Questions to be addressed

1
Questions to be addressed

• How does HIV cause progressive CD4 T cell loss
• Direct killing of CD4 T cells
• Indirect mechanisms (immunologic exhaustion)
• Both?
• What role might the innate immune system play?
• Do virus-related characteristics modify this
  phenomenon?
• Co-receptor tropism
• Drug resistance and replicative capacity

SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
2
Natural History of Untreated HIV Disease
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
3
Relationship between viral load and rate of CD4
T cell decline among untreated patients (n2005)
Baseline Plasma HIV RNA Level
Rodriguez, Lederman CROI 2005
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
4
HIV infects only a few cells of unclear relevance

• Only 0.01 to 1 of peripheral blood CD4 T cells
  are infected (chronic infection)
• Preferential infection of activated CD4 T cells
• Activated T cells are destined to die anyway
• Most cells most cells destined to die as a
  consequence of HIV infection are not infected
  with HIV
• Finkel TH et al. Nat Med. 19951129-134

SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
5
CD8 T Cell Activation is Particularly High in HIV
Disease
Hunt JID 2003
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
6
T Cell Activation Predicts Survival (among
patients with a CD4 lt 50)
CD8 T cell activation was a stronger predictor
of survival than CD4 count and plasma HIV RNA
levels among untreated patients with advanced
AIDS.
P0.001
Giorgi JID 1999
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
7
Pro-inflammatory aspects of HIV (which is unique
to this virus) results in continuous activation
and turnover of CD4 and CD8 T cells, leading to
eventual immunologic exhaustion
Grrossman et al, Nature Med 2002
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
8
Why not simply replenish CD4 T cells as they are
lost?
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
9
Dion et al CROI 2005
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
10
Is this activation due to increased antigen
exposure or due to an indirect effect of HIV on
the immune system (innocent bystanders)?Role of
Innate Immune System
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
11
Dendritic cells and SIV infection

• Pathogenic SIV/HIV infection results in T cell
  activation in contrast, limited activation
  observed in SMs
• Might this be driven by differences in dendritic
  cells?
• Comparative study of infected SM vs. macaques
• Macaques 25 to 50 of PDCs express CCR7
• Sooty mangabeys (n3) Most PDCs do not express
  CCR7
• PDCs from macaques but not SM are susceptible to
  activation via TLR-9 ligands (GpG) and SIV
• Lack of PDC activation may lead to an
  anti-inflammatory immune response

Staprans et al CROI 2005
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
12
Perhaps both direct and indirect mechanisms are
relevant
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
13
Terminal ileum, HIV uninfected
Terminal ileum, Week 3 HIV Infection
HIV infection results in a rapid and dramatic
depletion of CCR5 CD4 memory T cells in gut
(without evidence of increase activation/turnover)
Brenchley et al J. Exp. Med 2004
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
14
Most CD4 T cells are SIV infected during peak
viremia (acute)

• Tissue Gag (copies/cell) SIV Memory CD4 ()
• PMBC 1.45 30
• Mesn LN 1.51 54
• Inguinal LN 1.45 49
• Jejunum 1.61 60
• By day 14, 50 of total body CD4 T cells are
  depleted gone
• Loss of these cells can be attributed to direct
  SIV (HIV) infection

Douek and colleagues, Nature (in press)
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
15
SIV infection in the gut

• Comparative study of T cells in GI tract of
  uninfected monkeys
• Macaques (n5) 50 of the T cells CD4, and
  50 of these co-express CCR5.
• AGM (n12) lt 10 of the T cells expressed CD4,
  and of these, only 12 co-expressed CCR5.
• Sooty mangabeys (n3) CD4 T cells more common,
  but essentially none (lt3) of these co-expressed
  CCR5
• Susceptible effector T cells uncommon in natural
  hosts of SIV
• ? evolutionary advantage
• Why does SIV still replicate at high titer?

Veazy et al CROI 2005
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
16
How does HIV cause CD4 loss Acute Infection

• Acute HIV associated with rapid depletion of
  CCR5 memory CD4 T cells in intestines (where
  high proportion of cells are activated)
• Seen in macaques but not natural hosts
• Most (40) of CD4 T cells contain HIV
• 50 of total body CD4 T cells are depleted
  within first few months
• Data are consistent with massive death of cells
  from a direct lytic effect of the virus
• Immediate suppression of thymic function prevents
  CD4 replenishment
• Indirect mechanisms likely to remain critical in
  chronic disease

Brenchley JEM 04 Douek CROI 2005 Veazey CROI
2005 Mehandru JEM 04 Dion Immunity 04
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.
17
Cyclosporin for acute HIV infection

• Cyclosporin (CsA) down-regulates genes essential
  for activation of CD4 lymphocytes
• Acute HIV receiving
• HAART (n43)
• HAART CsA x 8 weeks (dosed to achieve levels
  gt1000 ng/mL)
• VL reduction over time similar in both groups,
  though more reached lt50 c/mL in the CsA group at
  Weeks 18, 24, and 36 (plt0.011)

1400


1200

Mean CD4 (cells/mm3)
1000
800
600
CsAHAART
HAART only
400
0
12
24
36
48
60
72
84
96
108
120
Week
STOP CsAWk 8
p0.006, p0.015, p0.07
Khonkarly M, et al. 12th CROI, Boston 2005, 567
SG Deeks, MD. Presented at IASUSA Atlanta
Course, March 11, 2005.