Dr.dr.Efrida Warganegara, M.Kes., Sp.

MK

KEY CONCEPTS
Preferentially binds to the CD4 receptor found on helper T cells & monocytes; the destruction of these cells ultimately disables the immune system & makes the infected individual vulnerable to opportunistic infections Transmitted through sexual contact, IV drug use, vertically (mother to child) Display antigenic variation Has a long latency period (average 10 years) Can currently be managed with antiviral drugs but is otherwise nearly 100% fatal

INTRODUCTION
HIV nononcogenic retrovirus Retroviridae - Lentivirinae Robert Gallo et al (1978) : isolated retrovirus from the lymphocytes of leukemia patient HTLV-I A second virus : HTLV-II was isolated in Seattle USA from the cells of patient with a rare hairy cell leukemia The illness of AIDS was first described in male homosexuals in 1981, and the virus was isolated by the end of 1983 Essex et al (1983) : 25 30 % AIDS Ag-Ab membrane HTLV-I

INTRODUCTION
The first isolation of retrovirus from AIDS case was made by Luc Montagnier & Barr-Sinoussi at the Pasteur Institute Paris (1983) LAV The virus isolated from haemofilia patient with lymphadenopathy It was quickly confirmed by Robert Gallo (1984) HTLV-III Levy (1984) : isolated AIDS-related retrovirus ARV Luc Montagnier (1986) isolated a fourth

CLASSIFICATION
Subfamily Disease caused Natural hosts
Human Oncovirinae HTLV-I Adult T-cell leukemia, lymphoma, tropical spastic paraparesis HTLV-II Hairy cell leukemia Spumavirina Inapparent e persistent infection Lentivirinae HIV-1 HIV-2 Immunodeficiency Immunodeficiency

Human Primates & other animals

Human Human & primates Monkey

The human AIDS virus are not homogenous, most are variants of HIV-1 A second virus HIV-2 seems prevalent only in West Africa, much less virulent Only about 40% of the sequences of HIV-1 and HIV-2 are identical Based on env gene sequences 9 subtypes of HIV-1 AI 5 subtypes of HIV-2 AE These subtypes are referred as clades. Within subtype there is extensive variability

PROPERTIES OF HIV
Virion : spherical, 80 100 nm, cylindric core Genome : SS-RNA, linear, positive sense, 9 10 kb Proteins : envelope glycoprotein, reverse transcriptase enzyme contained inside virions, protease required for production of infectious virus Envelope : present Replication : reverse transcriptase makes DNA copy from from genomic RNA; provirus DNA is template for viral RNA Maturation : particles bud from plasma membrane

STRUCTURE OF HIV

The virus contains the three genes required for a replication

gag : encodes the core protein (group-specific antigens pol : encodes the reverse transcriptase enzyme (polymease) env : encodes the glycoproteins that form projections on the envelope of the particle

Up to six additional genes regulate viral expression & important in disease pathogenesis in vivo. Although these auxiliary genes show a little sequence homology among lentivirus, their functions are conserved

 Additional genes :
tat or tax : transactivating regulatory gene encodes a nonstructural proteins that alters the transcription or translational efficiency of other viral gene rev : regulator of expression of virion

gp 120 : responsible for virus attachment to

the CD4 molecule and coreceptors & carries the major antigenic determinants that elicit neutralizing Abs gp 41 : contain transmembrane domain that anchors the glycoprotein in the viral envelope and a fusion domain that facilitate viral penetration into target cells

VIRAL REPLICATION

DISINFECTION & INACTIVATION

HIV completely inactivated by treatment for 10 minutes at room temperature with :
10 % household bleach 50 % ethanol 35 % isopropanol 0,5 % Lysol 0,5 % paraformaldehyde 0,3 % hydrogen peroxide

Also inactivated by extremes pH : pH 1.0 & 13.0 When HIV present in clotted or unclotted blood in needle or syringe, exposure to undiluted bleach at least 30 seconds for inactivation HIV inactivated by heating at 560C for 10 minutes

CELL TROPISM
IN VITRO

T lymphocyte, CD4+ Monocyte/macrophage Microglia Precursor CD 34+ cells Monocytic & T-cell lines Glioma & neuroblastoma cell lines Tumor cell lines T lymphocyte, CD4+ Monocyte/ macrophage Epithelial Langerhans cells Dendritic cells Endothelial cells of the brain Microglia, astroglia, oligodendroglia Cells of retina, cervix and colon

IN VIVO

IMMUNODEFICIENCY PROCESS
MODE OF TRANSMISSION
Parenteral (IV, drug use) Mucosal (sexual contact) Vertical (mother to child)

Free HIV

HIV in CD4+ T cells regional lymph nodes

Cellular IR

Humoral IR

Limphopenia CD4+ cells Free virus & p24 in blood Number of infected CD4 Virus rapid replication with control of IR 2 4 weeks

Total lymphocyte Antibody + : 2 3 weeks

CD8 months

PATHOGENESIS & PATHOLOGY

Stages : Primary infection Dissemination of virus to lymphoid organs Clinical latency Elevated HIV expression Clinical disease Death The duration between primary infection & progression to clinical disease 10 years Death usually 3 years after onset of clinical syndrome

 Following primary infection, viral replication occurs & viremia detectable for about 8 12 weeks Virus is widely disseminated throughout the body & the lymphoid organs become seeded

 The period of clinical latency may last for as long as 10 years. During this period, there is a high level of ongoing viral replication, estimated that 10 billion HIV particles are produced & destroyed each day.
The half life of virus in plasma is about 6 hours, and the virus life cycle (from the time of infection of cells to the production of new progeny that infect the next cell) averages 2.6 days

CLINICAL FINDINGS
AIDS is characterized by a pronounced suppression of the immune system & the development of unusual neoplasms (especially Kaposis sarcoma) or a wide variety of severe opportunistic infections Plasma viral load : the amount of HIV in the blood (viral load) is of significant prognostic value. Plasma HIV RNA levels can be determined using a variety of commercially available assays.

CLINICAL CATEGORIES OF HIV INFECTION IN PERSONS > 13 YEARS OF AGE 1. Category A :

Asymptomatic Persistent generalized adenopathy Symptomatic, acute (primary) HIV infection

2. Category B :
Some conditions are diagnosed

3. Category C :
Any of some conditions are diagnosed

CDC DEFINITION OF AIDS

CD4+ T-cells 500/l 200 499/l <200/l Clinical category AB C A1B1 A2B2 A3B3 C1 C2 C3

AIDS is diagnosed if the patient meets criteria for category A3, B3, C1, C2, or C3

OPPORTUNISTIC INFECTIONS
PROTOZOA
Toxoplasma gondii Isospora belli Cryptosporidium sp. BACTERIA
Mycobacterium aviumintracellulare Mycobacterium tuberculosis Listeria monocytogenes Nocardia asteroides Salmonella sp. Streptococcus sp.

FUNGI
Candida albicans Cryptococcus neoformans Coccidioides immitis Histoplasma capsulatum Pneumocystis carinii

VIRUS Cytomegalovirus Herpes simplex virus Varicella-zoster virus Adenovirus JC human papovavirus Hepatitis B virus

LABORATORY DIAGNOSIS
Evidence of HIV infection :
1. Virus isolation
Cultured from lymphocyte in peripheral blood or other specimens, but time consuming

2. Serologic determination of antiviral Abs

ELISA, antibody repeated Confirmation : immunofluorescence & radioimmunoprecipitation, Western blot : at least 2 bands of p24, gp41 or gp120/gp 160 should be present

3. Measurement of viral nucleic acid or Ag

LABORATORY DIAGNOSIS
Examination of immunity status - CD4, CD8 - Hematology Examination of opportunistic infection / malignancy

INTERPRETATION OF LABORATORY EXAMINATION

1. Positive HIV infection :
patient sera up to 15 months of age, HIV +, even mother has no HIV patient sera < 15 months of age, HIV +, mother HIV +, lymphocyte count p24 Ag + HIV culture +, Ag +, RT-ase enzyme +, probe + Positive test with specific tests

2. Negative HIV :
screening & confirmation tests -

3. Inconclusive :
Screening test for HIV +, confirmation, Ag, & culture are negative

ANTIRETROVIRUS DRUG FOR HIV INFECTION

NNRTI (NON-NUCLEOSIDE ANALOG REVERSE TRANSCRIPTASE INHIBITOR * Nevirapine * Delavirdine mesylate NRTI (NUCLEOSIDE ANALOG REVERSE TRANSCRIPATSE INHIBITOR) * Didanosine (ddI) * Lamivudine (3TC) * Zalzitabine (ddC) * Stavudine (d4T) * Zidovudine (AZT : Azydothymidine PROTEASE INHIBITOR * Indinavir * Ritonavir * Nelfinavir mesylate * Saquinavir