The viral set point in HIV1 subtype C infection: Role of host and viral factors

1
CAPRISA Scientific Advisory Meeting, 5 May 2003
The viral set point in HIV-1 subtype C infection
Role of host and viral factors
Carolyn Williamson, PhD Project Leader /Protocol
Chair CAPRISA Viral Diversity Core
Laboratory Institute for Infectious Diseases and
Molecular Medicine University of Cape Town
2
Why focus on viral setpoint?

• Best available predictor of progression of HIV-1
  infection to clinical disease and death (Mellors
  et al., 1997)
• Important secondary endpoint for vaccine and
  therapeutic trials.

3
Why subtype C?
Gag subtype distribution in southern African
region (gag gt1.4kb)
4
HIV-1 env
N Group
M Group
D
SIVcpz
O Group
B
F
CRF01 (E)
C
H
A
J
SIVcpz
10
5
What is set-point?
ACUTE PHASE
ASYMPTOMATIC PHASE
AIDS
1,200
107
STEADY STATE balance between production and
destruction of virus /infected cells
1,000
106
800
VIRAL LOAD (copies/ml)
105
600
CD4 T CELL COUNT (cells/ml3)
104
400
DEATH
103
VIRAL LOAD
200
102
0
0
6
12
YEARS (not drawn to scale)
WEEKS
6
Immunological responses associated with control
of replication
ACUTE PHASE
ASYMPTOMATIC PHASE
AIDS
1,200
107
1,000
106
800
VIRAL LOAD (copies/ml)
105
600
CD4 T CELL COUNT (cells/ml3)
104
400
DEATH
103
VIRAL LOAD
200
102
0
0
6
12
lt2 10 15
YEARS (not drawn to scale)
WEEKS
7
Why is subtype C heterosexual infection in Africa
different?

• Most studies on subtype B homosexual transmission
• Genetic and immunological differences between
  subtypes
• Biological differences between subtypes
• Complex relationship between virus, host,
  environment and immune response

8
PARTICIPANTS
175 HIV neg women (Oxfam) 50 HIV neg men
(Oxfam) 714 HIV neg women (Anal Sex) 700 HIV-
High Risk Women (HPTN035)
HIV NEGATIVE COHORTS
100 HIV- FSW
Follow Monthly
Follow Quarterly
HIV POSITIVE COHORTS
Ab pos OR HIV PCR pos
HIV Ab pos
Weekly for one month, fortnightly until 3 months
post infection
Monthly follow-up until 18 months post
infection Quarterly follow-up until end of study
9
(1) Clinical and behavioural
CTL
HIV RNA
Antibodies
Symptoms
0
1
2
4
3
exposure
Weeks following transmission
AIM - Describe clinical course of disease of
acute infection - Describe
psychosocial and behavioural changes
following acute infection
10
(2) Immunological and Virological To determine
association between immune response and viral
load
CTL
HIV RNA
Antibodies

0
Weeks
1
2
4
3
exposure

• Whole genome mapping of CTL responses
• Describe trends in neutralization responses
• Describe trends in coreceptor usage

11
Viral escape from autologous Nabs
AIM Determine the association between
neutralizing antibody responses, viral genetic
changes and viral set-point.
12
C. Gray, NICD
Aim Define regions of genome associated with
control of viral replication in acute infection
and monitor changes in responses, viral sequence
and viral loads.
13
Consequences Rapidly adapt and escape
Aim Assess effect of CTL, antibody and cell
tropism on targeted regions of genome and
determine effect on viral load
MS
14
Implications of Dual Infection Timing of second
infection?
RNA
Co- Infection
Superinfection
2nd infection
1st infection
15
Conclusion

• Identification of individuals in very early
  infection allows for a comprehensive analysis of
  clinical, immunological and virological events
  impacting on viral set-point.
• Contribute to future design and testing of
  vaccines
• Monitoring of therapeutic interventions

16
Acute Infection Project - Acknowledgements

• University of Natal
• Salim Abdool Karim
• (Carpisa PI)
• Koleka Mlisana (AI Project Director)
• Francois van Loggerenberg (Project Co-ordinator)
• Farida Amod
• Quarraisha Abdool Karim
• Sharon Cassol
• May Mashego (Mkhize)
• Janet Frohlich
• Ayesha Kharsany
• Tsidi Sebitolane

• University of Cape Town
• Carolyn Williamson (AI Project Leader / protocol
  Chair)
• Joanne van Harmelen

• NICD
• Clive Gray
• Lynn Morris
• Adrian Puren
• Maria Papathanosopoulos

• International
• Guido Ferrari (Duke)
• Bruce Walker (Harvard)
• Philip Goulder (Oxford)
• David Montefiori (Duke)
• Scott Hammer (Columbia)

• MRC
• Gita Ramjee