HIV/AIDS

MWANGI KJ(MSC HUMAN ANAT)

 OBJECTIVES OF THE LESSON

At the end of this session the student will be able to:

 Understand basic HIV structure
 Understand the significance of genetic diversity and
classification of HIV
 Know the replication cycle of HIV
 Target sites for anti retroviral drugs (arvs)
 HIV
Human Immunodeficiency Virus
oH = infects only human beings
oI = immunodeficiency virus weakens the immune system and
increases the risk of infection
oV = virus that attacks the body
 AIDS
Acquired Immune Deficiency Syndrome

oA = Acquired, not Inherited

oI = Weakens the Immune System

oD = Creates a Deficiency of CD4+ Cells in the Immune System

oS = Syndrome, or A group of Illnesses taking place at the same

time
 HIV AND AIDS
o When the immune system becomes weakened by HIV, the illness
progresses to AIDS

o Some blood tests, symptoms or certain infections indicate

progression of HIV to AIDS
 HIV VIRUS CLASSIFICATION
• A retrovirus from the lentivirus family.

• Genetic material consists of a single-stranded ribonucleic acid (rna)

• Viral particle is spherical in shape with a diameter of 80-100 nanometers

(nm).
 THE BIOLOGY OF THE HIV
oBasic virology:
oThere are two types of HIV.
oHIV – 1
oIs found worldwide
oIs the main cause of the worldwide pandemic
oHIV – 2
oIs mainly found in West Africa, Mozambique and Angola.
oCauses a similar illness to HIV – 1
oLess efficiently transmissible rarely causing vertical transmission
oLess aggressive with slower disease progression
HIV 1 SUBTYPES
HIV-1 SUBTYPE DISTRIBUTION IN AFRICA
• East and central
africa has mainly
subtype A and D.

• Southern africa
mainly subtype c.

• West africa
mainly a

• Different
subtypes can
combine to form
diverse
recombinants.
 HIV-1 SUBTYPES
oHIV-1 has many subtypes: A-K
oA-E are the predominant subtypes
oA: W. Africa, E. Africa, central africa east europe & Middle East
oB: N. America, Europe, Middle east, E. Asia, latin America
oC: S. Africa, S. Asia, Ethiopia
oD: E. Africa
oE: S. E. Asia
 HIV-1 VS. HIV-2

• HIV-1
• HIV-2
• More virulent
• Primarily found in western
• Responsible for africa
worldwide epidemic
• Not transmitted as
• Severity of infection efficiently
varies from person to
• Genome more closely
person
related to sivmm than HIV-1
 ORIGINS OF HIV
HIV-1 LIKELY DESCENDED HIV-2 LIKELY DESCENDED
FROM SIVCPZ FROM SIVSM

Sooty Mangabey
Pan troglodytes troglodytes
 THEORIES ON ORIGIN OF HIV

• Hunter theory
• Contaminated needle theory
• OPV theory
• Colonial theory
 ORIGINS OF HIV
• Researchers claim that these chimps are the source of HIV-1
• Chimps are only rarely infected with sivcpz
• Actual reservoir maybe a third unidentified primate species

• Definite source remains elusive

 ZOONOSIS: HOW DID IT HAPPEN?
• Human killing and eating of chimpanzees
• Contact with infected blood
• Ingestion of uncooked or undercooked meat
• Chat - polio vaccine
• Hypothesis: HIV is a recombinant construct that occurred when
SIV from a contaminated vaccine was administered to humans and
arose when human antigens were incorporated into the SIV
• Two reports in 2001 discount this theory(Blanco P. Et al. And
berry N. Et al.)
 ZOONOSIS: WHEN DID IT HAPPEN?
• Three earliest know HIV infections
• 1959 - serum sample from an adult male living in what is now
the democratic republic of Congo
• 1969 - tissue samples from a teenager who died in St. Louis
• 1976 - tissue samples from a Norwegian sailor
• January 2000 - study by Dr. Bette Korber estimates first case of HIV
infection to be 1930
• Study based on complicated computer model of hiv’s evolution
and has a 20yr error margin
 ZOONOSIS: WHERE DID IT HAPPEN?

• The two primates that carry the

sivs most closely related to HIV
are indigenous to western africa
 HIV
A BRIEF HISTORY OF THE
MODERN EPIDEMIC
 IN THE BEGINNING...

• 1675 - speculation that HIV was first transmitted from chimpanzees to

humans
• 1926-1946 - scientists believe HIV first spread from monkeys to humans
• 1959 - first proven AIDS death
• 1978 - gay men in US and sweden begin showing signs of what is now
known as AIDS
 THE FIRST INDICATIONS
• 1981 - CDC notices increase in cases of kaposi’s sarcoma
and pneumocystis carinii pneumonia
 DEFINING THE PROBLEM
• 1982 - the term AIDS (acquired immune deficiency syndrome) is used
for the 1st time
• 1983 - institute pasteur isolates HIV-1 CDC issues warning to blood
banks about potential problem
• 1984 - Dr. Robert Gallo claims discovery of HIV
 THE START OF THE WAR
• 1985 - FDA approves first HIV antibody diagnostic test
- First international conference on AIDS
• 1986 - HIV-2 isolated
• 1987 - AZT approved by FDA (1st anti -HIV drug)
 REALITY SETS IN
• 1987 - president Reagan says “AIDS” in public
- AIDS memorial quilt started
 THE WAR AGAINST HIV/AIDS

• 1988 - FDA begins granting pre-approval distribution status to

HIV/AIDS related drugs
• 1989 - first licensed HIV-1 diagnostic kit to directly detect
virus (rather than antibodies)
 FIGHTING A LOSING BATTLE?
• 1991 - 10 million people worldwide are hiv-positive
- Magic johnson publicly announces he is HIV positive
 CURRENT STATUS
• 1997 - 6,400,000 approximate worldwide death total
- 22,000,000 HIV-positive people in the world
• 1998-2001 - development and approval of new drugs
• 2003 - AIDSVAX developed by vaxgen fails in large clinical trial
• Trial did show statistically significant prevention in
African-Americans and other non-hispanic minorities
STRUCTURE OF HUMAN IMMUNODEFICIENCY VIRUS
 STRUCTURE OF HIV
• HIV is a retrovirus with a similar structure to other retroviruses.
• Genome: the genome is RNA with 2 identical strands of RNA.
• Size: 5% of the length of an E. coli bacterium or 6% of the
diameter of a human CD4+ white blood cell
 SURFACE STRUCTURE OF HIV
• Viral membrane: this is host-derived as a result of budding from the cell
surface.
• Surface glycoprotein: gp160 is encoded by the env (envelope) gene.
Gp160 is cleaved after translation to form gp120 and gp41.
• Gp 41 is embedded in the membrane; gp120 is not but is held to gp41 by
non-covalent interactions. It is easily shed from the virus particle.
• Gp120 is the protein that interacts with a receptor on the cell to be
infected.
• Gp41 is the one that is exposed after gp120 has bound to the cell.
 INTERNAL STRUCTURES
• Internal structural proteins: these are all encoded by the gag (group-
specific antigen) gene and the pol(polymerase) gene.
• The gag encodes P17 matrix (MA) protein and the nucleocapsid which
form the core of the virus (or capsid)which is is usually bullet-shaped.
• The pol (polymerase) gene encodes enzymes that participate in
integration and replication which include:
i. Reverse transcriptase - copies RNA genome into double stranded DNA.
ii. Integrase - integrates the double stranded DNA into the host cell
chromosome.
iii. Protease - cleaves the pol and gag-encoded polyproteins.
 INTERNAL STRUCTURES
• HIV has just 9 genes (compared to more than 500 genes in A bacterium)
• Gag, pol and env, contain information needed to make structural
proteins for new virus particles.
• The other 6 genes, known as tat, rev, nef, vif, vpr and vpu, code for
proteins that control the ability of HIV to infect A cell, produce new
copies of virus, or cause disease.
• At either end of each strand of RNA is a sequence called the long
terminal repeat, LTR, which helps to control HIV replication.
 THE GENOME OF HIV
• The HIV genome has 9 genes (3 structural & 6 non structural) from which 15 proteins are made.
a) Structural genes: Gag, Pol and Env genes.
b) Non structural genes include: vif, vpr, nef, tat, ref and vpu.
1. GAG gene is translated into 4 proteins that are found in the mature virus:
i. MA (matrix/p17),
ii. CA (capsid)
iii. NC (nucleocapsid/p24)
iv. P6.

2. POL gene is translated into:

i. pr (protease)
ii. rt (reverse transcriptase)
iii. in (integrase).

3. ENV gene is translated to a polyprotein (gp160), which is then cleaved to:

i. surface glycoprotein (gp120)
ii. transmembrane glycoprotein (gp41).
 CTD’ THE GENOME OF HIV

• In a addition to the 9 proteins derived from gag, pol and env,

• There are 6 other proteins made by HIV.
• 3 of these are incorporated into the virus (vif, vpr and nef)
• The others are not found in the mature virus: tat and rev are regulatory
proteins and vpu indirectly assists in assembly.
 CTD’ THE GENOME OF HIV
The genes that encode these proteins are known by three letter names
that are derived as follows
TAT: Trans-Activator of VPU: Viral Protein U VPR: Viral Protein R
Transcription
REV: Regulator of Virion VIF: Virion Infectivity Factor NEF: Negative Regulatory Factor
protein expression

TAT: TAT gene product binds to a sequence in all of the genes of HIV and
positively stimulates transcription thus it's a regulator of protein
synthesis.
 CTD’ THE GENOME OF HIV
• NEF: Nef protein reduces surface expression of MHC class I molecules.
This alters antigen presentation by the infected cell and is proposed to
protect the infected cell from attack by cytotoxic T cells.
• VPU: enhances viral particle release from the host cell.
• VIF: Vif (viral infectivity factor) protein, which is essential for infection
in vivo, may be very important in suppressing resistance to hiv infection
by the host.
• VPR: promotes hiv transcription
 SUMMARY STRUCTURE OF HIV
 Has an outer double lipid
membrane, (derived from the
host membrane).
 The lipid membrane is lined by
a matrix protein.
 The lipid membrane is studded
with the surface glycoprotein
(gp) 120 and the
transmembrane gp 41 protein.
 These glycoprotein spikes
surround the cone-shaped
protein core.
 HIV STRUCTURE
NOTE : The core (capsid) is made
up of several proteins:-

 P24 the main protein

 Within the capsid are
 2 identical single strands of RNA

(the viral genetic material).

 viral enzymes
 SUMMARY OF HIV STRUCTURE

HIV glycoproteins
• The gp120 and gp41 mediate the entry of virus into the host cells.
 SUMMARY HIV STRUCTURE
Viral enzymes
• Most important: reverse transcriptase (RT), protease and integrase.
• RT converts viral single-stranded RNA into a double stranded
deoxyribonucleic acid (DNA).
• DNA is incorporated into host nucleus as the proviral DNA.
• Integrase facilitates integration of the DNA into the host’s chromosomal
DNA.
• Protease enzyme splits generated macro-proteins into smaller viral proteins
(core, envelope & regulatory proteins and enzymes) which go into forming
new viral particles.
 HIV LIFE CYCLE

 Binding, fusion and entry

 Transcription
 Integration & replication
 Budding
 Maturation
 HIV LIFE CYCLE
Binding:
• For successful entry into cells the HIV envelope glycoprotein GP
120 binds to the host receptor CD4 molecule
• Co-receptors are necessary (CCR5/CXCR4).
 HIV LIFE CYCLE
FUSION and ENTRY:
• Viral binding to host cell triggers fusion of the viral and host cell
membranes
• Mediated by gp41
• Allows entry of virus core into host cell cytoplasm
• Core protein dissolved by host enzymes releasing viral RNA and enzymes
 HIV LIFE CYCLE

Integration
• Reverse transcriptase converts the viral RNA into a DNA molecule

• The DNA enters the host cell nucleus

• Integrase catalyses the process of integration of the viral DNA into

the host cell’s DNA
 HIV LIFE CYCLE
Replication
• Integrated viral DNA turns the host cell into a "factory"
for manufacturing more virus.
• Viral proteins are produced as a single multi-protein
molecule
• Viral proteins cleaved by protease enzyme
 HIV LIFE CYCLE
Budding and maturation:
• Viral proteins together with RNA gather at the membrane of
the CD4+ cells
• Viral particles are formed which bud off the cell and enter the
bloodstream
• The CD4 cells are often destroyed by HIV virus infection and
replication resulting in profound immunodeficiency.
 HIV LIFE CYCLE: ENZYMES
• TRANSCRIPTION:
Fusion & entry • ACTIVATION OF
HOST CELL
RESULTS IN
TRANSCRIPTION
OF VIRAL DNA
INTO MRNA.
• MRNA
• REVERSE TRANSLATED INTO
VIRAL PRECURSOR
TRANSCRIPTION PROTEINS
• THE VIRAL ENZYME • ASSEMBLY &
REVERSE BUDDING
TRANSCRIPTASE • VIRAL PRECURSOR
CONVERTS THE PROTEINS PROCESSED
SINGLE STRANDED Integration: BY PROTEASE ENZYME
INTO USABLE FORMS
VIRAL RNA INTO The viral enzyme
• PROTEINS
DOUBLE STRAND integrase inserts the ASSEMBLED WITH
viral DNA (viral genetic RNA TO FORM VIRAL
DNA material) into the host PARTICLES WHICH
DNA. THEN BUD
 TREATING HIV INFECTION
Three main sites for HIV drugs
A. Reverse transcriptase
B. HIV protease
C. HIV entry
D.Integration C.
B.

Main classes of HIV drugs A.

1. Nucleoside analogues (zidovudine) - A
2. Non-nucleoside (nevaripine) - A D.
3. Protease Inhibitors (indinavir) - B
4. Chemokine Receptor Antagonists
(maraviroc) – C
5. Fusion Inhibitors – (enfuvirtide) - C
6. Integrase Inhibitors - (elvitegravir) - D Peterlin et al Nature Reviews Immunol 3; 97-107 (2003)