2. • The Retroviridae are a family of enveloped
(+) sense ssRNA viruses that have been
intensely studied because of their
association with cancers, leukemias and
the AIDS syndrome
4. Transfer of SIV to Humans
• “Natural transfer” theory (Science 2000)
– SIV was transferred to humans through
hunting and handling of chimpanzees
– The epidemic required urbanization and
increased population mobility
– Most scientific-based theory
4
5. Transfer of SIV to Humans (2)
• “Human error” theory (Edward
Hooper,“The River” 2000)
– Oral polio vaccine used in West Africa during
the late 1950s may have been contaminated
with SIV
– SIV has not been recovered from this vaccine
5
in subsequent studies
6. Classification of HIV
• HIV class: Lentivirus
– Retrovirus: single stranded RNA transcribed
to double stranded DNA by reverse
transcriptase
– Integrates into host genome
– High potential for genetic diversity
– Can lie dormant within a cell for many
years, especially in resting (memory) CD4+
T4 lymphocytes
6
7. • HIV type (distinguished genetically)
– HIV-1 -> worldwide pandemic (current ~ 40 M
people)
– HIV-2 -> isolated in West Africa; causes AIDS
much more slowly than HIV-1 but otherwise
clinically similar
05:21
8. HIV Structure
surface
transmembrane
matrix protein
capsid protein
nucleocapsid protein
RT
Integrase
protease
10. Retroviral Proteins
• gag, pol, and env
– Gag protein proteolytically processed into
• MA (matrix)
• CA (capsid)
• NC (nucleocapsid)
– Pol protein encodes enzymes
• PR (protease)
• RT (Reverse Transcriptase which has both DNA polymerase and
RNase H activities)
• IN (Integrase)
– Env protein encodes
• SU surface glycoprotein
• TM transmembrane protein
• “Accessory” genes (in Complex Retroviruses) - regulate
and coordinate virus expression; function in immune
escape
12. Env Proteins: Surface (SU)
• Glycoprotein (gp, followed by apparent molecular weight)
• Attaches to a specific receptor on cell surface
• Major neutralizing antigen on retrovirus, also often highly
variable (EIAV, HIV). Hard to make vaccines.
SU (gp120)
Lipid Bilayer
(derived from cell)
TM (gp 41)
13. CXCr4 is the major coreceptor for T-cell-tropic strains
CCr5 is the major coreceptor for macrophage-tropic strains
18. Viral-host Dynamics
10
• About 10 (10 billion) virions are produced
daily
• Average life-span of an HIV virion in
plasma is ~6 hours
• Average life-span of an HIV-infected CD4
lymphocytes is ~1.6 days
• HIV can lie dormant within a cell for many
years, especially in resting (memory) CD4
cells, unlike other retroviruses
18
19. HIV Evasion Methods
• Makes 10 billion copies/day -> rapid
mutation of HIV antigens
• Integrates into host DNA
• Depletes CD4 lymphocytes
• Down-regulation of MHC-I process
• Impairs Th1 response of CD4 helper T
lymphocyte
• Infects cells in regions of the body where
antibodies penetrate poorly, e.g., the
19 central nervous system
21. Primary HIV Infection
• The period immediately after infection
characterized by high level of viremia (>1
million) for a duration of a few weeks
• Associated with a transient fall in CD4
• Nearly half of patients experience some
mononucleosis-like symptoms
(fever, rash, swollen lymph glands) Patient
21
enters “clinical latency”
22. Cells Infected by HIV
• Numerous organ systems are infected by
HIV:
– Brain: macrophages and glial cells
– Lymph nodes and thymus: lymphocytes and
dendritic cells
– Blood, semen, vaginal fluids: macrophages
– Bone marrow: lymphocytes
– Skin: langerhans cells
– Colon, duodenum, rectum: chromaffin cells
22 – Lung: alveolar macriphages
23. General Mechanisms of HIV Pathogenesis
• Direct injury
– Nervous (encephalopathy and peripheral
neuropathy)
– Kidney (HIVAN = HIV-associated
nephropathy)
– Cardiac (HIV cardiomyopathy)
– Endocrine (hypogonadism in both sexes)
– GI tract (dysmotility and malabsorption)
• Indirect injury
– Opportunistic infections and tumors as a
23 consequence of immunosuppression
24. General Principles of
Immune Dysfunction in HIV
• All elements of immune system are affected
• Advanced stages of HIV are associated with
substantial disruption of lymphoid tissue
– Impaired ability to mount immune response to
new antigen
– Impaired ability to maintain memory
responses
– Loss of containment of HIV replication
– Susceptibility to opportunistic infections
24
25. Consequence of Cell-mediated
Immune Dysfunction
• Inability to respond to intracellular
infections and malignancy
– Mycobacteria, Salmonella, Legionella
– Leishmania, Toxoplama, Cryptosporidium, Mi
crosporidium
– Histoplamosis
– HSV, VZV, JC virus, pox viruses
– EBV-related lymphomas
25
26. Transmission
• Modes of infection
– Sexual transmission at genital or colonic
mucosa
– Blood transfusion
– Mother to infant
– Accidental occupational exposure
26
27. Laboratory Markers of HIV
• Viral load Infection
– Marker of HIV replication rate
– Number of HIV RNA copies/mm3 plasma
• CD4 count
– Marker of immunologic damage
– Number of CD4 T-lymphocytes cells/mm3
plasma
– Median CD4 count in HIV negative Ethiopians
is significantly lower than that seen in Dutch
controls
• Female 762 cells/mm3 (IQR 604-908)
27
• Male 684 cells/mm3 (IQR 588-832)
28. HIV RNA Set Point Predicts
Progression to AIDS
• HIV RNA viral loads after infection can be
used in the following ways:
– To assess the viral set point
– To predict the likelihood of progression to
AIDS in the next 5 years
• The higher the viral set point:
– The more rapid the CD4 count fall
– The more rapid the disease progression to
AIDS
28
29. CD4 T-cell Count and Progression to AIDS
• In contrast to VL, baseline CD4 is not a
good predictor of time to progression to
AIDS
– Unless CD4<321 cells/ml
• However, as the CD4 count declines over
time, patients will develop opportunistic
infections
– Develop in a sequence predictable according
to CD4 count
29 – WHO Staging system
