Title: Figure 1' HIV1 RNA copies and CD4 T cell counts: January 1996March 2005'
1A Long-Term Nonprogressors Journey into HIV-1
Disease Association with Escape from Cellular
Immune Control Kimdar S. Kemal, Ph.D. Wadsworth
Center Albany, New York
2COLLABORATORS
- MRC, Human
- Immunology Unit,
- Oxford, UK
- Tara Beattie
- Tao Dong
- Julian Sutton
- Hongbing Yang
- Yang Chun Peng
- Sarah Rowland-Jones
- U. Toronto
- Rupert Kaul
- Wadsworth Center
- Harold Burger
- Barbara Weiser
- Sean Philpott
- Los Alamos National Laboratory
- Carla Kuiken
- Dorothy Lang
- U. Pennsylvania
- Ronald Collman
3- BACKGROUND
- A small proportion (1-5) of patients remain
free of HIV-related disease without
antiretroviral therapy for at least 10 years of
infection. - Such individuals are known as long term
nonprogressors (LTNP).
4- Background cont.
- Transition from LTNP infection
- to HIV-1 disease presents
- an opportunity to investigate pathogenesis and
disease progression in a defined
immunogenetic background.
5- PATIENT
- We studied a Caucasian male, who was exposed to
HIV-1 in May 1982 by sexual contact with a man
who later developed AIDS. - He remained disease-free without ART for over 18
years however he recently showed signs of
progression. -
6Viral Load and CD4 T Cell Count.
7- Objective
- To examine the virologic and cellular
immunologic aspects of the transition from LTNP
to progressive disease.
8- METHODS
- We obtained full-length and serial HIV-1 genomic
RNA sequences from plasma. -
9- Methods cont.
- A total of 50 autologous peptide epitopes (37 HLA
class I and 13 class II peptides), based on
the patients viral sequences and described for
his HLA alleles, were - screened by using IFN-? ELISpot assays.
-
10- Methods cont.
- The assays were performed using PBMC obtained
before and after disease progression.
11- RESULTS
- Virology
- No clearly attenuating mutations or
deletions in the patients HIV-1 sequences were
identified. - The length of the V2 region increased from
44/45 amino acids in 1998-2001 to 51/52 amino
acids in 2002-2004 .
12 HIV-1 gp120, V2
sequence alignments V2 insertion site
Length pNL4-3 FFYKLDIVPI
DNTSYRLISC 38 WC3-498 L..R..V...
KNNSTSY -.......N. 44 WC3-999
L..R..V... GNDTA SF -.N.....N. 44
WC3-901 L..R..V..L KNDSA SYY
-.......N. 45 WC3-602 L..R..V... GNDTA
SFNNSYNNSY --N.....N. 51 WC3-1202 L..R..VT..
KNDEN NTSEGNNTS ........N. 52 WC3-603
L..R..V... GNDTN SFNNSYNNSY .--.....N. 51
WC3-704 L..R..V... ENDTN SFNNSYNNSY
.--.....N. 51 . Identity with pNL4-3 strain, -
deletions, absence of insertions
13- Results cont.
- Throughout the course of infection the
patients virus utilized the CCR5 coreceptor. - Insertions in the HIV-1 gp120, V2 domain, have
been described to enhance CCR5 coreceptor usage.
14- Results cont.
- Immunology
- Before disease progression, PBMC
- from this patient made detectable
- IFN-? responses to 8 class I (CD8)
- and 3 class II (CD4) epitopes
- targeting 4 HIV-1 genes (env, gag,
- pol and nef).
15- Results cont.
- After disease progression, his PBMC made
detectable IFN-? response to 12 class I (CD8) and
4 class II (CD4) epitopes spanning 4 genes (env,
gag, pol, and nef).
16CD4 and CD8 T cell responses before and after
disease progression.
CD4 T cell responses
DR Int KR15
DR p24 GI15
DR Int QR15
DR p24 KY15
DR gp160 TR13
2002 2004
B8 p24 GI9
B8 p17 GL8
B8 p17 EL9
CD8 T cell responses
B8 p17 EI9
Autologous peptide epitope
B8 Nef WM8
B8 Nef FL8
B8 gp160 YL8
B8 gp160 RL12
B51 RT VL9
B51 p24 NL10
B51 gp160 LI9
A6801 RT AK9
A1, B8 Nef VT15
0
200
400
600
800
1000
SFU / Million PBMC
17- Results cont.
- The transition from LTNP to progressive disease
was associated with CTL escape and targeted
depletion of HIV-1-specific CD4 T cells.
18- Results Cont.
- A dramatic loss in T cell recognition was seen
to the emerging env gp160 YL8 and Nef AL9 epitope
variant. - A concomitant loss of recognition was seen
towards the p24 KY15 CD4 T cell epitope despite
the absence of sequence variation over time in
this epitope.
19gp160 YL8 CD8 T cell epitope
1000
gP160 B8 YL8 epitope 04/1998 QARVLAVERY
LKDQQLLGLW GCSGKLICTT 09/1999
.......... .......... .......... 09/2001
.......... .R........ .......... 06/2002
.......... .R........ .......... 12/2002
.......... .R........ .......... 06/2003
.......... .R........ .......... 07/2004
.......... .R........ ..........
800
600
SFU / Million PBMC
400
200
NT
0
YLKDQQLL
1999
2002
2004
YLRDQQLL
Sample year
20Nef AL9 CD8 T cell epitope
1000
Nef B51 AL9 180 190
200 08/1992 MEDPEKEVLV WKFDSRLAFH
HMARELHPEY 03/1993 .......... ..........
.......... 10/1993 .......... ..........
.......... 04/1998 .........M ..........
.......... 06/2002 .......... .........R
......... 12/2002 .......... .........R
.......... 06/2003 .......... .........R
.......... 07/2004 .......... .........R
..........
800
600
SFU/Million PBMC
400
200
0
2004
Sample year
WKFDSRLAFHHMARELHPEY
WKFDSRLAFRHMARELHPEY
21gag KY15 CD4 T cell epitope.
gag DR KY15 270 280 290
08/1992 IYKRWIILGL NKIVRMYSPT SILDIRQGPK
03/1993 .......... ..........
.......... 10/1993 .......... ..........
.......... 04/1998 .......... ..........
.......... 12/2002 .......... ..........
.......... 06/2003 .......... ..........
.......... 07/2004 .......... ..........
..........
22- CONCLUSIONS
- In this patient the LTNP phase was associated
with - A broadly directed T cell immune response.
- The presence of elongated V2 domain.
-
- Consistent usage of coreceptor CCR5 throughout
the course of infection.
23- Conclusions cont.
- The transition from LTNP to progressive disease
was associated with - The acquisition of viral mutations conferring CTL
escape. - Targeted depletion of HIV-1-specific CD4 T
cells.
24- Conclusions cont.
- These data help to identify the correlates of
protection from disease progression.
25 We thank the patient for his long-term
participation in the study.