2. HIV & AIDS
HIV = Human Immunodeficiency Virus
First cases of Acquired Immune Deficiency Syndrome (AIDS)
were reported in 1981
HIV-1 isolated in 1984, and HIV-2 in 1986
Belongs to the lentivirus subfamily of the retroviridae
Enveloped RNA virus, 120nm in diameter
HIV-2 shares 40% nucleotide homology with HIV-1
HIV-1 genome consists of 9749 nucleotides
5. GLOBAL HIV PREVALENCE ESTIMATES
An estimated 36.7 million people were
living with HIV globally in 2016
2.1 million were children less than 15
years
Sub-Saharan Africa has been the most
hit accounting for an estimated 69% of
all the people living with HIV and 70%
of all AIDS deaths in 2011.
Source: UNAIDS data 2012/2017
7. Zambia: Adult HIV Prevalence rates by Province
HIV PREVALENCE BY PROVINCE
2004 2007 2016
NORTHERN 8.0 6.8 9.7
NORTH WESTERN 9.0 6.9 6.9
EASTERN 13.0 10.3 8.2
LUAPULA 10.0 13.2 9.3
SOUTHERN 16.0 14.5 13.4
WESTERN 12.0 15.2 16.0
COPPERBELT 18.0 17.0 14.2
CENTRAL 14.0 17.5 13.4
LUSAKA 20.0 20.8 16.1
Average National
Prevalence (15-49 y.o) 16.0 14.3 11.6
Among adults ages 15 to 59 years, prevalence
of HIV varies geographically across Zambia,
ranging from 5.9 percent in Muchinga
Province
to 16.0 percent in Western Province and 16.1
percent in Lusaka. (ZAMPHIA 2016)
MUCHINGA 5.9
Males: 8.6
Females: 14.5
(ZAMPHIA 2016)
8. RETROVIRUSES
HIV belongs to a group of Retroviruses
called lentiviruses.
Retroviruses infect a wide range of
animal species and cause a variety of
diseases.
They are enveloped viruses with an
RNA genome.
9. RETROVIRUSES
The name is derived from the fact that the
virus particle contains an RNA dependent
DNA Polymerase (Reverse
transcriptase)
This enzyme converts the RNA genome
into DNA, which then integrates into the
host chromosomal DNA.
The reverse transcriptase is highly error
prone and rapid genetic variation is a
feature of this group of viruses.
10. TRANSMISSION OF HIV
1. Sexual transmission - male homosexuals and constitute the
largest risk group in N. America and Western Europe. In
developing countries, heterosexual spread constitute the
most important means of transmission.
2. Blood/blood products - IV drug abusers represent the
second largest AIDS patient groups in the US and Europe.
Haemophiliacs were one of the first risk groups to be
identified: they were infected through contaminated factor
VIII.
3. Vertical transmission - the transmission rate from mother
to the newborn varies from around 15% in Western Europe
to up to 50% in Africa. Vertical transmission may occur
transplacentally route, perinatally during the birth process,
or postnatally through breast milk.
13. Long Terminal Repeats (LTR)
•HIV RNA genome is flanked by LTR
There are two important functions for the LTR:
1. They are "sticky ends" which the integrase protein uses to insert the
HIV genome into host DNA.
2. They act as promoters/enhancers - when integrated into the host
genome, they influence the cell machinery which transcribes DNA,
to alter the amount of transcription which occurs. Protein binding
sites in the LTR are involved with RNA initiation.
14. HIV LIFECYCLE
1. Viral fusion into cells
2. Reverse transcription
3. Integration
4. Transcription/Translation
5. Viral Assembly and Release
20. Viral setpoint
“the quasi-steady viral load during the asymptomatic period of HIV-
1 infection”
(The HIV set point is the viral load of a person infected with HIV,
which stabilizes after a period of acute HIV infection)
High set points are correlated with rapid disease progression, high
infectiousness, and poorer responses to treatment
21. The profound immunosuppression seen in AIDS is due to the
depletion of T4 helper lymphocytes.
In the immediate period following exposure, HIV is present at a
high level in the blood (as detected by HIV Antigen and HIV-
RNA assays).
It then settles down to a certain low level (set-point) during the
incubation period. During the incubation period, there is a
massive turnover of CD4 cells, whereby CD4 cells killed by HIV
are replaced efficiently.
Eventually, the immune system succumbs and AIDS develops
when killed CD4 cells can no longer be replaced (witnessed by
high HIV-RNA, HIV-antigen, and low CD4 counts).
PATHOPHYSIOLOGY
22. HIV alters ability to fight infection in 2 main ways:
• CD4 cell depletion – occurs as HIV infects CD4+ cells and
replicates using host cellular mechanisms, ultimately resulting
in death of the host cell
• Immune dysfunction
The higher the viral burden (or viral load), the greater the
likelihood that immune function will be compromised
Results in development of opportunistic infections (OIs)
23. The CD4+ CELL COUNT, as well as the CD4% (as part of the total lymphocyte
count), are used to predict disease progression
The risk of opportunistic infection and progression to AIDS increases as the CD4+
count declines to less than 350, or less than 20% of the total lymphocyte count.
The CD4+ count and/or percentage is an indicator of damage already done to the
immune system.
The VIRAL LOAD is a measure of pending damage to the immune system.
The viral load often changes prior to changes in the CD4+ lymphocyte (T-helper
cell) count.
The viral load is a predictor of prognosis.
An untreated patient with a viral load of less than 10,000 copies/mL has a
relatively good prognosis. Values above this level are associated with a greater risk
of disease progression.
PROGNOSTICATORS
24. HIV INFECTS CD4 T CELLS, DENDRITIC CELLS AND MACROPHAGES
HIV shows cellular tropism ability
HIV enters cells in association with gp120 and gp41
Gp120 has high affinity for CD4
Gp41 causes fusion of the viral envelope and the plasma
membrane
This fusion process has provided a target for drug therapy
Peptide analogs of the carboxy-terminal peptide of gp41 inhibit
fusion of the viral envelop with the plasma membrane of cells.
E.g. T-20 caused 20 fold decline in plasma HIV RNA levels.
25. In addition to CD4, HIV needs a coreceptor. Several different
molecules can serve as co-receptors for HIV entry- chemokine
receptors.
There are 2 important viral co-receptors:
CCR5 and CXCR4
Both are chemokine receptors
Chemokines are divided into two groups according to a conserved
dicysteine motif that they contain. These are the C-C group and the
C-X-C group.
The receptors are named for the type of cytokine that they bind
(CCR- or CXCR-).
HIV CO-RECEPTORS
26. Most viruses can use only
CCR5: R5 viruses
Many can use both
coreceptors: R5/X4 (D/M)
A few can use only
CXCR4: X4 viruses
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27. Viral Tropism
Key components of HIV tropism
Differential use of CCR5 and CXCR4
Expression patterns of CCR5 and CXCR4
HIV-1 Cell Tropism
Macrophage
CD4+ CCR5+
Primary T cell
CD4+ CCR5+/CXCR4+
T-cell line
CD4+ CXCR4+
R5 Virus Strains
M-tropic virus
Transmission
R5/X4 Virus Strains
Dual-tropic virus
X4 Virus Strains
T-tropic virus
Emerge late
Viral tropism refers to which cell types HIV infects
28. CCR5—associated with virus transmission
Coreceptor switch
CXCR4—associated with disease progression
Coreceptor Is Required for Viral Entry
M-tropic strains use the chemokine coreceptor CCR5
T-tropic strains use the chemokine coreceptor CXCR4
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30. Opportunistic Tumours
The most frequent opportunistic tumour, Kaposi's
sarcoma, is observed in 20% of patients with AIDS.
KS is observed mostly in homosexuals (in the U.S.) and its
relative incidence is declining. It is now associated with a
human herpes virus 8 (HHV-8).
Malignant lymphomas are also frequently seen in AIDS
patients.
32. Other Manifestations
It is now recognised that HIV-infected patients may develop a
number of manifestations that are not explained by
opportunistic infections or tumours.
The most frequent neurological disorder is AIDS
encephalopathy which is seen in two thirds of cases.
Other manifestations include characteristic skin eruptions
and persistent diarrhoea
34. Co-receptors and HIV infection
Cells with homozygous mutant CCR5 molecules are not
infected by HIV
1 in 100 Caucasians
No Africans
Persons with heterozygous mutant CCR5 molecules progress to
AIDS more slowly
35. 25% of long term survivors are CCR5 or CCR2 mutants (deletions)
The same CCR5 mutation (called “delta 32”) is thought to be the
mutation that rendered some people immune to the plague in the
middle ages
Long Term Non-Progressers
36. Long Term Non-Progressors
People who have been infected with HIV for more than seven
years that have stable CD4+ cell counts above 600/ml with no
symptoms and no chemotherapy
Many have produced a very good immune response to the
virus
37. TREATMENT OF HIV:
Antiretroviral Drugs (ARVs)
Nucleoside reverse transcriptase inhibitors
(NRTIs)- block reverse transcriptase (an HIV enzyme). HIV uses
reverse transcriptase to convert its RNA into DNA (reverse
transcription). Blocking reverse transcriptase and reverse transcription
prevents HIV from replicating. E.g zidovudine (ZDV) lamivudine (3TC),
tenofovir disoproxil fumarate (TDF)
Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)- bind to and block HIV reverse
transcriptase (an HIV enzyme). HIV uses reverse transcriptase to
convert its RNA into DNA (reverse transcription). Blocking reverse
transcriptase and reverse transcription prevents HIV from replicating.
E.g nevirapine (NVP), delavirdine (DLV), efavirenz (EFV) and etravirine.
Protease inhibitors (PIs)- block protease (an HIV enzyme).
By blocking protease, PIs prevent new (immature) HIV from
becoming a mature virus that can infect other CD4 cells.-
E.g saquinavir(SQV), ritonavir (RTV), indinavir (IDV), nelfinavir (NFV),
Amprenavir(APV)
38. Distinguishing between mode of action of
NRTIs and NNRTIs
Drug Class
Mode of Action
(Both drugs inhibit Reverse Transcriptase)
NRTIs
NRTIs contain faulty versions of the building blocks
(nucleotides) used by reverse transcriptase to convert RNA to
DNA. When reverse transcriptase uses these faulty building
blocks, the new DNA cannot be built correctly
NNRTIs
NNRTIs inhibit viral DNA synthesis by attaching itself directly
(binding) to reverse transcriptase enzyme and thereby
preventing it from converting RNA to DNA.
39. TREATMENT OF HIV:
Antiretroviral Drugs (ARVs)
Integrase inhibitors (INSTIs)- block integrase (an HIV
enzyme). HIV uses integrase to insert (integrate) its viral DNA into the
DNA of the host CD4 cell. Blocking integrase prevents HIV from
replicating. raltegravir (Isentress), dolutegravir (Tivicay)
elvitegravir (available in combination with other drugs; no longer available alone)
bictegravir (available in combination with other drugs; not available alone)
Fusion inhibitors (FIs)- A fusion inhibitor blocks the HIV
envelope from merging with the host CD4 cell membrane (fusion). This
prevents HIV from entering the CD4 cell. E.g Enfuvirtide
Chemokine receptor antagonists (CCR5
antagonists) -block the CCR5 co-receptor on the surface of
certain immune cells, such as CD4 T lymphocytes (CD4 cells). This
prevents HIV from entering the cell. E.g T20
Editor's Notes
26
27
28
A chemokine receptor may be one reason why these people remain healthy. What part this co-receptor plays in the biology of HIV we shall see later. The T cells or macrophages of non-progressors are very resistant to HIV because they have a mutant chemokine receptor. In some rather rare mutations of CCR5 (macrophage co-receptor), it is virtually impossible for the virus to enter the cell.
Other long term non-progressors appear to make high levels of chemokines that block the chemokine receptor and therefore block binding of HIV to the cell.