Download HIV Genetic Composition

HUMAN IMMUNODEFICIENCY
VIRUSES (HIV-1, HIV-2)
Introduction
• HIV is a sexually transmitted, human virus.
• The viruses (HIV-1 and HIV-2) were recognized in the
1980s.
• HIV-1 is largely responsible for the acquired immune
deficiency syndrome (AIDS) pandemic, while HIV-2 is
mainly restricted to West Africa.
• In the absence of treatment, and normally after many
years of infection, HIV infection damages the immune
system to the point where the body cannot combat
common infections and AIDS results.
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Origins of HIV-1 and HIV-2
• It is certain that HIV-1 and HIV-2 arrived in the human
population as zoonoses.
• These viruses are related to a group of more than 40 simian
immunodeficiency viruses (SIV), most of which has a
relatively benign nonpathogenic interaction with its natural
primate host.
• In 1999, a strain of SIV (called SIVcpz) was found in a
chimpanzee that was almost identical to HIV in humans.
• The researchers who discovered this connection concluded
that it proved chimpanzees were the source of HIV-1, and
that the virus had at some point crossed species from chimps
to humans.
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Characteristics
• They belong to the lentivirus genus of the Retroviridae
family.
• They contain two identical + single-stranded RNA
molecules.
• HIV exhibits a characteristic cone-shaped core.
• HIV is enveloped “lipid bilayer derived from the host cell
membrane”.
• The viral envelope is studded by virally encoded envelope
glycoproteins:
• gp120 (surface unit)
• gp41 ( transmembrane unit)
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Characteristics
• Other proteins in the virus particle:
• P17 (matrix protein), lines the inner surface of the virus
particle
• P24 (major capsid protein), surrounds two copies of RNA
• P9 (nucleic acid binding protein)
• Protease
In the capsid
• Integrase
• Reverse transcriptase
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HIV Genetic Composition
• HIV-1 and H IV-2 have genomes about 9.3 kb in length.
1. Structural genes
• encode for products which participate in formation of
functional structure of virus
a) env (envelope):
• Encodes the viral envelope proteins; gp120 and gp41
b) gag (group associated antigen):
• Encodes the viral proteins p24; capsid “CA” and p17 “MA” (membrane
associated matrix protein).
• P6 and P7 nucleocapsid proteins protect RNA from digestion by
nucleases.
c) pol (polymerase):
• Encodes the viral enzymes; reverse transcriptase, integrase, and protease
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HIV Genetic Composition
• gag and pol genes cooperate to form fusion proteins which
cause fusion of cells enabling HIV to pass from one cell to
another thus evading the components of the immune
system.
• gp 41 has a domain which acts as fusion protein.
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HIV Genetic Composition
2. Regulatory Genes
a) Tat (transactivator of transcription)
• Regulates HIV replication and accelerates viral protein production
by a thousand fold.
b) Rev (regulator of virion)
• Permits unspliced mRNA to leave the nucleus, it inhibits transcription of
the regulatory genes while enhancing expression of the viral structural
genes.
c) Vif (viral infectivity factor)
• Increases viral infectivity and may be responsible for the efficient cell-tocell transmission of HIV.
d) Nef (negative regulatory factor)
• Enhances HIV replication and makes the virus more pathogenic.
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HIV Genetic Composition
e) Vpr (viral protein R)
• Plays a role in the regulation of viral and cellular gene expression and
may be important in viral assembly and infection of macrophages, it may
also induce apoptosis.
f)
Vpu (viral protein u)
• Influences release of HIV from the cell surface and contributes to CD4
degradation within the endoplasmic reticulum.
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Life Cycle of HIV
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HIV Infections and Pathogenesis
• During the early phase of HIV infection before seroconversion,
the virus propagates mainly in peripheral blood mononuclear cells
(PBMC).
• Primary infection may cause a temporary depletion of CD4 +
PBMCs
• HIV infection usually elicits strong cell-mediated immune
responses (CD8+ cytotoxic T cells) and humoral responses help
to clear virus load but fail to eradicate HIV infection.
• During asymptomatic period, the virus is not completely latent
but remains active in lymphoid tissue as proved by PCR
technique.
• Monocytes are resistant to destruction by HIV, they may act as a
reservoir for the virus, as well as, a vehicle which transmits HIV
to distant parts of the body.
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HIV Infections and Pathogenesis
• The primary targets of HIV are activated CD4+ T4 helper
lymphocytes but the virus can also infect several other cell types
including macrophages.
• one of the main role of CD4+ cells is to send signals to other types
of immune cells, including CD8 killer cells, which then destroy the
infectious particle.
• It is the loss of T4 helper lymphocytes that leads
to immunosuppression in the patient and the consequent
fatal opportunistic infections.
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Death
Epidemiology of HIV
• The world pandemic of AIDS has been with us for more than
thirty years and about 39 million people have died of the
disease.
• About 1.2 million people around the world die of AIDS each
year.
• Today, at least 36.9 million people are infected and there are
more than 7,000 new infections every day.
• In 2015, 15 million infected persons were receiving antiretroviral therapy.
• In sub-Saharan Africa, more than 22 million people are
living with HIV infection, accounting for about 70% of total
cases.
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36.9 million (100%)
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Modes of Transmission
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Sexual contact (homosexual, heterosexual)
Transplacental transmission
Drug injection
Percutaneous occupational exposure
Receipt of infected blood
Receipt of contaminated organs or tissues
Breast feeding
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Common Opportunistic Infections
and Malignancies Associated with AIDS
A. Opportunistic infections
1. Bacteria
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Mycobacterium species
Streptococcus pneumonia
Haemophilus influenza
Salmonella species
2. Viruses
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Herpes simplex
Herpes zoster
Epstein-Barr virus
Adenovirus
Cytomegalovirus
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Common Opportunistic Infections
and Malignancies Associated with AIDS
3. Fungi
• Candida albicans
• Histoplasma capsulatum
• Cryptococcus neoformans
4. Protozoa
• Toxoplasma gondii
• Pneumocystis carnii
• Cryptosporidium species
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Common Opportunistic Infections
and Malignancies Associated with AIDS
B. Malignancies
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Kaposi’s sarcoma
Burkitt-like lymphoma
Hodgkin’s disease
CNS lymphoma
Immunoblastic sarcoma
Peripheral organ lymphoma
Lymphatic pre-leukemia
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Prevention and Control
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Health education
Early diagnosis
Blood supply testing
Early therapy
Counseling services
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Prevention of HIV Infection in Health
Care Workers
• Wear coats and gloves when processing patient specimens
• Use masks and eyewear if splashing or aerosolization is
anticipated
• Use precautions when handling needles and lancets
• Decontaminate work surfaces with a chemical germicide, e.g.,
chlorox
• Wash hands and remove protective clothing before leaving work
place
• Dispose of contaminated materials in autoclavable bags
• Avoid contaminating the outside of containers upon specimen
collection-the lid should be tight
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Targets for Antiviral Therapy
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Targets for Antiviral Therapy
• Resistant strains of HIV-1 to many drugs have emerged.
• A combination of antiviral drugs is recommended to
overcome resistant strains
• Combined therapy may include “Highly Active
Antiretroviral Therapy; HAART”, for example:
• one protease inhibitor plus two reverse transcriptase inhibitors
• Three reverse transcriptase inhibitors
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Gene Therapy
• Take stem
cells from
the HIV
patients' blood
, then "knock
out" a gene
known as
CCR5, which
controls a
protein that
allows HIV to
enter a cell.
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Problems Facing the development of
Effective vaccine against HIV:
• Antigenic diversity due to rapid mutation rate and
recombination thus escaping from antiretroviral immune
recognition
• Lack of a small animal model
• Live attenuated vaccine may revert to virulence
• Early establishment of latent viral reservoirs
• Viral evasion of humoral and cellular immune responses
• Little pharmaceutical interest
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Diagnosis of HIV Infection
• Assays for the Diagnosis of HIV Infection
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Serological screening
Antigen detection
Cell culture
Gene amplification “polymerase Chain Reaction, PCR”
CD4 count
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Diagnosis of HIV Infection
• Serological Screening
• Detects circulating anti-HIV antibodies
• ELISA … must be confirmed by:
• Immunofluorescence,
• Radioimmunoprecipitation, or
• Western blot [detects p24, gp41, gp120]
• Molecular Biology Techniques
• Reverse transcriptase-polymerase chain reaction(RT-PCR).
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