Lecture 1

Viral Replication &

Pathogenesis

HIV/AIDS: uma visão geral e

patogeneses
 HIV/AIDS: Overview and
Pathogenesis.
HIV/AIDS: uma visão geral e patogeneses
Suggested literature:
Stevenson M HIV-1 Pathogenesis. Nat Med. 2003 9:853-60
Shattock RJ, Moore JP. Inhibiting sexual transmission of HIV-1
infection. Nat Rev Microbiol. 2003 1:25-34
Stebbing J, Gazzard B, Douek DC. Where does HIV live? N. Engl J
Med. 2004 350:1872-80
Haase AT. Perils at mucosal front lines for HIV and SIV and their
hosts. Nat Rev Immunol. 2005 5:783-92.
Gonzalez-Scarano F, Martin-Garcia J.The neuropathogenesis of
AIDS. Nat Rev Immunol. 2005 5:69-81.
The course of HIV infection
O Curso da Infecção pelo HIV
 The course of HIV infection
O Curso da Infecção pelo HIV

1. Acute Phase (fase aguda)

2. Intermediate (asymptomatic) phase -viral load stabilizes at
a “set point”. (Fase Intermediária (assintomático). Carga viral estabiliza
em um limiar).
3. Late (symptomatic) phase (Fase tardia-sintomática).
 The acute phase of replication
A fase aguda da replicação

1. Massive replication occurs in gut

lymphoid tissue
1. Replicação maciça ocorre no tecido linfóide do intestino.
2.CD4+ CCR5+ memory T-cells are main
targets for infection.
2. Células de memória CD4+CCR5+ são os principais alvos da infecção.
3.Replication spills out into lymph nodes
and blood.
3. A Replicação espalha-se para linfonodos e sangue.
The importance of gut-associated lymphoid tissue (GALT)
A importância dos tecidos linfóides associados ao intestino (GALT)

• GALT is the body’s major reservoir of activated,

CD4 CCR5+ T-cells, the preferred targets for R5
virus replication.
GALT é o maior reservatório de células T CD4+CCR5+. Os alvos
preferidos para replicação do vírus R5.

• Rapid depletion of these T-cells from the GALT

occurs after infection of macaques by R5 viruses -
SIVmac, SHIV-162P (R. Veazey, A. Lackner; J.
Harouse, C. Cheng-Mayer).
Rápida depleção dessas células T do GALT ocorre após a infecção de
macacos por virus R5- SIVmac, SHIV-162P
Depletion of Human Gut CD4+ T Cells

• Gut biopsies from >50 individuals

• CCR5+ CD4 T cells are massively depleted from gut
• High frequency of infected cells at all stages of disease
What can this look like?
HIV- HIV+

• There is a marked reduction in mucosal lymphoid

tissue even in acute infection Ha uma reducao marcada de
mucosal lymphoid tecido ate na infeccao aguda
Courtesy of Rick Koup
 The course of HIV infection
O Curso da Infecção pelo HIV

1. Acute Phase (Fase aguda)

2. Intermediate (asymptomatic) phase -viral load stabilizes at
a “set point”. (Fase intermediária (assintomática)-carga viral
estabiliza em um limiar.
3. Late (symptomatic) phase. Fase tardia (sintomática)
 Viral "Set Point" as a Predictor of Disease

% of patients with AIDS

7 at 5 years
(Log, plasma RNA)

6 85
Viral Load

62
5
49
4 26
8
3

Time
 The course of HIV infection
O Curso da infecção pelo HIV

1. Acute Phase (Fase aguda)

2. Intermediate (asymptomatic) phase -viral load stabilizes at
a “set point”. (Fase intermediária (assintomática)-carga viral
estabiliza em limiar.
3. Late (symptomatic) phase. Fase tardia (sintomática)
 HIV Associated Dementia

• About 30% AIDS patients suffer severe neurological

disorders known as AIDS dementia complex (ADC) or
HIV-associated dementia (HAD).
Cerca de 30% dos pacientes com AIDS sofrem graves
alterações conhecidas como Complexo demencial da AIDS
(ADC) ou Demencia associada ao HIV (HAD).

• Cognitive, behavioral, and motor deficits resulting from

HIV-1 infection within the brain.
Deficites cognitivo, comportamental e motor resultam da
infecção pelo HIV-1 dentro do cérebro.
What causes AIDS ?
How are CD4+ T-cells lost?
Como as celulas T CD4+ sao perdidas?

Is it the virus?
E o virus?

Or an indirect mechanism?
Ou um mecanismo indireto?
 What causes AIDS?
O que causa AIDS?

• There is a direct relationship between virus

set-point and progression to AIDS.
Existe uma relação indireta entre o limiar do vírus e a progressão
para a AIDS.

• AIDS is a direct consequence of CD4

lymphocyte depletion.
AIDS é uma consequência da depleção de linfócitos CD4.

• HIV-1 is cytopathic for CD4 lymphocytes.

HIV-1é citopático para linfócitos CD4
 What causes AIDS?
O que causa AIDS?

• Logically therefore, high level virus

replication and lymphocyte destruction
must be the cause.
Logicamente, então, o alto nível da replicação do virus e a
destruição de linfócitos devem ser as causas.
• This view is not supported by studies of
non-pathogenic SIV infection.
Esse visão não é confirmada por estudos de infecção de SIV
não patogênico.
 SIVsm in SIVmac in Rhesus macaques
Sooty
Mangabeys HIV-2 in Humans

SIVcpz in HIV-1 in Humans

Chimps

No disease AIDS
 Sooty Mangabeys do not develop disease
Sooty Mangabeys não desenvolvem doença
---High levels of virus replication.
Altos níveis de replicação viral.

---Continuous rounds of viral replication with infected cells dying as

quickly as in HIV infections.
Contínuo círculo de replicação viral com células infectadas morrendo tão
rápido quanto na infecção pelo HIV.

---Bystander apoptosis is low.

Apoptose “bystander” é baixa

---Immune activation is low.

A ativação imunológica é baixa

Conclusion: Viral killing of lymphocytes may be necessary but not

sufficient for immunodeficiency.
Conclusão: morte viral dos linfócitos pode ser necessária,
mas não suficiente para causar imunodeficiência.
Sousa, Giorgi et al. 02

CD4+ T-cell depletion correlates more

closely with levels of immune activation
than viral load.

Depleção de células T CD4+é melhor correlacionada com os níveis

de ativação imunológica que a carga viral
 Cause of pathogenic primate lentivirus
infections:
Causas de infeccões patogênicas de lentivirus de primatas.

• Pathogenic: Immunodeficiency, profound viremia, CD4

cell turnover, immune activation, neuropathogenicity.
Patogenica: imunodeficiência, intensa viremia, renovação de
células CD4, ativação imunológica, neuropatogênicidade.

• Non-pathogenic: profound viremia, CD4 cell turnover.

Não-patogênica: intensa viremia, renovação de células CD4.

Therefore, it is the extent of immune activation that

determines pathogenicity.
Assim, é a extensão da ativação imunológica que
determina a patogenicidade.
 Cause of disease?
O que causa AIDS?
• Hypothesis: Massive acute replication produces
viral proteins which damage the integrity of the
gut wall. Hipotese: a replica aguda produz a proteina viral
que danifica a integridade da parede da tripa.
• Bacterial products (LPS) are able to cross the
mucosa and cause inflammation/activation of
underlying cells. May promote eventual
destruction of lymphoid tissue. Os produtos
bacterianos (LPS) sao capazes de cruzar a mucosa e a
inflamacao/ativacao de causa da celulas subjacentes. Pode
promover a destruicao eventual do tecido lymphoid
0 dpi 14 dpi
The Gut and Immune Activation in
HIV

Does microbial translocation occur as a result of

HIV-induced CD4 T cell depletion of the gut mucosa,
thereby causing systemic immune activation?

Courtesy of Rick Koup

 Yes
Plasma LPS levels are a quantitative indicator of microbial translocation

Increased plasma LPS levels in HIV+ individuals

Courtesy of Rick Koup
 Non-Pathogenic Natural SIV
Infection
Natural SIV infection — non-pathogenic, high VL, low immune activation
Do they have less microbial translocation?

No evidence for microbial translocation in non-

pathogenic natural SIV infection of sooty mangabeys
Courtesy of Rick Koup
 CD4+ T cell depletion
allows bacteria to cross
the mucosa?
Since when are CD4+ T
cells involved in control
of bacteria?
Control of Extracellular Microbial
Pathogens
• Neutrophils

•Th17 cells

•Memory CD4 T cells that produce IL-17 and IL-22 (not IFN or IL-4)
•IL-17 is thought to be important for anti-bacterial immunity
•Recruits neutrophils
•Induces proliferation of GI enterocytes
•Induces production of anti-bacterial defensins

•What is the status of Th17 cells in HIV-infection?

• Quantity, phenotype, infection frequency, antigen specificity,
functionality in blood and GI tracts of HIV-infected and uninfected
individuals
 Antigen specificity of Th17
cells

Th17 cells are specific for bacterial and fungal

but not common viral antigens (even those in
mucosa) As celulas Th17 sao especificas para bacterias e fungos mas nao
antigenos virais comuns (ate aquela mucosa)
Courtesy of Rick Koup
 Th17 Cells in GI Tract: HIV-
Negative

Th17 cells are more prevalent in the GI tract

than the blood As Celulas Th17 sao mais prevalentes na via GI do
que no sangue Courtesy of Rick Koup
 Th17 Cells in GI Tract: HIV-
Infected

anti-CD3

PMA/iono

Th17 cells are preferentially lost from

the GI tract of HIV-infected
 Cause of Disease?
• Destruction of Th17 cells undermines ability
to control microbial agents resulting in
immune activation.
• Does immune activation undermine CD4
homeostasis?
• Why is mucosal integrity undermined only in
pathogenic infection?
 How do we stop it?
• Very early therapy to stop massive viral
onslaught
• Preservation of mucosal integrity
• Anti-inflammatory strategies to prevent
chronic damage.