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VRUS DA IMUNODEFICINCIA HUMANA (HIV)

HIV
1. 2. 3. 4. 5. 6. 7.

Caractersticas Gerais Estrutura e Composio Classificao Patogenia Diagnstico Laboratorial Epidemiologia Preveno, Tratamento e Controle

A Histria Natural da Doena Determinado Tanto pelo Vrus, Quanto pelo Hospedeiro
Doena causada por vrus determinada por quais clulas so infectadas, a velocidade de replicao viral, alteraes na fisiologia celular decorrentes de produtos gnicos virais e na defesa do hospedeiro. A replicao viral interrompida quando se esgotam os alvos. . . Ou quando mecanismos (imune) do hospedeiro, os quais inativam vrus extracelular, neutralizam ou matam clulas infectadas.

Pergunta
Como ficamos de joelhos por um vrus que tem apenas nove protenas e 3.000 aminocidos?

HIV
1. Caractersticas Gerais
um retrovrus, membro da subfamlia Lentivirinae. Apresenta um nucleide cilndrico no vrion maduro. No oncognico. Infecta clulas do sistema imune. O pr-vrus permanece associado a clulas. A replicao altamente espcie- especfica.

HIV
1. Caractersticas Gerais
Provoca doena crnica lentamente progressiva. totalmente inativado por tratamento com desinfetante domstico a 10%; etanol a 50%; isopropanol a 35%; Nonidet P40 1%; Lysol a 0,5%; paraformaldedo a 0,5% ou H2O2 a 0,3%, por 10 min. a temperatura ambiente.

inativado por extremos de pH.


inativado em lquidos ou soro a 10% por aquecimento a 56 C, durante 10 minutos.

HIV
2. Estrutura e Composio Genoma constitudo de RNA, composto de trs genes necessrios para replicao viral(gag, pol e env.). O gene env codifica as protenas do envoltrio viral. Seu produto (gp 120) fixa o vrus a molcula CD4 e co-receptores, determina tropismos para linfcitos e macrfagos e induz a produo de anticorpos neutralizantes, e ( gp 41) que facilita a penetrao do vrus nas clulasalvo.

HIV Genome

HIV Structure

HIV
2. Estrutura e Composio A protena rev necessria para a expresso das protenas estruturais virais. Apresenta seis genes adicionais que regulam a expresso viral e so importantes na patogenia in vivo. A protena tat-fase inicial da replicao e atua na transativao. Presena da enzima de replicao no interior do vrus-transcriptase reversa. Presena de proteases importantes para produo de vrus infecciosos.

HIV
2. Estrutura e Composio

HIV
3. Classificao
HIV-1, com nove subtipos (A-I)

HIV-2, com cinco subtipos (A-E)

4. Patogenia

HIV

Caractersticas importantes:
O vrus transmitido por troca de fluidos

orgnicos. O vrus persiste no hospedeiro por definitivo, podendo estar em nveis baixos. O vrus apresenta alta taxa de mutao. A infeco evolui lentamente atravs de estgios especficos. s vezes, necessrio vrios anos para o desenvolvimento da doena.

Clulas do Sistema Imune

Clulas
Linfcitos NK Clulas Dendrticas Macrfagos e Moncitos Neutrfilos Eosinfilos Mastcitos Basfilos

Linfcitos
So as nicas clulas com receptores especficos para antgenos
Chaves da imunidade adaptvel.

Morfologicamente semelhantes
So heterogneos em:
Linhagem Funcionamento Fentipo Capacidade de respostas e atividades biolgicas complexas e atividades.

Linfcitos B
So as nicas clulas capazes de produzir anticorpos
Imunidade humoral.
Expresso de ac de sup
Receptores que reconhecem antgenos Antgenos solveis e antgenos na superfcie de micrbios e outras clulas Ativao celular Resposta imune humoral.

Linfcito T
Imunidade Celular
Receptores reconhecem fragmentos de peptdeos de ag
Ligados a major histocompatibility complex (MHC) ou complexo de histocompatibilidade principal (MHC).

T CD4+ = helper ou auxiliares


Ajudam B a produzir anticorpos Fagcitos a destruir micrbios fagocitados

T CD8+ = citotxicos ou citolticos


Destroem clulas que abrigam micrbios intracelulares

Linfcitos NK
NK = Natural Killer ou assassina natural
Mediadores de imunidade inata No expressam receptores de antgeno como as clulas B ou clulas T. Importante contra vrus e tumores

Clulas Apresentadoras de Antgenos ou Antigen Presenting Cells -APCs


Portas de entrada para micrbios
a pele, rea gastrointestinal e rea respiratria,

Contm clulas especializadas localizadas abaixo do epitlio que captura Ag e os transporta para tecidos linfides.
Clulas dendrticas e macrfagos

Clulas Dendrticas
A funo de APC melhor representada pelas clulas dendrticas
Nome por causa dos processos dendrticos longos. Capturam ag proticos Exibem partes dos Ags para os linfcitos T
Pele: clulas de Langerhans

Macrfago

Macrfagos
Clula grande com vacolos citoplasmticos Apresenta diferentes nomes, de acordo com o tecido Presente em tecidos saudveis Fagocitose Apresentao de antgenos

Macrfago + pseudopodes

macrfago interagindo com vrios linfcitos

Resumindo as Clulas

HIV
4. Patogenia
Receptores do Vrus:
CD4 presente em macrfagos e linfcitos T.

Quimiocinas

CCR5- macrofagotrpica CXCR4- linfocitotrpica

4. Patogenia

HIV

Receptores do Vrus:

4. Patogenia

HIV

Estgios da Infeco:
Infeco Primria: Ocorre replicao viral e viremia

(detectada em cerca de 8-12 semanas) Disseminao do vrus para rgos linfides: 50 a 75% desenvolvem sndrome semelhante Mononucleose aguda, em 3 a 6 semanas. Latncia clnica: Alta taxa de replicao viral, com aparecimento de sintomas ou a doena, podendo perdurar por 10 anos. Doena clnica: Expresso elevada do vrus e surgimento de doenas oportunistas.
Morte.

HIV Infection and Antibody Response


---Initial Stage---- ---------------Intermediate or Latent Stage-------------Flu-like Symptoms Or No Symptoms

---Illness Stage---

Symptom-free

AIDS Symptoms

----

Infection Occurs

Virus Antibody

---< 6 month
~ Years ~ Years ~ Years ~ Years

4. Patogenia
Estgios evolutivos

HIV

Overview
Start with CD4 of 1000cells/ml blood In HIV infected persons, the CD4 count declines by about 10cells/ml blood/year initially

However, towards the end, the CD4 count declines by 30-60cells/ml blood/year

How does HIV infection progresses? Primary infection/seroconversion


Clinical latency/intermediate stage

AIDS

Primary infection/ seroconversion


The incubation periods is 2-4 weeks. Silent both clinically and serologically
Symptomatic in 70 %-80% of cases

Occurs 6-8 weeks after exposure

Primary infection/ seroconversion


Symptoms include
Fever Arthralgia/ Myalgia Headache Photophobia Lethargy Sore throat with cervical lymphadenopathy Mucosal ulcers Occasionally a transient faint pink maculopapular rash.

Rash of acute HIV infection

Primary infection/ seroconversion Symptomatic recovery occurs after 1-3 weeks

and recovery is usually complete Parallel to return of CD4 count and fall in the viral load

How does HIV infection progresses?


Primary infection/seroconversion

Clinical latency/intermediate stage


AIDS

Clinical latency/ intermediate stage

Early Immune deficiency (CD4>500)


and

Intermediate Immune Deficiency (CD4 200-500)

Prolonged asymptomatic period (8-10 years) Active viral replication takes place within lymphoid tissue Sustained viraemia with decline in CD4 count Generally good immune response

Early Immune deficiency (CD4>500)

Serocon Early version (CD4>500)

Intermediate CD4 <500>200

Advanced CD4<200

PGL Polymyositis Recurrent vaginal candidiasis

CD4 CELL COUNT

500

200

100 50

Early Immune deficiency (CD4>500)


Persistent generalized lymphadenopathy (PGL)
Lymphadenopathy(<1cm) at two or more extrainguinal sites for more than 3 months in the absence of causes other than HIV infection. Usually symmetical, firm, mobile and non-tender. May disappear with disease progression

Intermediate Immune Deficiency (CD4 200-500)


Signs and symptoms of immunocompromised
Risk of opportunistic infection and malignancy Develop constitutional symptoms such as fever, weight loss, and night sweats Skin and mucosal surfaces are first affected

Serocon Early version (CD4>500)

Intermediate CD4 <500>200

Advanced CD4<200

Acute primary infection PGL Polymyositis Recurrent vaginal candidiasis

CD4 CELL COUNT

500

200

Pulmonary tuberculosis Herpes zoster Oropharyngeal candidiasis Oral hairy leukoplakia Salmonellosis Kaposis sarcoma HIV associated ITP Cervival intraepithelial neoplasia II-III Lymphoid interstitial pneumonitis(LIP)

100 50

How does HIV infection progresses?


Primary infection/seroconversion Clinical latency/intermediate stage

AIDS

Acquired Immunodeficiency Syndromes(AIDS)


Diagnosis:
Having a CD4 count of less than 200 Serologic evidence of HIV infection One of the AIDS-defining opportunistic infections

Develops for a median of 2 years followed by death

Serocon Early version (CD4>500)

Intermediate CD4 <500>200

Advanced CD4<200

Acute primary infection PGL Polymyositis Recurrent vaginal candidiasis Pulmonary tuberculosis Herpes zoster Oropharyngeal candidiasis Oral hairy leukoplakia Salmonellosis Kaposis sarcoma HIV associated ITP Cervival intraepithelial neoplasia II-III Lymphoid interstitial pneumonitis(LIP) PCP Chronic mucocutaneous herpes simplex Chronic cryptosporidial diarrhoea Microsporidium Oesophageal candidiasis Miliary or extrapulmonary tuberculosis HIV-asociated wasting Peripheral neuropathy Cerebral toxoplasmosis Cryptococcal meningitis Non-Hodgkin Lymphoma MAI CMV

CD4 CELL COUNT

500

200

100 50

Acquired Immunodeficiency Syndromes(AIDS)

Summary
1000 900 800 700 600 500 400 300 200 100 0

Primary Infection

CD4

Clinical latency/ Intermediate stage

AIDS-defining illness

Years : mean survival ~ 10 yrs.

Immunosuppression and Opportunistic Complications

Progressive Multifocal Leukoencephalopathy

Primary HIV Infection Rash

Primary HIV Infection Oral Ulcers

Pneumocystis Carinii Pneumonia

Severe PCP

Cytomegalovirus Retinitis

Herpes Simplex Virus

Herpes Simplex Virus, Treated

Dermatomal Herpes Zoster

Progressive Multifocal Leukoencephalopathy

Oral Candidiasis

CNS Toxoplasmosis

CNS Toxoplasmosis, Treated

Kaposi Sarcoma

Kaposi Sarcoma, Severe

Human Papillomavirus

Seborrheic Dermatitis

HIV
5. Diagnstico Laboratorial
Isolamento do vrus:
Co-cultura

Sorologia:
ELISA: sensibilidade e especificidade > 98% Western blot: Detecta anticorpos contra protenas

do HIV com peso molecular especfico Deteco do cido nuclico ou dos antgenos virais. ( Carga Viral ) PCR

RT-PCR. ( Real Time PCR)

HIV
6. Epidemiologia
Distribuio mundial. Na dcada de 90 houve aumento significativo no nmero de casos de HIV em mulheres e contato heterossexual. transmitido pelo contato sexual, sangue ou seus derivados contaminados e por via vertical. A presena de outras DST aumenta em at 100 vezes o risco de transmisso sexual do HIV.

6. Epidemiologia

HIV

As taxas de transmisso vertical variam de 13 a 42%. O risco estimado de transmisso aps nico contato com fluidos infectados pelo HIV de < 0,1%. O HIV foi isolado da saliva. O HIV pode sobreviver por vrias horas a dias em insetos que se alimentam de sangue com altas concentraes de HIV; porm, no h replicao viral no inseto.

Global summary of the HIV and AIDS epidemic, 2005


Number of people living with HIV in 2005 People newly infected with HIV in 2005 AIDS deaths in 2005
Total million] Adults million] Women million] Children under 15 years 38.6 million [33.4 46.0 36.3 million [31.4 43.4 17.3 million [14.8 20.6 2.3 million [1.7 3.5 million] 4.1 million [3.4 6.2 million] 3.6 million [3.0 5.4 million] 540 000 [420 000 670

Total Adults Children under 15 years 000]

Total Adults Children under 15 years 000]

2.8 million [2.4 3.3 million] 2.4 million [2.0 2.8 million] 380 000 [290 000 500

Global estimates for adults and children, 2005



People living with HIV 38.6 million [33.4 46.0

million]
New HIV infections in 2005 Deaths due to AIDS in 2005 4.1 million [3.4 6.2 million] 2.8 million [2.4 3.3 million]

Regional HIV and AIDS statistics and features, 2003 and 2005
REGION Adults (15+) and Adults (15+) and children children living with HIV newly infected with HIV 2005
Sub-Saharan Africa North Africa and Middle East Asia Oceania Latin America Caribbean Eastern Europe and Central Asia North America, Western and Central Europe TOTAL
24.5 million 440 000 8.3 million
[5.712.5 million] [250 000720 000] [21.627.4 million]

Adult (15-49) prevalence (%) 2005


6.1
[5.46.8]

Adult (15+) and child deaths due to AIDS 2005


2.0 million
[1.72.3 million]

2003
23.5 million 380 000 7.6 million
[5.211.3 million] [220 000620 000] [20.826.3 million]

2005
2.7 million
[2.33.1 million]

2003
2.6 million
[2.33.0 million]

2003
6.2
[5.57.0]

2003
1.9 million
[1.72.3 million]

64 000
[38 000210 000]

54 000
[31 000150 000]

0.2
[0.10.4]

0.2
[0.10.3]

37 000
[20 00062 000]

34 000
[18 00057 000]

930 000
[620 0002.4 million]

860 000
[560 0002.3 million]

0.4
[0.30.6]

0.4
[0.20.6]

600 000
[400 000850 000] [19005500]

500 000
[340 000710 000] [13003600]

78 000
[48 000170 000]

66 000
[41 000140 000]

7200
[350055 000]

9000
[4300-69 000]

0.3
[0.20.8]

0.3
[0.20.7]

3400

2300

1.6 million
[1.22.4 million]

1.4 million
[1.12.0 million]

140 000
[100 000420 000] [26 00054 000]

130 000
[95 000310 000]

0.5
[0.41.2]

0.5
[0.40.7]

59 000
[47 00076 000]

51 000
[40 00067 000]

330 000 1.5 million


[1.02.3 million] [240 000420 000]

310 000 1.1 million


[790 0001.7 million]

37 000

34 000
[24 00047 000]

1.6
[1.12.2]

1.5
[1.12.0]

27 000
[19 00036 000]

28 000
[19 00038 000]

[230 000400 000]

220 000
[150 000650 000] [52 00098 000]

160 000
[110 000440 000] [52 00098 000]

0.8
[0.61.4]

0.6
[0.41.0]

53 000
[36 00075 000]

28 000
[19 00039 000]

2.0 million
[1.42.9 million]

1.8 million
[1.32.7 million]

65 000

65 000

0.5
[0.40.7]

0.5
[0.30.6]

30 000
[24 00045 000]

30 000
[24 00045 000]

38.6 million
[33.446.0 million]

36.2 million
[31.442.9 million]

4.1 million
[3.46.2 million]

3.9 million
[3.35.8 million]

1.0
[0.91.2]

1.0
[0.81.2]

2.8 million
[2.43.3 million]

2.6 million
[2.23.1 million]

Global estimates for adults and children, 2005



People living with HIV 38.6 million [33.4 46.0

million]
New HIV infections in 2005 Deaths due to AIDS in 2005 4.1 million [3.4 6.2 million] 2.8 million [2.4 3.3 million]

Adults and children estimated to be living with HIV, 2005


Western & Eastern Europe Central Europe & Central Asia North America
[770 000 2.1 million]

1.3 million

[550 000 950 000]

720 000

[1.0 2.3 million] East Asia [420 000 1.1 million]

1.5 million

Caribbean
[240 000 420 000]

330 000

North Africa & Middle East


[250 000 720 000]

680 000

440 000

South & South-East Asia

Sub-Saharan Africa Latin America


[1.2 2.4 million]

1.6 million

[21.6 27.4 million]

24.5 million

7.6 million

[5.1 11.7 million] Oceania [48 000 170 000]

78 000

Total: 38.6 (33.4 46.0) million

Estimated number of adults and children newly infected with HIV, 2005
Western & Eastern Europe Central Europe & Central Asia North America
[34 000 65 000]

43 000

[18 000 33 000]

22 000

[150 000 650 000] East Asia [55 000 290 000]

220 000

Caribbean
[26 000 54 000]

37 000

North Africa & Middle East


[38 000 210 000]

97 000

64 000

South & South-East Asia

Sub-Saharan Africa Latin America


[100 000 420 000]

140 000

[2.3 3.1 million]

2.7 million

830 000

[530 000 Oceania 2.3 million] [3500 55 000]

7200

Total: 4.1 (3.4 6.2) million

Estimated adult and child deaths from AIDS, 2005


Western & Eastern Europe Central Europe & Central Asia North America
[11 000 26 000]

18 000

12 000
[<15 000]

[36 000 75 000] East Asia [20 000 49 000]

53 000

Caribbean
[19 000 36 000]

27 000

North Africa & Middle East


[20 000 62 000]

33 000

37 000

South & South-East Asia

Sub-Saharan Africa Latin America


[47 000 76 000]

59 000

[1.7 2.3 million]

2.0 million

560 000

[370 000 Oceania 810 000] [1900 5500]

3400

Total: 2.8 (2.4 3.3) million

Children (<15 years) estimated to be living with HIV, 2005


Western & Eastern Europe Central Europe & Central Asia North America
[3500 27 000]

11 000

[<8000]

4000

[3400 14 000]

6900

East Asia
[2000 16 000]

Caribbean
[9800 43 000]

22 000

North Africa & Middle East


[12 000 75 000]

6400

31 000

South & South-East Asia

Sub-Saharan Africa Latin America


[19 000 59 000]

32 000

[1.5 3.0 million]

2.0 million

170 000

[70 000 Oceania 380 000] [830 7900]

3000

Total: 2.3 (1.7 3.5) million

Estimated deaths in children (<15 years) from AIDS, 2005


Western & Eastern Europe Central Europe & Central Asia North America

<100
[<200]

<100
[<200]

[620 2300]

1200

East Asia
[530 2700]

Caribbean
[1600 5100]

3100

North Africa & Middle East


[2000 9500]

1400

4900

South & South-East Asia

Sub-Saharan Africa Latin America


[1800 4900]

2900

[250 000 440 000]

330 000

29 000

[14 000 Oceania 54 000] [200 1800]

600

Total: 380 000 (290 000 500 000)

Estimated number of children (<15 years) newly infected with HIV, 2005
Western & Eastern Europe Central Europe & Central Asia North America
[<1000]

500

[<400]

200

[1400 3900]

2300

East Asia
[1000 4100]

Caribbean
[2100 5800]

3700

North Africa & Middle East


[3200 12 000]

2300

6900

South & South-East Asia

Sub-Saharan Africa Latin America


[3500 8000]

5000

[370 000 590 000]

470 000

44 000

[23 000 Oceania 75 000] [400 2800]

1100

Total: 540 000 (420 000 670 000)

Over 11 000 new HIV infections a day in 2005


More than 95% are in low and middle income countries
About 1500 are in children under 15 years of age About 10 000 are in adults aged 15 years and older of whom: almost 50% are among women over 40% are among young people (15-24)

2005 global HIV and AIDS estimates


Children (<15 years)

Children living with HIV New HIV infections in 2005 Deaths due to AIDS in 2005

2.3 million [1.7 3.5 million] 540 000 [420 000 670 000] 380 000 [290 000 500 000]

Ocorreram no mundo cerca de 14 000 novas infeces/dia pelo HIV em 2004.

O Brasil tem, aproximadamente, 597 mil portadores do HIV Na Regio Sul a estimativa de 89 840 a108 029 portadores.
Projeto-Sentinela 2001

1980 at dezembro 2005 = 403 mil casos de AIDS Taxa de Incidncia Crescente at meados da dcada de 90. 1998 = 17 casos novos por 100.000 hab.

80% dos casos no Sul e Sudeste 2004 = estimativa de 593 mil pessoa entre 15 e 49 anos vivendo com HIV/AIDS (0,61%). 208 mil mulheres 385 mil homens

HIV
7. Preveno, Tratamento e Controle

Vacinas contra HIV


Agentes antivirais Medidas de controle Educao sanitria.

zidovudina (AZT)

nevirapina efavirenz
Tenofovir

saquinavir indinavir nelfinavir ritonavir


Lopinavir/r

didanosina estavudina lamivudina abacavir

amprenavir
Atazanavir

Efuvertida

Tipranavir

5-Tratamento especfico com anti-retrovirais


Inibidores da transcriptase reversa: 1) anlogos do nucleosdeo - zidovudina (AZT) didanosina (ddI ) estavudina(d4T) lamivudina(3TC) abacavir (ABC) 2) Anlogo de nucleotdeo tenofovir (TFV) 3) No-anlogos do nucleosdeo: nevirapina (NVP) efavirenz (EFZ)

5-Tratamento especfico com anti-retrovirais


Inibidores da Protease: indinavir (IDV) saquinavir (SQV) ritonavir (RTV) nelfinavir (NFV) amprenavir (APV) lopinavir/r (LPV) atazanavir (ATV) tipranavir (TPV) Inibidores da Fuso : efuvertida