MHRP/WRAIR Nigeria

HIV INFECTION AND AIDS

PATHOGENESIS
AND IMMUNOLOGY

The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the Department of Defense.
MHRP/WRAIR Nigeria

When, where and how did HIV

originate?

What do you know about this topic?

Why should you know about this topic?
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Scanning Electron Micrograph and Cartoon of the
Structure of an HIV Virion

Envelope glycoprotein (GP 120) molecules

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PATHOGENISIS OF HIV INFECTION

 Relationship of HIV Viremia and CD4 Depletion

 Plasma “set point” for HIV RNA determines the
rate of CD4 depletion (high set points result in
rapid CD4 depletion)
• HIV is difficult to cure because it infects long-
lived cells in the body, also called “reservoirs”.
• Having a small HIV reservoir size may benefit
health.
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PATHOGENISIS OF HIV INFECTION

 HIV DNA in peripheral blood cells is a marker of the

HIV reservoir size, establishes a set-point level
during the first 6 weeks of infection and changes
little over time without HIV medications.
 However, if HIV medications are started early, the
reservoir size declines rapidly, and is 300-fold lower
than that seen in untreated persons.
 Currently the most effective way to significantly
lower the HIV reservoir size is with very early
treatment.
MHRP/WRAIR Nigeria
PATHOGENISIS OF HIV INFECTION

 Relationship of HIV Viremia and CD4 Depletion

 Plasma “set point” for HIV RNA determines the rate of
CD4 depletion (high set points result in rapid CD4
depletion)
 CD4 counts determine the clinical course of HIV infection,
but the rate of CD4 depletion is highly variable
 Plasma “set point” for HIV RNA levels are:
• established early (3-6 months post infection)
• relatively constant subsequently
• determined by the HIV replication rate
MHRP/WRAIR Nigeria

Relating Disease Progression to Plasma HIV-1 RNA

Level and CD4 Cell Count

Viral Load
1,000
100
10,000
200
100,000
300

400

1000 900 800 700 600 500

CD4 COUNT
MHRP/WRAIR Nigeria HIV RNA Set Point Levels
Predict Progression to AIDS

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PATHOGENISIS OF HIV INFECTION:

No Progression With Low Level Viremia

Primary HIV Chronic Non-progressive HIV Infection

CD4

RNA Set Point ~ 103

RNA

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PATHOGENISIS OF HIV INFECTION:

Rapid Progression With High Level Viremia
Primary HIV AIDS

RNA RNA Set Point ~ 106

CD4

2 3

Years

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Cells infected by HIV

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General Mechanisms of HIV Pathogenesis
 Direct injury by HIV
 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 as a consequence of
Immunosuppression
 Multiple cancers for which HIV increases risk
MHRP/WRAIR Nigeria General principles of
Immune Dysfunction in HIV
 All elements of immune system are affected

 Advanced stages of HIV are marked by 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
MHRP/WRAIR Nigeria Mechanisms of CD4 depletion and
dysfunction
 Direct
 Loss of plasma membrane integrity because of: viral
budding and Interference with cellular RNA processing
 Indirect
 Pyroptosis – necrosis of “bystander” T lymphocytes
 Apoptosis
 Immune destruction of HIV-infected cells by virus-specific
immune response
MHRP/WRAIR Nigeria

PATHOGENESIS OF HIV INFECTION:

Anatomic Compartments of HIV
The Pathogenesis of HIV-1 Infection:
Compartments

Colon, Duodenum and Brain Macrophages

Rectum Chromaffin Cells and Glial Cells

Lymphocytes in Blood, Lymph Nodes

Semen and Vaginal Fluid

Thymus Gland
Bone Marrow

Lung Alveolar
Skin Langerhans’ Cells
Macrophages
MHRP/WRAIR Nigeria PATHOGENISIS OF HIV INFECTION
Mechanisms of Injury to Immune System

1) Lymph Node Enlargement and Destruction

a. Lymph nodes heavily infected

b. Proliferation of B cells in germinal centers in nodes causes enlargement

(1-2cm, mobile, non-tender) early in disease

c. IgG levels in blood increase 2° to polyclonal B cell hyperactivity

d. Lymph node depletion causes nodes to shrink before AIDS diagnosis

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CAUSES OF MORBIDITY AND MORTALITY

Without sophisticated medical treatment:

1. In much of the underdeveloped world, tuberculosis and
diarrheal diseases are often the first and ultimately fatal
opportunistic infections
2. Both lead to wasting, malnutrition, and death from
starvation, dehydration, and secondary pneumonias
MHRP/WRAIR Nigeria
CAUSES OF MORBIDITY AND MORTALITY

With sophisticated medical care:

1. Combinations of antiretrovirals often reverse

progressive CD4 depletion and restore immune function

2. Immune reconstruction protects against

opportunistic infections and neurologic deterioration and
often diminishes fatigue, diarrhea, or weight loss
MHRP/WRAIR Nigeria
CAUSES OF MORBIDITY AND MORTALITY

2. Evidence for immune reconstruction in response to combination

antiretroviral therapy

a. Epidemiologic - Since introduction of protease inhibitors

(HAART) in 1996, rates of death and opportunistic infections have been
reduced

b. Immunologic - CD4+ cell counts often increase 2-8 fold when

plasma viral levels are suppressed to low or undetectable levels
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CAUSES OF MORBIDITY AND MORTALITY

c. Clinical

i. Previously progressive (CMV retinitis) or

persistent (cryptospordiosis) OI are often cured by
HAART

ii. CD4 thresholds for risk of OIs are

similar after to those who have not been
treated (e.g. for PCP, risk is minimal if CD4 > 200)
MHRP/WRAIR Nigeria
CAUSES OF MORBIDITY AND MORTALITY

3. Antimicrobial prophylaxis can protect those with low

CD4 lymphocyte counts from:
a. Pneumocystis or toxoplasmosis - e.g.
Cotrimoxazole for CD4 < 200
b. Mycobacterium avium complex (MAC) - e.g.
azithromycin for CD4 < 75
c. Mycobacterium tuberculosis –isoniazid
d. Candida or cryptococcus - fluconazole for
patients with recurrent (candida) or treated
(cryptococcus) until CD> 200
MHRP/WRAIR Nigeria What is the current approaches to an
HIV vaccine?
 So far, these vaccines have not been effective for
either
 prevention of HIV infection or
 therapy of infection in HIV+ persons

 Conserved structures on HIV (“common” HIV

antigens) such as parts of gp120 are targeted by
vaccines to increase levels of neutralizing Ab

 Placing these antigens in other viruses such as

adenoviruses is thought to increase responses
MHRP/WRAIR Nigeria Why such a difficult virus to prevent with vaccines or or remove
from the body

 High rates of genetic variation that change antigens

evades vaccines

 Integration of HIV into the DNA of long- lived human

cells provides a reservoir that can’t easily be
eliminated
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THANK YOU ALL