1. HUMAN IMMUNODEFICIENCY VIRUS INFECTION

2. Acquired immunodeficiency syndrome was first reported in 1981 in the Morbidity and Mortality Weekly Report under the title “ Pneumocystis pneumonia – Los Angeles”. Acquired immunodeficiency syndrome was first reported in 1981 in the Morbidity and Mortality Weekly Report under the title “ Pneumocystis pneumonia – Los Angeles”. In 20 years, the AIDS epidemic has grown from a series of small outbreaks in several risk groups throughout the United States and western Europe into a global public health calamity. Tremendous advances have been made in understanding the molecular mechanisms, in achieving of antiretroviral therapy and blood-supply safety. In 20 years, the AIDS epidemic has grown from a series of small outbreaks in several risk groups throughout the United States and western Europe into a global public health calamity. Tremendous advances have been made in understanding the molecular mechanisms, in achieving of antiretroviral therapy and blood-supply safety. Although the disease was first encountered in homosexual men andinjection-drug users, the risk groups soon included transfusion recipients, infants,female sexual contact of infected men, prisoners, Haitians and Africans. Although the disease was first encountered in homosexual men andinjection-drug users, the risk groups soon included transfusion recipients, infants,female sexual contact of infected men, prisoners, Haitians and Africans.

3. Structure of the HIV-1 virion Table 1. Genes and gene products of HIV 1 and 2 GenesProteins GagPolEnvVifVprTatRevVpuNefvpx p17, p24, p1, p2, p6, p7. Protease, RT, integrase gp120, gp41 virion infectivity protein viral protein R transactivator of of transcription regulator of expression of virion protein viral protein U (HIV-1 only) negative regulatory factory virion protein X (HIV-2 only).

4. The life cycle of HIV-1 The major steps in the HIV life are: Afferent functions 1.Binding and entry. 2.Reverse transcription, nuclear import, and integration of viral DNA 2.Reverse transcription, nuclear import, and integration of viral DNA Efferent functions Viral transcription (production of mRNA Viral transcription (production of mRNA Production of viral regulatory factors Production of viral regulatory factors Virion assembly. Virion assembly. Virus budding and release Virus budding and release

5. Pathogenesis of HIV disease The main target of HIV infection is the CD4- positive-lymphocyte population, although infection of tymocytes, macrophages and dendritic cells, can occur. The main target of HIV infection is the CD4- positive-lymphocyte population, although infection of tymocytes, macrophages and dendritic cells, can occur. Additional co-receptor which are used for virus entry into CD4-T cells are: Additional co-receptor which are used for virus entry into CD4-T cells are: 1. CC-chemokine receptor CCR5 1. CC-chemokine receptor CCR5 2. CXC-chemokine receptor (CXCR4 )-. 2. CXC-chemokine receptor (CXCR4 )-.

6. Acute HIV infection Viral load levels in the blood rise; Viral load levels in the blood rise; Dissemination of the virions Dissemination of the virions CD4 T-cells count decrease CD4 T-cells count decrease Appearance of HIV-specific CTL (cytotoxic T lymphocytes) which kill infected cells and secrete antiviral cytokines and chemokines). Appearance of HIV-specific CTL (cytotoxic T lymphocytes) which kill infected cells and secrete antiviral cytokines and chemokines). Chronic HIV infection CD4 T-cells number and function continue to decline during the period of clinical latency; CD4 T-cells number and function continue to decline during the period of clinical latency; Defects in T-cell function/loss of specific responses to recall antigens; Defects in T-cell function/loss of specific responses to recall antigens; Abnormalities in B-cell, natural killer, monocytes and dendritic cell functions Abnormalities in B-cell, natural killer, monocytes and dendritic cell functions Altered cytokine secretion with reduced production of IFN-gamma, IL-2 and IL-12 may occur Altered cytokine secretion with reduced production of IFN-gamma, IL-2 and IL-12 may occur The virus continue to replicate at all stages of infection The virus continue to replicate at all stages of infection

7. Mechanisms of immune depletion are: Direct cytopathic effect Direct cytopathic effect Syncytium or multinucleated cell formation, Syncytium or multinucleated cell formation, Apoptosis (programmed cell death). Apoptosis (programmed cell death). Removal of infected CD4 T cells and dendritic cells by the vigorous HIV-specific CTL responses Removal of infected CD4 T cells and dendritic cells by the vigorous HIV-specific CTL responses

8. Clinical manifestations Classification of HIV-1 disease into six stages is based on a combination of clinical features and CD4 count: Classification of HIV-1 disease into six stages is based on a combination of clinical features and CD4 count: 1.Initial infection (acute seroconversion syndrome) 1.Initial infection (acute seroconversion syndrome) 2.Early HIV-1 disease 2.Early HIV-1 disease 3.Intermediate HIV-1 disease 3.Intermediate HIV-1 disease 4.Late HIV-1 disease 4.Late HIV-1 disease 5.Advanced HIV-1 disease 5.Advanced HIV-1 disease 6.Terminal HIV-1 disease. 6.Terminal HIV-1 disease.

9. Initial infection (acute seroconversion syndrome) – usually occurs within 2 to 6 weeks (median=21 days) after exposure to the virus. - may be asymptomatic or - may be asymptomatic or - may evolve with symptoms of flu-like or mononucleosis-like - may evolve with symptoms of flu-like or mononucleosis-like illness illness The most common symptoms are: The most common symptoms are: fever, fever, lymphadenopathy lymphadenopathy pharyngitis, esophagitis, aphthous ulcerations pharyngitis, esophagitis, aphthous ulcerations myalgias, arthralgias myalgias, arthralgias headache headache diarrhea diarrhea morbilliform skin eruption morbilliform skin eruption neurologic manifestations: meningitis, peripheral neuropathy, myopathy, cranial nerve palsies. neurologic manifestations: meningitis, peripheral neuropathy, myopathy, cranial nerve palsies.

10. Early HIV-1 disease - is defined by a CD4 cell count greater than 500cells/mmc. Most persons are asymptomatic. Early HIV-1 disease - is defined by a CD4 cell count greater than 500cells/mmc. Most persons are asymptomatic. Among symptoms: -lymphadenopathy (cervical, axillary and inguinal chains), -lymphadenopathy (cervical, axillary and inguinal chains), - dermatologic abnormalities: seboreic dermatitis, perifolliculitis, eosinophilic folliculitis, - dermatologic abnormalities: seboreic dermatitis, perifolliculitis, eosinophilic folliculitis, - oral lesions: aphtous ulcerations, hairy leucoplakia. - oral lesions: aphtous ulcerations, hairy leucoplakia. Intermediate stage of HIV-1 disease – is defined by a CD4 count between 200 and 500 cells/mmc and could evolves without symptoms or with mild disease manifestations: Intermediate stage of HIV-1 disease – is defined by a CD4 count between 200 and 500 cells/mmc and could evolves without symptoms or with mild disease manifestations: - Recurrent herpes simplex infection - Recurrent herpes simplex infection - Oropharyngeal/vaginal candidiasis - Oropharyngeal/vaginal candidiasis - Varicella zoster virus infection - Varicella zoster virus infection - Weight loss - Weight loss - Bacterial sinusitis, bronchitis, pneumonia - Bacterial sinusitis, bronchitis, pneumonia - Headache, myalgias, arthralgias - Headache, myalgias, arthralgias

11. Late-stage disease – is defined by a CD4 cell count between 50 and 200 cells/mmc. These patients have a great risk of developing : opportunistic infections such as Pneumocystis carini pneumonia, Toxoplasma gondii infection, cryptosporidiosis, tuberculosis, Kaposi’s sarcoma, esophagial candidiasis and opportunistic infections such as Pneumocystis carini pneumonia, Toxoplasma gondii infection, cryptosporidiosis, tuberculosis, Kaposi’s sarcoma, esophagial candidiasis and hematologic abnormalities (anemia, neutropenia, idiopathic thrombocytopenia). hematologic abnormalities (anemia, neutropenia, idiopathic thrombocytopenia). Advanced HIV disease – is defined as a CD4 count of less than 50 cells/mmc. The most frequent conditions seen during this stage are: MAC disease, cryptococcal meningitis, cytomegalovirus retinitis, progressive multifocal leukoencephalopathy. Terminal HIV disease – symptoms of disease cannot be controlled because no treatment are available The management includes psychological support, family support, and pain management. The management includes psychological support, family support, and pain management.

12. Classification Table 2. Clinical categories Clinical category A Clinical category B Clinical category C Asymptomatic HIV infectionPersistent generalized lymphadenopathyPrimar y (acute) HIV illness Symptomatic, nonA or C conditions Candidiasis, oropharyngeal Candidiasis, vulvovaginal(>1 mo) Bacillary angiomatosis Cervical displasia, severe, or carcinoma in situ Constitutional symptoms: fever, diarrhea>1 month Candidiasis: esophageal, trachea, bronchi Coccidioidomycosis, extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis>1mo CMV retinitis, or in other than liver, spleen, nodes HIV encephalopathy Histoplasmosis, extrapulmonary, disseminated Isosporiasis>1 mo Kaposi’s sarcoma Lymphoma M.avium/kansasii: extrapulmonary M. tuberculosis infection Pn.carinii pneumonia Pneumonia, recurrent Progressive multifocal leukoencephalopathy Salmonella bacteremia, recurrent Toxoplasmosis, cerebral Wasting syndrome HIV encephalopathy

13. Table 3. Classification system CD4 cell category CLINICAL CATEGORY A B C 1) >500/mmc A1B1C1 2) 200-499/mmc A2B2A2 3) <200/mmc A3B3A3

14. Pulmonary diseases Any CD4 level: Any CD4 level:CD4<200/mmcCD4<100/mmc - Cryptococcosis - Cryptococcosis - Coccidioidomycosis - Coccidioidomycosis - Histoplasmosis - Histoplasmosis CD4<50/mmc CD4<50/mmc - Aspergilosis - Aspergilosis - M. avium - M. avium

15. Neurologic manifestations Brain involvement Brain involvement A. Focal lesions B. Nonfocal complications Spinal cord Meninges Peripheral nerve and root lymphomatous meningitis; lymphomatous meningitis;

16. Table 4. Classification of oral lesions: Viral lesions Hairy leukoplakia Herpes simplex Herpes zoster Cytomegalovirus Fungal lesions CandidiasisHistoplasmosisCryptococcosis Bacterial lesions Periodontal disease Necrotizing stomatitis Mycobacterium avium complex Bacillary angiomatosis Neoplastic lesions Kaposi’s sarcoma Kaposi’s sarcoma Non-Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Hodgkin’s lymphoma Hodgkin’s lymphoma Autoimmune/idiopathic lesions Salivary gland disease Salivary gland disease Aphtous ulcers Aphtous ulcers Abnormal pigmentation Abnormal pigmentation

17. Dermatologic complications Table 5. Skin lesions Maculopapular lesions Moluscum contagiosum Syphilis Mycobacterial infectionKaposi’s sarcoma Nodular, verrucous, and/or ulcerative lesions Bacillary angiomatosis CryptococcosisSporotrichosis MAC infections Kaposi’s sarcoma Vesicular, bulous or pustular lesions Herpes simplex virus Varicella-zosterCytomegalovirus Staphylococcal impetigo Stevens-Johnson syndrome Papulosquamous lesions Seborrheic dermatitis Dry-skin syndrome Psoriasis Norwegian scabies Staphylococcal folliculitis Eosinophilicfolliculitis

18. Table 6. Acute infectious diarrhea Campylobacter jejuni Clostridium difficile Clostridium difficile Enteric viruses Enteric viruses Enteroadherent E. coli Enteroadherent E. coli Salmonella Salmonella Shigella Shigella Cryptosporidia Cryptosporidia Cytomegalovirus Cytomegalovirus Entamoeba histolytica Entamoeba histolytica Isospora belli Isospora belli Microsporidia Microsporidia Mycobacterium avium Mycobacterium avium

19. Spectrum of associated malignancies Kaposi’s sarcoma Kaposi’s sarcoma Primary CNS lymphoma Primary CNS lymphoma Non-Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Cervical carcinoma Cervical carcinoma Hodgkin’s disease Hodgkin’s disease Seminoma Seminoma

20. Laboratory tests HIV antibody tests HIV antibody tests Enzyme immunoabsorbant assay (EIA). Enzyme immunoabsorbant assay (EIA). Western-Blot (WB). Western-Blot (WB). Immunofluorescent assay Immunofluorescent assay 1.Rapid detection methods 1.Rapid detection methods 2.Home tests kits 2.Home tests kits Viral detection Viral detection

21. Treatment Table 7. Antiretroviral drugs Antiretroviral drugs Doses Nucleoside reverse-transcriptase inhibitors (NRTI) Group A drugs Zidovudine (ZDV) – Retrovir Stavudine (D4T) – Zerit Group B drugs Didanosine (ddi) – VidexZalcitabine (ddC) - HIVIDLamivudine (3TC) - Epivir 300 mg bid or 200 mg tid 40 mg bid (>60 kg), 30 mg bid (<60kg) 200 mg bid (>60 kg), 125 mg bid (<60kg)0,75 mg tid 150 mg bid` Non-nucleoside reverse-transcriptase inhibitors (NNRTI)Nevirapine-ViramuneDelavirdine - Rescriptor 200 mg qdx2 wks, then 200 mg bid 400mg tid Protease inhibitors Saquinavir - Invirase Saquinavir - Fortovase Indinavir – Crixivan Ritonavir – Norvir Nelfinavir - Viracept 600 mg q8h with meals 1200 mg q8h with meals 800 mg q8h, empty stomach 300 mg q12 h-2 wks, then 600mg bid 750 mg q8h

22. Initial regimens Preferred: Preferred: - 2 nucleosides and a PI - 2 nucleosides and a PI - 2 nucleosides and a NNRTI - 2 nucleosides and a NNRTI Under evaluation: Under evaluation: 3 nucleosides 3 nucleosides In patients with CD4 100 000c/ml: In patients with CD4 100 000c/ml: - 2NRTIs + 2 PI - 2NRTIs + 2 PI - 2NRTIs + PI + NNRTI - 2NRTIs + PI + NNRTI HAART (highly active antiretroviral therapy) is an antiretroviral regimen that can be expected to reduce the viral load to<50c/ml in treatment-naïve patients. HAART (highly active antiretroviral therapy) is an antiretroviral regimen that can be expected to reduce the viral load to<50c/ml in treatment-naïve patients.

23. Indications for Antiretroviral therapy Table 8. Indications for the initiation of antiretroviral therapy (DHHS Guidelines-2000) Clinical category CD4 cell count/HIV RNA Recommendation Asymptomatic CD4<500/mmc, or RNA>10000 (bDNA), or >20000 (RT-PCR) Treat Asymptomatic CD4>500/mmc and HIV RNA 500/mmc and HIV RNA<10000 (bDNA), or <20000 (RT-PCR) Delay therapy and observe, or treat Acute HIV, or <6 mo after seroconversion All Treat Treat Symptomatic (AIDS, unexplained fever) AllTreat