Virology
Dr. Bara' H. Hadi
HIV
The human immunodeficiency virus (HIV) is a member of the genus Lentivirus, part of
the family Retroviridae. Lentiviruses have many morphologies and biological properties in
common. Many species are infected by lentiviruses, which are characteristically responsible
for long-duration illnesses with a long incubation period. Lentiviruses are transmitted as
single-stranded, positive-sense, enveloped RNA viruses. Upon entry into the target cell, the
viral RNA genome is converted (reverse transcribed) into double-stranded DNA by a virally
encoded reverse transcriptase that is transported along with the viral genome in the virus
particle.
Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was
initially discovered and termed both LAV and HTLV-III. It is more virulent, more infective,
and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2
compared to HIV-1 implies that fewer of those exposed to HIV-2 will be infected per
exposure.
1
Virology
Dr. Bara' H. Hadi
Structure and genome:
HIV is different in structure from other retroviruses. It is roughly spherical with a diameter
of about 120 nm. It is composed of two copies of positive single-stranded RNA that codes
for the virus's nine genes enclosed by a conical capsid composed of 2,000 copies of the viral
protein p24. The single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and
enzymes needed for the development of the virion such as reverse transcriptase, proteases,
and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the
integrity of the virion particle. This is, in turn, surrounded by the viral envelope. Embedded
in the viral envelope are proteins from the host cell and about 70 copies of a complex HIV
protein that protrudes through the surface of the virus particle. This protein, known as Env,
consists of a cap made of three molecules called glycoprotein (gp) 120, and a stem
consisting of three gp41 molecules that anchor the structure into the viral envelope. This
glycoprotein complex enables the virus to attach to and fuse with target cells to initiate the
infectious cycle. Both these surface proteins, especially gp120, have been considered as
targets of future treatments or vaccines against HIV.
Genes and proteins of HIV:
Gene
Protiens encoded by
gene
1-Structural genes found in all retroviruses:
Function of proteins
gag
P 24,p7,
P17
Nucleocapsid
matrix
pol
Reverse transcriptase
Protease
Integrase
gp 120
gp 41
Transcribes RNAgenome into DNA
Clave precursor polypeptides
Integrates viral DNA into host DNA
Attachment to CD4 protein
Fusion with host cell
env
2-Regulatory genes that are required for replication:
tat
Tat
rev
Rev
Activation of transcription of viral
gene
Transport of late mRNAfrom
nucleus to cytoplasm
3-Regulatory genes that are not required for replication(accessory genes):
nef
Nef
Decrease CD4 protein and class l
2
Virology
Dr. Bara' H. Hadi
vif
Vif
vpr
Vpr
vpu
Vpu
MHC
Enhances infectivity by inhibiting
the enzyme that cause mutation in
retroviral DNA
Transport viral core from
cytoplasm into nucleus in non
dividing cells
Enhances virion release from cell
Pathogenesis :
 HIV-1 gains entry by attachment of the virion surface glycoprotein gp 120 to the
CD4 molecule on the surface of helper T lymphocytes and monocytes-macrophages.
 The glycoprotein gp 120 also interacts with a second cellular corecepter ,a
chemokine receptor(CXCR4 on T cells or CCR5 on macrophages ),that facilitates
efficient fusion of the viral envelope with the cell plasma membrane and entry.
 Chemokine
coreceptor dictate the cell tropisim of different HIV-1 strains
(T-tropic or M-tropic)
 Individuals with homozygous mutations in the CCR5 gene are resistant to HIV-1
infection ,demonstrating the physiological importance of the chemokine receptor.
 Mucosal dentritic cells can also be infected by HIV -1 by binding through lectin
receptor and transport virus to T cells or macrophages in draining lymph node.
 HIV-1 may infect both activated and non activated CD4 T cells in the draining
lymph node.
 Virus remains latent in non activated (resting) T cells but replicates in T cells
activated by infection or cytokines or both.
 Free virus and virus- infected cells leave the lymph node and spread to other
lymphoid organs,blood,and other tissues.
 The loss of CD4 T lymphocytes is the primary defect in AIDS pathogenesis.This is
due to direct killing of CD4 T lymphocytes by virus and a cytotoxic T-cell response
to HIV –infected cells.
 Latently infected T cells serve as a reservoir for HIV -1 and escape immune detection
.
 Latently infected T cells can switch to viral gene expression and release of infectious
virus after antigen activation.
3
Virology
Dr. Bara' H. Hadi
 Ultimately ,the decline in CD4+ T cells leads to a generalized failure of cellmediated immunity ,leaving the patient vulnerable to opportunistic infections and
certain types of can.
transmission:
 Sexual transmission, presence of STD increases likelihood of transmission.
 Exposure to infected blood or blood products.
 Use of contaminated clotting factors by hemophiliacs.
 Sharing contaminated needles (IV drug users).
 Transplantation of infected tissues or organs.
 Mother to fetus, perinatal transmission variable, dependent on viral load and
mother’s CD 4 count.
Replication Cycle:
1. HIV attaches to two cell-surface receptors (the CD4 antigen and a specific
chemokine receptor).
2. The virus and cell membrane fuse, and the virion core enters the cell.
3. The viral RNA and core proteins are released from the virion core and are then
actively transported to the nucleus.
4. The viral RNA genome is converted into double-stranded DNA through an
enzyme unique to viruses, reverse transcriptase .
5. The double-stranded viral DNA moves into the cell nucleus.
6. Using a unique viral enzyme called integrase, the viral DNA is integrated into
the cellular DNA.
7. Viral RNA is synthesized by the cellular enzyme RNA polymerase II using
integrated viral DNA as a template. Two types of RNA transcripts shorter
spliced RNA and full-length genomic RNA are produced.
4
Virology
Dr. Bara' H. Hadi
8. Shorter spliced RNAs are transported to the cytoplasm and used for the
production of several viral proteins that are then modified in the Golgi
apparatus of the cell .
9. Full-length genomic RNAs are transported to the cytoplasm .
10.New virion is assembled and then buds off.
11.
Mature virus is released.
Clinical manifestation :
 Acute phase in 50-70% of infected persons (days or weeks after infection ) is
characterized by flulike or infectious mononucleosis like syndrome .Infected persons
may exhibit fever .pharyngitis, malaise , myalgia , headache, or generalized
lymphadenopathy.
 The acute phase is followed by an asymptomatic phase of clinical latency(about 10
years to AIDS).
 During the asymptomatic phase, patient may sporadically present with fatigue,
weight loss, night sweat, or lymphadenopathy.
 The symptomatic phase and AIDS is the end stage of HIV disease.
 AIDS is characterized by decrease in CD4+ T lymphocyte and so many opportunistic
infections.
Opportunistic Infections :
 Respiratory system: Pneumocystis Carinii Pneumonia (PCP) , Tuberculosis (TB) ,
Kaposi's Sarcoma.
 Gastro-intestinal system : Cryptosporidiosis, Candida ,Cytomegolavirus (CMV) ,
Kaposi's Sarcoma.
 Central/peripheral
Nervous
system:
Cytomegolavirus
,
Toxoplasmosis,
Cryptococcosis, Non -Hodgkin's lymphoma ,Varicella Zoster, Herpes simplex .
 Skin : Herpes simplex, Kaposi's sarcoma, Varicella Zoster.
5
Virology
Dr. Bara' H. Hadi
Laboratory Diagnosis:
 HIV rapid antibody test : Screening test for HIV.
 HIV enzyme-linked immunosorbent assay (ELISA) : Screening test for HIV
sensitivity > 99.9%
 Western blot :Confirmatory test , speicificity > 99.9% (when combined with ELIZA)
 Absolute CD4 lymphocyte count: Predictor of HIV progression , risk of opportunistic
infections
 HIV viral load tests: Best test for diagnosis of acute HIV infection ,correlates with
disease progression and response to HAART
 RT-PCR : to diagnose pediatric HIV
Treatment:
The treatment of HIV includes antiretroviral drugs and fusion inhibitor drugs.
 Antiretroviral Drugs:
 Nucleoside Reverse Transcriptase inhibitors:- AZT (Zidovudine)
 Non-Nucleoside Transcriptase inhibitors:- Viramune (Nevirapine)
 Protease inhibitors:- Norvir (Ritonavir)
 fusion inhibitor drugs: Block fusion of HIV gp with CD4+ cells (enfuvirtide)
 Highly Active Antiretroviral Therapy (HAART): Combination of 3 classes of
antiretroviral drugs to avoid viral resistance.
 Perinatal administration of drug : AZT to HIV infected pregnant womenand
their newborn infants
6