Acquired Immuno-deficiency

Syndrome (AIDS)

Savitha R S

JSSCP, Mysore

 Introduction

  Caused by retrovirus human immunodeficiency

virus (HIV)

  Profound Immunosuppression

  Leading to opportunistic infections,

secondary neoplasms and neurologic
manifestations

 Retrovirus

  Family - Retroviridae, family of RNA viruses 80-100nm

in diameter.

• enveloped and containing two identical molecules of

positive sense, single stranded RNA

• Seven genera - Mammalian type B, type C, Avian type

C, Type D, Bovine leukemia virus - Human T cell
leukemia-lymphoma virus (BLV-HTLV), retroviruses,
lentivirus and spumovirus

 Properties of HIV

  Non-transforming human retrovirus

  Tropism to CD4+ molecules present on sub

population of T cells

  HIV - cytopathic virus - cytolytic for T cells causing

immunodeficiency

  HTLV - transforming virus - transforms target cells

into T cell leukemia.

 Types of HIV

  HIV - 1 - more common associated with AIDS in

Europe, USA and Central Africa

  HIV - 2 - Principally west Africa and India

  Blood tests screened for seropositivity for

both

 Structure of HIV

  Spherical containing electron dense cone- shaped core

  surrounded by lipid envelope

  Virus core contains

  major capsid protein (p24)

  nucleocapsid protein p7/p9

  two copies of genomic RNA and

  three viral enzymes (reverse transcriptase, integrate,

protease)

  p-24 most readily detected viral antigen and is

target for antibodies used for diagnosis of HIV
infection in ELISA (enzyme-linked
immunosorbent assay)

 Routes of Transmission

• Sexual contact. Homosexual and bisexual males (50%) and heterosexual males
and females.

• Parenteral transmission. (about 25%) Occurs in 3 groups of high risk populations

i.
Intravenous drug abusers (sharing needles and syringes)

ii.
Hemophiliacs who have received large amounts of factor VIII concentrates
from pooled blood concentrates from multiple donors

iii.
Recipients of blood and blood products who have received multiple
transfusions of whole blood or components like platelets and plasma.

• Perinatal transmission. From infected mother to the newborn during pregnancy

by transplacental spread or during delivery (intrapartum) through an infected
birth canal or in immediate post-partum period by ingestion of breast milk.

Pathogenesis

  Profound Immunosuppression affecting cell mediated immunity -

Hallmark of HIV infection

  CD cells important for HIV infection

  CD4 - type 1 transmembrane protein (proteins having -COOH

terminal inside and -NH2 terminal outside the cell)

  found on helper T cells, monocytes, macrophages and dendritic

cells

  CD8 - type 1 transmembrane protein

  found on suppressor (cytotoxic) T cells, some natural killer cells

and most thymocytes

  Both cells are involved in T-cell recognition of antigen

  HIV enters body through mucosal cells and

blood ; first infects T cells, dendritic cells and
macrophages

  Infection becomes established in lymphoid

tissue, where infection remains latent for long
periods of time.

  Active viral replication is associated with

progression to AIDS.

 Sequence of Events - 1

  Selective tropism and internalization

  CD4 molecule a high affinity receptor for HIV

  Virus shows selective tropism for CD4+ T cells, other

CD4+ cells - monocytes/macrophages and dendritic
cells

  Envelope glycoprotein gp120 of virion binds to CD

molecule and virus is internalized into the cell

  Correceptors - CCR5 and CXCR4

 Sequence of Events - 2

  Uncoating and proviral DNA integration

  Virus uncoated and genomic RNA transcribed to proviral DNA

by reverse transcriptase enzyme

  Proviral DNA may remain in linear episomal form in T cells or

circularize in dividing T cells and enter nucleus to be integrated
into host genome (integrase enzyme)

  Provirus after integration may be locked in the chromosome for

years or may be transcribed with formation of complete viral
particles.

 Sequence of Events - 3

  Budding and Syncytia formation

•  On activation, the infected CD4+ T cells bear

budding viral particles due to multiplication which
further attract more number of CD4+ T cells
resulting in syncytia formation

•  Syncytia - a multinucleate protoplasmic mass formed

by secondary union of originally separate cells.

 Cytopathic effects

  Infected T cells develop into cytopathic phase

  Quantitative depletion of CD4+ T cells

  Qualitative defect in ability of these cells to

respond to antigens

  CD4-p120 interaction also leads to infection with

other viruses like CMV, hepatitis, herpes simplex
etc.

 Effects on Monocytes/
Macrophages

  Monocytes and macrophages expressing CD4

(dendritic cells, microglial cells) are also
infected by HIV

  don't cause cytopathic effects but they act as

reservoirs of HIV infection and may be source
of infection to other organs like nervous
system

 HIV infection of nervous system

  Do not directly invade nerve cells but affects their health and
function.

  viral factors, host factors and co factors may be involved.

  proteins encoded by viral genome.

  infections in host whereby HIV infected CD4+ monocytes/

macrophages are carried to nervous system - may damage
neurons

  social, behavioral characteristics and co-morbid conditions

contribute to amplify pathogenicity of HIV.

Neurological manifestations

  Confusion, forgetfulness, behavioral changes

  Headaches, loss of sensation in arms and legs,

peripheral neuropathy

  Cognitive motor impairment

  Alters size of certain brain structures involved

in learning and information processing.

 Signs & Symptoms

  Major signs

  weight loss > 10% of body weight

  chronic diarrhea > 1 month duration

  prolonged fever (intermittent or

continuous) for > 1 month

 Signs & symptoms

  Minor signs

  Recurrent oropharyngeal candidiasis

  persistent generalized lymphadenopathy

  persistent cough > 1 month

  Generalized pruritic dermatitis

  Recurrent herpes zoster

  Progressive disseminated herpes simplex infection

  As per WHO, AIDS is defined as the existence

of at least two major signs associated with at
least one minor sign.

 Stages of HIV infection

  Early acute phase

  Middle chronic phase

  Final crisis phase

 Early acute phase

  High levels of plasma viremia due to replication of virus

  Seroconversion after 3-6 weeks of initial exposure

  Reduction in CD4+ T cells (helper T cells) followed by return to

normal levels

  Increase in CD8+ T cells ( HIV specific cytotoxic T cells)

  Appearance of flu-like or infectious mononucleosis-like viral

illness (50-70% patients)in 3-6 weeks of infection

  Symptoms resolve spontaneously in 2-3 weeks.

 Middle Chronic Phase

  Seroconversion is followed by phase of competition between HIV and

host immune response

  Increase in viral load with passing of time

  Chronic stage depends on host immune system (7-10yrs)

  Moderate fall in CD4+ T cells despite their proliferation

  High cytotoxic CD8+ T cell counts

  Clinical stage of latency. Patient may be asymptomatic or mild

constitutional symptoms or persistent generalized lymphadenopathy

 Final Crisis Phase

  Characterized by profound immunosuppression and onset of full-blown

AIDS

  Marked increase in viremia

  Reduction of CD4+ T cells (< 200 per micro liter)

  Fever, Weight loss (> 10% body weight), chronic diarrhea lasting more
than one month.

  Neurological manifestations - viral meningoencephalitis, aseptic

meningitis, peripheral neuropathy, AIDS- dementia complex

  Opportunistic infections

  Secondary neoplasms - kaposi’s sarcoma, non-hodgkin’s lymphoma,

primary CNS lymphoma etc

  Average survival after full-blown AIDS is 18-24

months

Laboratory Diagnosis of AIDS

  Initial testing for antibodies against HIV by

ELISA and confirmation by Western blot or
immunofluroscence test

Enzyme Immmunoassays

Quantitative assay to measure HIV antibodies

Most detect antibodies to HIV-1 and HIV-2

Antigens coated in microwells

HIV Antigen / Antibody reaction is detected

by color change

Intensity of color reflects amount of antibody

present serum

 Western Blot

  Used as supplemental test

for confirmation

  Detects antibodies to
specific HIV antigens on
cellulose strip

 Indirect Tests

  CD4 & CD8 cell counts; reversal of CD4-CD8

ratio

  Lymphopenia

  Lymph node biopsy

  Platelet count revealing thrombocytopenia

  Increased B2 micro globulin levels

 Specific Tests

  Antigen detection tests using envelope and

core proteins of HIV by recombinant DNA
techniques

  Virus isolation and culture in neoplastic T cell

line

  Polymerase chain reaction (PCR)

Questions?

 The type of HIV virus

principally associated with
AIDS in India is

1.  HIV – 1

2.  HIV – 2

3.  HIV – 3

4.  HIV - 4

 Which of the following is

NOT a method for diagnosis
of HIV infection?

1.  ELISA

2.  Flow Cytometry

3.  Immunoflourescence test

4.  Virus isolation and culture

 According to WHO,
diagnosis of AIDS requires
presence of

  One major and two minor symptoms

  Two major and one minor symptoms

  Two major and two minor symtoms

  One major and four minor symptoms