diseases (Stage 4): Ongoing HIV replication. Duration of the latent stage of 2 . weight loss. 4 “C" . lesions of the peripheral nervous system and internal organs.severe. Has been a gradual decline in T-4 lymphocytes. life-threatening opportunistic infections. 4 "A" . Kaposi's sarcoma. resulting in the death of the T-4 lymphocytes and the development of secondary immunodeficiency in the background (opportunistic) diseases.it is characterized by bacterial. fungal and viral lesions of the mucous and skin. on average 6 .

Even adequately performed antiviral therapy and treatment for opportunistic infections are not effective and the patient dies within a few months.End-stage (Stage 5): The defeat of the organs and systems are irreversible trend. . Keep in mind that the HIV epidemic in Russia is young and the sick in the later stages are only a small percentage of all Russians living with HIV.

Clinical Features 1. Presents with an infectious mononucleosis like illness. The median incubation period is 8-10 years.seen in 10% of individuals a few weeks after exposure and coincides with seroconversion. 2. Full-blown AIDS. . Incubation period . Seroconversion illness . 3.this is the period when the patient is completely asymptomatic and may vary from a few months to a more than 10 years. 4. AIDS-related complex or persistent generalized lymphadenopathy.

499/mm3 <200/mm3 A A1 A2 A3 B B1 B2 B3 C C1 C2 C3  (the equivalence between CD4 counts and CD4 % of total lymphocytes is [>500=>29%]. [<200= <14%] ) . [200-499= 14-28%].HIV classification system      Clinical categories CD4 cell category > 500/mm3 200.

Clinical category A Asymptomatic HIV infection. atleast 1cm in diameter for > 3months . Persistant generalised lymphadenopathy (PGL) Acute (primary) HIV illness PGL: nodes in 2 or more extrainguinal sites.

vulvovaginal: Persistant > 1month.50c) or diarrhea >1 month The above must be attributed to HIV infection or have a clinical course or management complicated by HIV If weight loss >10% suspect HIV . cervical dysplasia. candidiasis. not A or C conditions examples include but not limited to :Bacillary angiomatosis.Clinical category B Symptomatic.g fever (38. poorly responsive to reaction Candidiasis. severe or carcinoma in situ Constitutional symptoms e. oropharyngeal.

pulmonary or extrapulmonary. Wasting syndrome due to HIV All conditions with HIV (1)CD4 T-lymphocytes count <200/mm 3 (CD4<14%) (2)Pulmonary tuberculosis (3)Recurrent pneumonia (>2 episodes within 1 year) (4)Invasive cervical carcinoma . Salmonella bacteremia. cryptococcosis. invasive Cryptococcosis. Kaposis sarcoma. Herpes simplex with mucocutaneous ulcer >1 month. chronic intestinal (>5 months) CMV retinitis. extrapulmonary isosporiasis.Clinical category C Candidiosis – esophageal. extrapulmonary. M.disseminated. pneumonia. cerebral. immunoblastic. primary brownin. bronchi. Histoplasmosis. extrapulmonary cervical cancer.tuberculosis. kansasii. chronic >1 month. recurrent toxoplasmosis. spleen. HIV encephalopathy. avium or M. or CMV in other than liver. coccidiodomycosis. Pneumocystis carinii pneumonia. extrapulmonary. M. Lymphoma: burkitt’s . node. Bronchitis. trachea. Pneumonia recurrent (> 2 episodes in 1 year) Progressive multifocal leukocephalopathy.

Natural Course of HIV-1 Infection .

HSV. VZV. crytococcosis histoplasmosis. MTB atypical mycobacterial disease salmonella septicaemia multiple or recurrent pyogenic bacterial infection CMV. toxoplasmosis.Opportunistic Infections Protozoal pneumocystis carinii (now thought to be a fungi). coccidiodomycosis Mycobacterium avium complex. JCV Fungal Bacterial Viral . crytosporidosis candidiasis.

is observed in 20% of patients with AIDS. Malignant lymphomas are also frequently seen in AIDS patients. It is now associated with a human herpes virus 8 (HHV-8).Opportunistic Tumours  The most frequent opportunistic tumour. Kaposi's sarcoma. KS is observed mostly in homosexuals and its relative incidence is declining.   .

Kaposi’s Sarcoma .

Other manifestations include characteristic skin eruptions and persistent diarrhoea.Other Manifestations  It is now recognised that HIV-infected patients may develop a number of manifestations that are not explained by opportunistic infections or tumours.  The most frequent neurological disorder is AIDS encephalopathy which is seen in two thirds of cases.  .

Vertical transmission may occur transplacentally route.6–42. . In developing countries. heterosexual spread constitute the most important means of transmission. 3. which killed 2. This is more than in any one year before. Sexual transmission .2–6.male homosexuals and constitute the largest risk group in N. or postnatally through breast milk.8 million people (range: 4. In 2003. 4.6–3. Blood/blood products . Vertical transmission .3 million) are living with HIV. perinatally during the birth process. 2. Haemophiliacs were one of the first risk groups to be identified: they were infected through contaminated factor VIII.IV drug abusers represent the second largest AIDS patient groups in the US and Europe.Epidemiology 1. Today. some 37. an estimated 4.8 million people (range: 34.3 million) became newly infected with HIV. and over 20 million since the first cases of AIDS were identified in 1981.3 million) in 2003.9 million (range: 2. America and Western Europe.the transmission rate from mother to the newborn varies from around 15% in Western Europe to up to 50% in Africa.

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and low CD4 counts). HIV-antigen. It then settles down to a certain low level (set-point) during the incubation period.    Eventually. .HIV Pathogenesis  The profound immunosuppression seen in AIDS is due to the depletion of T4 helper lymphocytes. there is a massive turnover of CD4 cells. HIV is present at a high level in the blood (as detected by HIV Antigen and HIV-RNA assays). In the immediate period following exposure. whereby CD4 cells killed by HIV are replaced efficiently. During the incubation period. the immune system succumbs and AIDS develop when killed CD4 cells can no longer be replaced (witnessed by high HIVRNA.

Such cells are very long lived.5 days.      . Such long-lived cell populations present a major challenge for antiretroviral therapy. and have an estimated half-life of approximately three to six months. Production of virus by short-lived. these cells have a half-life of at least 5-6 months.HIV half-lives  Activated cells that become infected with HIV produce virus immediately and die within one to two days. Resting cells that become infected produce virus only after immune stimulation. The time required to complete a single HIV life-cycle is approximately 1. Some cells are infected with defective virus that cannot complete the virus life-cycle. activated cells accounts for the vast majority of virus present in the plasma.

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HIV pathogenesis .

ELISAs are the most frequently used screening assays. The sensitivity and specificity of the presently available commercial systems now approaches 100% but false positive and negative reactions occur. Serological tests can be divided into screening and confirmatory assays. Confirmatory assays . . Some assays have problems in detecting HIV-1 subtype O. Screening assays should be as sensitive whereas confirmatory assays should be as specific as possible.Laboratory Diagnosis    Serology is the usual method for diagnosing HIV infection. Line immunoassays incorporate various HIV antigens on nitrocellulose strips. The interpretation of results is similar to Western blot it is more sensitive and specific. its sensitivity is lower than screening EIAs. Screening assays . However.Western blot is regarded as the gold standard for serological diagnosis.

HIV DNA and p24 become detectable in the blood from approximately 16 days post-infection. HIV antibodies are detectable from approximately 24 days post-infection . after which the RNA levels decrease to a viral set point that is maintained for a prolonged period.Immunological markers for HIV Viral RNA is detectable in the blood from approximately 11 days post-infection. There is a rapid rise in viral RNA levels (viral load) until the immune system responds. p24 le-vels then become undetectable until the end stage of disease. at which time p24 levels rise.

ELISA for HIV antibody Microplate ELISA for HIV antibody: coloured wells indicate reactivity .

Western blot for HIV antibody  There are different criteria for the interpretation of HIV Western blot results e. American Red Cross. and gp41 p24 antibody is usually present but may be absent in the later stages of HIV infection   .g. WHO. CDC. gp160. The most important antibodies are those against the envelope glycoproteins gp120.

and 3rd and 4th generation ELISA assays are more reliable than those previously available. . The Western Blot is however a useful tool for differentiating between infections with HIV-1 and HIV-2. Antibodies directed against HIV proteins bind to relevant areas on a strip and are detected by the addition of an enzyme-labelled secondary enzyme and substrate.Western Blot was previously used as a confirmatory test. as it is expensive and labour intensive. Most laboratories no longer use Western Blot.

Other diagnostic assays  It normally takes 4-6 weeks before HIV-antibody appears following exposure. and RNA. A diagnosis of HIV infection made be made earlier by the detection of HIV antigen. diagnosis of HIV infection in babies born to HIV-infected mothers.   . pro-DNA. there are very few circumstances when this is justified e. However.g.

g. HIV viral load . RT-PCR. . It was soon apparent that detection of HIV p24 antigen was not as good as serial CD4 counts.they were widely used as prognostic assays.HIV viral load in serum may be measured by assays which detect HIV-RNA e. or bDNA. The use of HIV p24 antigen assays for prognosis has now been superseded by HIV-RNA assays. HIV Antigen tests . HIV viral load has now been established as having good prognostic value. it is important to monitor the patient at regularly for signs of disease progression and response to antiviral chemotherapy. and in monitoring response to antiviral chemotherapy.Prognostic tests Once a diagnosis of HIV infection had been made. NASBA.

.MONITORING DISEASE PROGRESSION AND RESPONSE TO THERAPY Monitoring of HIV-1 infection should not rely on any single marker. The patient’s clinical condition needs to be considered in addition to the HIV-1 viral load and the CD4+ T lymphocyte count.

o a viral load below detection limit of the assay after 12-24 weeks of therapy. The viral load is given as a value representing RNA copies per millilitre. This test serves a number of purposes: • It determines the viral setpoint and acts as a long-term predictor of prognosis.g. e. as well as a log value.HIV-1 Viral Load Quantitative HIV-1 RNA testing (HIV-1 viral load) detects and quantifies the HIV-1 RNA in plasma. 1000 = 3 log. o a viral load of 5000 copies or less after 12 weeks of therapy. unless the patient has been recently infected and has not yet reached a viral setpoint. 10000 = 4 log etc. Certain guidelines recommend starting treatment if the viral load is greater than 100 000 copies/ml. An acceptable response to therapy is considered to be: o a viral load reduction of more than 1 log from the baseline value after 6-8 weeks of therapy. • It acts as a guide for deciding when to initiate HAART. • It is an indicator of the development of viral resistance to therapy: o Primary failure of therapy is indicated by a viral load that does . 100 = 2 log. The log value provides an easier number to work with and better indicates significant changes in viral load. • It is a measure of viral response to therapy.

. 15. Such results can lead to confusion and misdiagnosis. It must be noted that the HIV-1 viral load should not be used for the diagnosis of HIV-1 infection.not decrease as expected after initiation of HAART. This is because low false positive results (usually less than 2000 copies/ml) can occur with quantitative HIV-1 RNA testing. 14. o Secondary failure of therapy refers to an increase in the viral load of 1 log or greater on two separate specimens at least two weeks apart after an initial adequate response to HAART 13.

The Southern African HIV Clinicians Society recommends initiating HAART as above. As the immune system becomes exhausted. a mention must be made of the CD4+ T lymphocyte count. The South African National Antiretroviral Treatment Guidelines agree with the WHO. but also advises initiation if the CD4+ T lymphocyte count is 200-350 and has been shown to be decreasing rapidly. the CD4+ T lymphocyte count should be monitored every 6 months. A patient requiring HAART should be managed by a medical practitioner with experience in the care of patients with HIV.CD4+ T lymphocyte count For completeness. the CD4+ T lymphocyte level increases. If HAART is not yet indicated. but rarely returns to pre-infection levels. Once on treatment. the CD4+ T lymphocyte count begins to decrease. There are a number of different guidelines available recommending when to start HAART. the CD4+ T lymphocyte count should be repeated every 3-6 months. North American and European Guidelines offer HAART for CD4+ T lymphocyte counts less than 350 cells/ml 16. The World Health Organisation recommends initiating HAART when the CD4+ T lymphocyte count is less than 200 cells/ml or higher if the patient has an AIDS-defining illness. . Once the viral load has reached its setpoint. The CD4+ T lymphocyte count should be tested after diagnosis of HIV infection. The CD4+ T lymphocyte count declines with acute infection.

This can be done in-house and the results interpreted automatically by the HIV sequence database in the US. Commercial systems (Trugene. It is reported that the outcome would be better if the results are interpreted by an expert in this area. Genotypic – the RT and Protease genes are sequenced. ABI and others) available which relies on their own database and interpretation by a panel of experts that meet regularly. . There are two types of antiviral susceptibility assays:    Phenotypic – very difficult and expensive to carry out.Anti-Retroviral Susceptibility Testing    It is now generally accepted that anti-viral susceptibility testing should be a routine part of the management of HIV-infected patients. Thought to give a better idea of the actual situation in vivo.

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non-cross-resistant and no overlapping toxicity. especially for trials involving multiple agents including protease inhibitors. (HAART . it may be possible to reduce toxicity.Treatment  Zidovudine (AZT) was the first anti-viral agent shown to have beneficial effect against HIV infection.highly active anti-retroviral therapy) The rationale for this approach is that by combining drugs that are synergistic.  Combination therapy has now been shown to be effective. improve efficacy and prevent resistance from arising. AZT-resistant strains rapidly appears which limits the effect of AZT.  . after prolonged use. However.

g.g. mortality from HIV has declined dramatically in the developed world. ddI. AZT. Nevirapine Protease Inhibitors e. lamivudine Non-nucleoside analoque reverse transcriptase.g.Anti-Retroviral Agents      Nucleoside analogue reverse transcriptase inhibitors e. Indinavir. . e. Fuzeon (IM only) HAART (highly active anti-retroviral therapy) regimens normally comprise 2 nucleoside reverse transcriptase inhibitors and a protease inhibitor.g. AZT. Ritonavir Fusion inhibitors e. Since the use of HAART. inhibitors e.g. lamivudine and indinavir.

A phase III trial involving a recombinant gp120 of HIV subtype B was reported in Feb 2005 to be ineffective in preventing HIV infection. AZT had been shown to be effective in preventing transmission of HIV from the mother to the fetus. Since 1987. . more than 30 HIV candidate vaccines have been tested in approximately 60 Phase I/II trails. The incidence of HIV infection in the baby was reduced by two-thirds.Prevention      The risk of contracting HIV increases with the number of sexual partners. The spread of HIV through blood transfusion and blood products had virtually been eliminated since the introduction of blood donor screening in many countries. A change in the lifestyle would obviously reduce the risk. Anti-viral prophylaxis had been shown to be of some benefit but it is uncertain what is the optimal regimen.000 healthy volunteers. involving more than 10. Vaccines are being developed at present but progress is hampered by the high variability of HIV. The management of health care workers exposed to HIV through inoculation accidents is controversial.