HIV1 infection decreases CD127

1

• HIV-1 infection decreases CD127
• and PD1 expression on duodenal
• CD8T cells
• Liliana Belmonte, PhD
• Academia Nacional de Medicina
• Buenos Aires, Argentina

2
Background

• The GI tract is a major site of HIV
  replication and pathogenesis, regardless of the
  specific tissue site of viral entry.
• Persistence of HIV in the duodenal mucosa
  even when effective therapy suppresses HIV-RNA in
  blood to undetectable levels, has been
  demonstrated by previous studies from our group.
• (Belmonte L et al, AIDS 200721(15)2106-8).

3
Chronic HIV infection often results in
ineffective CD8 T-cell responses. However the
mechanisms triggered by persisting virus
infection and their impact on CD8 T-cell effector
functions and tissue distribution, remain
unknown.

• Specific Aim
• To analyse the quality of duodenal CD8 T cells
  in chronically HIV-infected patients.

4
Distal Duodenal biopsies
26 patients with chronic HIV-1 infection under
HAART
13 HIV-1 seronegative individuals were included
as control (C)

• We analyzed the presence of HIV-DNA in the
  duodenal tissue. A biopsy was labeled as HIV
  if HIV-DNA was detected by standard PCR
• (using the primers SK145 and SKCC1B to define
• a sequence of 155 nucleotides within the highly
  conserved region of the HIV-1 gag gene)

5
Distal Duodenal biopsies
26 patients with chronic HIV-1 infection under
HAART
13 HIV-1 seronegative individuals were included
as control (C)

• Endoscopic material were disrupted mechanically
  and a cell suspension was prepared. Expression
  of CD4, CD8, CD27, CD28, CD45RO, CD45RA, CCR7,
  CD127, PD-1 (BD) was analysed by flow cytometry
  (FacScan, BD).

• We analyzed the presence of HIV-DNA in the
  duodenal tissue. A biopsy was labeled as HIV
  if HIV-DNA was detected by standard PCR
• (using the primers SK145 and SKCC1B to define
• a sequence of 155 nucleotides within the highly
  conserved region of the HIV-1 gag gene)

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Percentages of CD4 and CD8 T cells in the
duodenal mucosa
7
Duodenal Memory CD8 T cell differentiation
(CD45RA, CCR7 expression)
Terminally differentiated cells
Pre-terminally differentiated cells
Precursor memory T cells
8
Duodenal Memory CD8 T cell differentiation
(CD27, CD28 expression)
CD8 CD28 CD27
Early Differentiated cells
CD8 CD28- CD27
Intermediate Differentiated cells
Late effector cells
CD8 CD28- CD27-
9
High Programmed-death 1 (PD-1) expression on
duodenal CD8 T cells from HIV patients
pns
HIV biopsies
HIV- biopsies
Controls
10
Decreased CD127 high (IL7R) expression on
duodenal CD8 T cells from HIV patients
pns
HIV biopsies
HIV- biopsies
Controls
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Conclusions

• Our results demonstrate an accumulation of the
  pre-terminally differentiated subset of memory
  cells. This findings could be due to a depletion
  of terminally differentiated CD8 T cells and/or
  lack of CD4 helper activity.

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Conclusions

• Our results demonstrate an accumulation of the
  pre-terminally differentiated subset of memory
  cells. This findings could be due to a depletion
  of terminally differentiated CD8 T cells and/or
  lack of CD4 helper activity.

• The pool of late effector CD8 T cells (CD27-,
  CD28-) was higher in HIV patients than in C.
  However, in HIV patients with HIV biopsies this
  value was lower than in those with HIV- biopsies,
  suggesting that continuous Ag exposure leads to
  late effector cell loss.

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Conclusions

• PD-1 was significantly up-regulated on duodenal
  CD8 T cells in HIV patients. Functional
  impairment (exhaustion) could lead to ineffective
  viral control, since in the biopsies where HIV
  persisted, the of exhausted cells tended to be
  higher.

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Conclusions

• PD-1 was significantly up-regulated on duodenal
  CD8 T cells in HIV patients. Functional
  impairment (exhaustion) could lead to ineffective
  viral control, since in the biopsies where HIV
  persisted, the of exhausted cells tended to be
  higher.

• HIV infection suppressed CD127high expression
  on duodenal CD8 T lymphocytes. The proportion of
  CD127-expressing cells was slightly lower in the
  biopsies where HIV persisted and this could be
  related to T cell exhaustion. These data support
  further the concept that HIV infection can alter
  memory CD8 differentiation.

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Aknowledgements

• Gastroenterology Unit- City Hospital Juan A
  Fernandez
• Alberto Zalar, MD
• Norma Correa, MD
• Infectious Diseases Unit-City Hospital Juan A
  Fernandez
• Pedro Cahn, MD, PhD
• Maria Inés Figueroa, MD
• Laboratory of Immunology- Academia Nacional de
  Medicina
• Ana Coraglia, PhD st
• Maria Marta de E de Bracco, PhD
• ANPCyT-MinCyT and Roemmers Foundation for
  financial support