2. Learning Objectives
• Describe the origin and basic virology of HIV-1
• Describe the normal immunological response to HIV-1
• List the mechanisms used by HIV-1 to evade the normal
immune responses
• Explain the principles of HIV-1 pathogenesis
• Describe the natural course of HIV-1
2
3. Basic terms
• Antigen: A substance which is recognized as foreign by
the immune system. Antigens can be part of an organism
or virus, e.g., envelope, core (p24) and triggers antibody
production.
• Antibody: A protein (immunoglobulin) made by the
body’s immune system to recognize and attack foreign
substances
3
4. Basic terms
• Retrovirus. A virus, such as HIV, whose RNA codes for DNA,
which is then inserted into some part of the host's DNA. This virus
comes with its own special enzyme, called reverse transcriptase,
which facilitates this insertion.
• Lentivirus-any of a group of retroviruses producing illnesses
characterized by a delay in the onset of symptoms after infection.
• Simian- similar to/ resembling to apes and monkeys
4
5. Introduction
The human immunodeficiency virus (HIV) was
unknown until the early 1980's when increasing
numbers of cases of unusual opportunistic
infections and Kaposi sarcoma in persons with
lymphadenopathy in the setting of impaired cell-
mediated immunity were reported.
5
6. Since then HIV has infected millions of persons
in a worldwide pandemic.
The result of HIV infection is relentless
destruction of the immune system leading to
onset of the acquired immunodeficiency
syndrome (AIDS).
6
7. The AIDS pandemic has already resulted in the
deaths of over half its victims.
All HIV-infected persons are at risk for illness
and death from opportunistic infectious,
neoplastic complications, and comorbidities
because of the inevitable manifestations of AIDS
as well as long-term treatment of HIV.
7
8. Human sexual practices with promiscuity have
included a larger number of persons in
populations around the world.
A practical and easily available means for
delivery of drugs of abuse through injection
became more widespread in the 20th century
8
9. The AIDS pandemic has evolved over time, with
four main phases of evolution.
1st Phase
2nd Phase
3rd Phase
4th Phase
9
10. 1st Phase
In the initial phase, HIV emerged from endemic
rural areas to spread among urban populations
at an accelerating rate
10
11. 2nd Phase
In the second phase, dissemination occurred
and involved definable risk groups. Behaviors in
these risk groups, including sexual promiscuity
and injection drug use
11
12. 3rd Phase
Involved escalation of the spread of the disease,
which occurred through the 1980’s
12
13. 4th Phase
A phase of stabilization has occurred in some
regions such as western Europe, North America,
and Australia, where control measures appear to
be having a positive effect.
However, some regions such as central Africa
and Asia continued to experience escalation of
the pandemic through the 1990's and into the
21st century.
13
14. Globally, the incidence of new HIV infections
probably peaked in 1997.
At the end of the 20th century, over 21 million
persons worldwide had died from AIDS, over 34
million were living with HIV infection, and over
95% of living HIV infected persons resided in
developing nations.
Nine countries in southern Africa, with 2% of the
world’s population, accounted for a third of all
HIV-infected persons.[
14
15. At the start of the 21st century, the worldwide
prevalence of HIV infection stabilized at about
0.8%.
The age group most affected, young persons
from 15 to 24 years of age, accounted for 45%
of new HIV infections.
Worldwide, over half the victims of AIDS are
women, and a consequence of this is potential
perinatal infection and children born with HIV
infection.
15
16. The scope of the HIV/AIDS pandemic has
already led to serious consequences, not only
for health care systems of countries unable to
cope with many HIV/AIDS victims, but also for
the national economies of those countries
because of the loss of young to middle aged
persons who are economically most productive
16
17. What is HIV?
• Human: Infecting human beings
• Immunodeficiency: Decrease or weakness in the body’s
ability to fight off infections and illnesses
• Virus: A pathogen having the ability to replicate only
inside a living cell
17
18. Types of HIV
• HIV 1
• Most common in sub-Saharan Africa and throughout the
world
• Groups M, N, and O
• Pandemic dominated by Group M
Group M comprised of subtypes A - J
• HIV 2
• Most often found in West Central Africa, parts of Europe
and India
18
19. What is SIV?
• S-Simian
• I-immunodeficiency
• V-viruses
19
20. • “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
• 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 in subsequent
studies 20
TRANSFER OF SIV TO HUMAN
21. What is AIDS?
• Acquired: To come into possession of something new
• Immune Deficiency: Decrease or weakness in the
body’s ability to fight off infections and illnesses
• Syndrome: A group of signs and symptoms that occur
together and characterize a particular abnormality
21
22. HIV lives in the following bodily fluids of an infected person:
• blood
• semen and pre-seminal fluid (“pre-cum”)
• rectal fluids/anal mucous
• vaginal fluids
• breast milk.
22
HIV TRANSMISSION
25. The HIV Epidemic Unfolds
• Sudden outbreak in USA of opportunistic infections and
cancers in homosexual men in 1981
• Pneumocystis carinii pneumonia (PCP), Kaposi’s sarcoma, and
non-Hodkins lymphoma
• HIV isolated in 1984 - Luc Montanier (Pasteur Institute,
Paris) and Robert Gallo (NIH, Bethesda, USA)
• HIV diagnostic tests developed in 1985
• First antiretroviral drug, zidovudine, developed in 1986
• Exploding pandemic
• Has infected more than 50 million people around the world
25
26. 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
• HIV type (distinguished genetically)
• HIV-1 -> worldwide pandemic (current ~ 33 M people)
• HIV-2 -> isolated in West Africa; causes AIDS much more
slowly than HIV-1 but otherwise clinically similar
26
27. Classification of HIV-1
• HIV-1 groups
• M (major): cause of current worldwide epidemic
• O (outlier) and N (Cameroon): rare HIV-1 groups that arose
separately
• HIV-1 M subgroups (clades)
• >10 identified (named with letters A to K)
• Descended from common HIV ancestor
• One clade tends to dominate in a geographic region
• Clades differ from each other genetically
• Different clades have different clinical and biologic
behavior
27
28. Origin and Distribution of HIV-1
• HIV-1 rapidly evolves by two mechanisms:
• Mutation: changes in single nucleosides of the RNA
• Recombination: combinations of RNA sequences from two
distinct HIV strains
• Several common clades (e.g., A/G ad A/E) are recombinants
• Geographic distribution of HIV group M clades
• A in Central Africa
• B in North American, Australia, and Europe
• C in Southern and Eastern Africa (Ethiopia)
28
31. How HIV Enters Cells
• gp120 env protein binds to CD4 molecule
• CD4 found on T-cells macrophages, and microglial cells
• Binding to CD4 is not sufficient for entry
• V3 loop of gp120 env protein binds to co-receptor
• CCR5 receptor - used by macrophage-tropic HIV variants
• CXCR4 receptor - used by lymphocyte-tropic HIV variants
• Binding of virus to cell surface results in fusion of viral
envelope with cell membrane
• Viral core is released into cell cytoplasm
31
32. Viral-host Dynamics
• About (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
32
34. Cells of the Immune
System
• All blood cells are manufactured in the bone marrow.
• These include;
Red Blood Cells ( RBCs)
White Blood Cells (WBCs)
Platelets
• The WBCs are responsible for fighting invading bacteria
and viruses.
35. Cont…
• Several types of WBCs exist, but the lymphocytes are of
interest in HIV infection.
• There are two main types;
T- Lymphocytes
B- Lymphocytes
• B-cells facilitate the process of phagocytosis while T-cells
regulate the immune system and kill specific bacteria and
viruses.
36. The human body has two forms of immunity:
- natural/Innate and
- Acquired.
Immune responses conferring protection against disease can
be induced by;
a) Direct infection and
b) Artificial exposure of the individual to inactive forms
of the infectious organism, for example, immunization.
37. In terms of HIV/AIDS the focus is on acquired immunity.
This includes:
• Humoral immunity involving antibody protection and
complement, and
• Cell-mediated immunity.
38. 38
Intracellular
infection
Naïve
B-Cell
Naïve
T8 cell
Naïve T4
helper cell
MHC I presentation
of endogenous
antigen MHC II
presentation of
exogenous antigen
Cell-mediated
(CTLs)
Humoral
(plasma cells /
antibodies)
Free antigen
Th1 Th2
Overview of Adaptive Immune
Response Extracellular
infection
APC
Diagram courtesy of Dr. Samuel Anderson
39. Overview of Adaptive Immune Response
The adaptive immune response is the main response to HIV (as
opposed to the innate immune response).
• The adaptive immune response is divided into two types:
- the cell-mediated (cytotoxic t-cell) type and
- the humoral (antibody-mediated) type.
- In general, the location of the infection (intracellular or
extracellular) determines the type of adaptive immune
39
40. Overview of Adaptive
Immune Response
• Intracellular infections stimulate a cell-mediated response that
will ultimately kill the infected cell. This is mediated by T8
cells, and utilizes the MHC I system.
• Extracellular infections stimulate a humoral response that will
help contain these free antigens.
• Some extracellular antigens will be picked up by APC and be
presented by way of MHCII to the Thc, which will further
differentiate into either TH1 or TH2.
40
41. Overview of Adaptive
Immune Response
• TH1 in turn will augment the cell-mediated response and
Th2 augments the humoral.
• CENTRAL TO THE ADAPTIVE IMMUNE RESPONSE
IS THE TH4 CELL. BECAUSE HIV DEPLETES AND
DISTRUPTS THE FUNCTION OF THIS CELL,
ADAPTIVE IMMUNITY IS IMPAIRED.
41
42. General Principles of
Viral-host Interactions:
• Host: mounts HIV-specific immune responses
• Cellular (cell-mediated) - most important
• Humoral (antibody-mediated)
• Virus: disorganises the immune system
• Infects CD4 cells that control normal immune responses
• Integrates into host DNA
• High rate of mutation
• Hides in tissue not readily accessible to immune system
• Induces a cytokine environment that the virus uses to its own
replicative advantage
• Achieved by “activation” of the immune system
42
43. Cellular Immune
Responses to HIV
• CD8 Cytotoxic T lymphocyte (CTL)
• Critical for containment of HIV
• Derived from naïve T8 cells, which recognize viral
antigens in context of MHC class I presentation
• Directly destroy infected cell
• Activity augmented by Th1 response
43
44. Cellular Immune
Responses to HIV
• CD4 Helper T Lymphocyte (Th)
• Plays an important role in cell-mediated response
• Recognizes viral antigens by an antigen presenting cell
(APC)
• Utilizes major histocompatibility complex (MHC) class II
• Differentiated according to the type of “help”
• Th1 - activate Tc (CD8) lymphocytes, promoting cell-mediated
immunity
• Th2 - activate B lymphocytes, promoting antibody mediated
immunity
44
45. Humoral Immune
Response to HIV
• Neutralization
• Antibodies bind to surface of virus to prevent attachment to
target cell
45
46. HIV Evasion Methods
• Makes 10 billion copies/day -> rapid mutation of HIV
antigens
• Integrates into host DNA
• Depletes CD4 lymphocytes
• Impairs Th1 response of CD4 helper T lymphocyte
• Infects cells in regions of the body where antibodies
penetrate poorly, e.g., the central nervous system
46
48. 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
• Lung: alveolar macriphages
48
49. 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 consequence of
immunosuppression
49
50. 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
50
51. Mechanisms of CD4
Depletion and Dysfunction
• Direct
• Elimination of HIV-infected cells by virus-specific immune
responses
• Loss of plasma membrane integrity because of viral
budding
• Interference with cellular RNA processing
• Indirect
• Apoptosis
• Autoimmunity
51
52. Role of Cellular Activation
in Pathogenesis of HIV
• HIV induces immune activation
• Which may seem paradoxical because HIV ultimately
results in severe immunosuppression
• Activated T-cells support HIV replication
• Intercurrent infections are associated with transient
increases in viremia
• The magnitude of this increase correlates inversely with
stage of HIV disease
• Accounts for why TB worsens underlying HIV disease
52
53. Role of Cytokine Dysregulation in
Pathogenesis of HIV
• HIV is associated with increased expression of pro-
inflammatory cytokines
• TNF-alpha, IL-1,IL-6, IL-10, IFN-gamma
• Associated with up-regulation of HIV replication
• HIV results in disruption and loss of immunoregulatory
cytokines
• IL-2, IL-12
• Necessary for modulating effective cell-mediated immune
responses (CTLs and NK cells)
53
54. Consequence of Cell-mediated
Immune Dysfunction
• Inability to respond to intracellular infections and
malignancy
• Mycobacteria, Salmonella, Legionella
• Leishmania, Toxoplama, Cryptosporidium, Microsporidium
• PCP, Histoplamosis
• HSV, VZV, JC virus, pox viruses
• EBV-related lymphomas
54
56. Transmission
• Modes of infection
• Sexual transmission at genital or colonic mucosa
• Blood transfusion
• Mother to infant
• Accidental occupational exposure
• Viral tropism
• Transmitted viruses is usually macrophage-tropic
• Typically utilizes the chemokine receptor CCR5 to gain cell
entry
• Patients homozygous for the CCR5 mutation are relatively
resistant to transmission
56
57. 57
Cell free
HIV
Skin or
mucosa
24 hours 48 hours
Immature cell
Via lymphatics or
circulation
T-cell
PEP
Burst of HIV
replication
Early Phases of HIV Infection of
Mucosal Surfaces
58. Laboratory Markers of HIV
Infection
• Viral load
• 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)
• Male 684 cells/mm3 (IQR 588-832)
58
60. 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)
• Primary infection resolves as body mounts HIV-specific
adaptive immune response
• Cell-mediated response (CTL) followed by humoral
• Patient enters “clinical latency”
60
61. 61
Window Period: Untreated Clinical
Course
--------------------------------------------PCR
P24
ELISA
0 2 3 4
Weeks since infection
a b Time from a to b is the window period
viremia
antibody
Asymptomatic
Acute HIV syndrome
Primary
HIV
infection
Source: S Conway and J.G Bartlett, 2003
years
62. Window period
62
•The window period begins at the time of infection and can
last 4 to 8 weeks.
•During this period, a person is infected, infectious and
viremic, with a high viral load and a negative HIV antibody
test.
•The point when the HIV antibody test becomes positive is
called the point of seroconversion.
•Source of graph: S Conway and J.G Bartlett, 2003
64. Natural History
•Acute (primary) retroviral syndrome is the initial
event after infection, which is characterized by a
rapid decline in CD4 cell count and high plasma
viremia.
•Development of cytotoxic T-cell (CTL) response
results in clinical recovery of acute infection and a
reduction in plasma viremia. The virus reaches
“set point” as a result of this immune response.
The viral load at this “set point” correlates with the
rate of CD4 decline and disease progression.
64
65. Natural History
•Overtime, HIV RNA levels gradually increase.
•In parallel, the CD4 cell count gradually declines
over several years, but rapidly drops 1.5 to 2
years before an AIDS-defining diagnosis.
•Source: Fauci AS, Pantaleo G, Stanley,
Weissman D. Immunopathogenic mechanisms of
HIV infection. Ann Intern Med 1996;124:654-63.
Galens Curriculum, Module 8, p. 17.
65
66. 66
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
67. HIV RNA Set Point Predicts
Progression to AIDS
• The rate of disease progression - is determined
by the patient’s viral load.
• With levels between 1,000 and 10,000 viral
copies, the likelihood of AIDS in 5 years is 8%.
• At 10,000 to approximately 50,000, the
likelihood is 26%.
• At 50,000 to <100,000 it is 49%.
• Between 100,000 to 1,000,000 the likelihood is
62% at 5 years.
67
68. 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
• WHO Staging system
68
69. Key Points
• HIV is a retrovirus, capable of integrating into host
genome and establishing chronic infection
• HIV can be classified into subgroups (clades) which have
characteristic geographic distribution
• The important steps in the lifecycle of HIV include cell
entry, reverse transcription, integration, and
maturation/assembly
• Cell-mediated immunity is critical for containment of
HIV infection and other intracellular infections
• HIV evades host immunity by a variety of mechanisms
69
70. Key Points (2)
• HIV activates the immune system to increase its own
replication
• CD4 count declines by both direct and indirect
mechanisms
• HIV RNA set point predicts rate of progression to AIDS
• CD4 count decline is associated with a predictable
sequence of opportunistic infections
70
