HIV Pathogenesis and Natural

Course of the Disease

Wondwossen Amogne MD, PhD

August 2016
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 Learning Objectives
About HIV-1:
 Describe the origin and basic virology.
 Describe the immune response to HIV.
 List the mechanisms used to evade the
normal immune responses
 Explain the principles of antiretroviral
therapy.
 Explain HIV preventive strategies.

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HIV epidemiology
(Global & local)

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HIV: LANDMARKS IN HISTORY

1931: Probable first case

Primate → human (butchering)
1981: Disease discovery – AIDS
1983: HIV discovery
Luc Montagnier & R. Gallo
1985: Blood Test
Risks – blood, MTCT & sex (HSV-2)
1986: AZT Trial
1996: Vancouver meeting - HAART

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 Historical Overview and Status of
HIV/AIDS in Ethiopia
 1984: The first evidence of HIV infection in
 1986: The first two AIDS case were reported
 1989: Surveillance in Ethiopia started

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 Ethiopia: single point HIV prevalence
estimate, 2004–2010
All Ages
2004 2005 2006 2007 2008 2009 2010
Adult prevalence (%)
Total 2.2 2.1 2.1 2.1 2.2 2.3 2.4

Male 1.7 1.7 1.7 1.7 1.8 1.8 1.9

Female 2.6 2.5 2.5 2.6 2.6 2.8 2.9

HIV-positive population
Total 891,862 901,893 929,699 977,394 1,037,267 1,116,216 1,216,908

Males 363,666 368,542 379,797 399,376 424,452 457,373 499,239

Females 528,196 533,351 549,902 578,018 612,815 658,843 717,669

Pregnant women 69,774 70,686 71,851 75,420 79,183 84,189 90,311

Annual HIV-positive
births 13,820 13,970 13,836 14,148 14,093 14,140 14,276

9 Ethiopia FHAPCO. June 2007. Single point HIV prevalence estimate.

 National Estimates for 2014 Estimate Low High

- Total People Living with HIV 724400 558900 988600

- Total New HIV Infections 28500 14100 50000
- Total Annual AIDS Related Deaths 20460 14410 34100
- Adults 15+ Living with HIV 635600 490800 871900
- Adults 15+ Prevalence 15-49 years old* 1.22 1.00 1.45
- Adults 15+ new infections 22970 10700 41750
- Annual AIDS related deaths Adults 15+ 16310 10300 30350
- Need for ART 15+ 528870 412540 781490
- Children (0-14 years) living with HIV 88700 68400 112800
- New HIV Infections among children (0-14 5400 2960 8800
years)
- Need for ART in children (0-14) 88700 68400 112800
- Mothers needing PMTCT 28310 20430 38000

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 Status of Ethiopian HIV epidemic, 2011

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 According to the 2014 HIV
estimates, the national
HIV prevalence in
Ethiopia is 1.14%,
indicating the country has
achieved the MDG 6
target of 2.5%. Annual
new HIV infections
declined by 90% & AIDS
related deaths by 53% in
the last decade (b/n 2000
and 2011).
Source:
http://www.afro.who.int/en/ethiopia/country-programmes/topics/4480-
hivaids.html
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 Status of Ethiopian HIV epidemic, 2011

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HIV-1 Virology

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Spread of HIV in Host Tissues

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 Overview of Adaptive Immune Response
Extracellular
APC infection
Intracellular
infection Free antigen
MHC I presentation
of endogenous
antigen MHC II presentation
of exogenous
antigen

Naïve Naïve
T8 cell B-Cell
Naïve T4
helper cell

Cell-mediated Humoral
Th1 Th2 (plasma cells /
(CTLs) antibodies)
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Diagram courtesy of Dr. Samuel Anderson
 HIV interaction with CD4 Cell
Co-receptor
interaction HIV
HIV
gp41
HIV Anchorage
gp120
HIV
CD4 CXCR4
CCR5
Attachment CD4
gp41

TH-Cell

Fusion HIV HR1-HR2

Complete interaction
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 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
 HIV-2 - isolated in West Africa

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 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 group 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

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 Origin and Distribution of HIV-1 Clades
 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)

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 Viral- host Dynamics

 About 1010 (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

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HIV Immunology

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 General Principles of
Viral-host Interactions:
 Host: mounts HIV-specific immune responses
 Cellular (cell-mediated) - most important
 Humoral (antibody-mediated)
 Virus: subverts 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

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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

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 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

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Humoral Immune Response to HIV

 Neutralization
 Antibodies bind to surface of virus to
prevent attachment to target cell
 Antibody-dependent cell-mediated
cytotoxicity (ADCC)
 Fc portion of antibody binds to NK cell

 Stimulates NK cell to destroy infected

cell

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 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 central nervous system

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Pathogenesis of HIV

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 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 macrophages

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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

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 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

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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
 Syncytium formation

 Apoptosis

 Autoimmunity

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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

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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

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Natural History of
HIV Infection

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 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

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Principles of HAART

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 Antiretroviral drugs
Monotherapy Dual therapy Triple therapy
ddC Delavirdine ddI EC Tenofovir Atripla

Nevirapine Trizivir Truvada Raltegravir

3TC Combivir ABC Kivexa Etravirine

AZT ddI d4T Efavirenz FTC Rilpivirine

1987 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07 ’08 ’09 ’10 ‘11

NRTI SQV HG NFV LPV/r TPV

PI RTV APV ATV DRV

NNRTI IDV fAPV Maraviroc

Fusion-I
SQV SG Enfuvirtide
CCR5-I

Integrase-I 47
http://www.fda.gov/oashi/aids/virals.html
Viral dynamics after HAART

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Goals of antiretroviral therapy
1. Clinical goals
- Prolong life & improve quality.
2. Virologic goals
- VL < 50 copies/ mL
3. Immunologic goals
- CD4 - Immune reconstitution
4. Therapeutic goals
- Rational sequencing.
5. Epidemiologic goals
- Reduce HIV transmission

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Preventing HIV infection

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 Biomedical prevention of HIV.

Circumcise
Behavioral
intervention

STD
Vaccine Control?

Barrier
Condoms Pre exposure Post exposure

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 What is combination prevention?
1 2

4 3
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Coates et al., Lancet 2008
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Mother to Child Transmission

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 Key Points(1)
 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

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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

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