HIVIT_GWAS - Immuno-therapy in HIV positive patients: a genomic approach - by Sergio Crovella

1. HIVIT_GWAS
Immuno‐therapy in HIV positive
patients: a genomic approach
SERGIO CROVELLA PhD
crovelser@gmail.com
Outgoing Fellowship
Biotechnologies and Diagnostics

2. ORIGIN Organisation
Children Hospital Burlo
Garofolo, TRIESTE,
ITALY
HOST Organisation
Insituto de Medicina
Integral Prof. Fernando
Figueira, RECIFE,
BRAZIL

3. HIV Vaccines
Obtaining an HIV vaccine has been one of the biggest challenges
of this century. To date numerous clinical trials have been
conducted to test candidate products as prophylactic vaccine.
Currently, about 20 clinical trials are underway, most protocols
for Phase I.

4. Innate immunity genes and patients response
to Denditric cell‐based HIV immuno‐treatment

5. • Age: 18 to 41 years (median 25)
• Gender/contamination :male/homosex. 2;
female/heterosex. 16.
• Seropositive for 13 to 65 ms (median 24.5)
• Never treated:15 pts /Treated during pregnancy
for 3 ms: 3 pts
• CD4 T‐cells : 270 ‐1.009/µl ( median,523)
• Plasma viral load: 11.000 to 300.000/ml
(geometric mean, 48.400; median, 37.600)
Characteristics of the 18 patients

7. The best patient

8. The Host Genome

9. We studied the “innate immune genome” of weak/transient
responders (WTR) and durable responders (DR) HIV infected
patients, enrolled in the study of Lu et al. in order to understand
the reasons of the success or not of the DC vaccine and its
relationships with the host innate immunity genome

10. SNPs selection:
SNPBrowser, HapMap,
QuickSNP, Tagger
• 149 INNATE IMMUNITY genes, 768 SNPs
• 1) non‐synonymous coding SNPs (nsSNPs), that
include a group of SNPs having the highest impact
on phenotype due to their potential to directly
affect the structure, function and interactions of
expressed protein
• 2) Tag SNPs, which represent a subset of SNPs
capturing most of the haplotype diversity of each
haplotype block or gene‐specific region.
Illumina's GoldenGate Assay

11. • NOS1 Nitric Oxide (NO) is a
pro‐inflammatory and antiviral
molecule, produced by
monocytes and DCs during
HIV infection
• MBL role in HIV infection is still
debated, since high levels of
serum MBL are usually
associated with a good
virological response, but some
authors also showed that MBL
enhances HIV replication,
hypothetically through the
induction of TNF‐α.

12. ‐1
‐0,5
0
0,5
1
1,5
p3 p3‐84 p17 p17‐84 p24 p24‐84 p18‐84 p31‐84 eric
"nos1 expression level"
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
1 2 3 4
T0
T1
T2Dia
6
2h
s
48
hs
T0 T1 T2
NOS1 Expression in DC from HIV infected patients

13. Inflammasome and HIV in DC
• NALP3‐inflammasome is an innate mechanism, alternative to type‐1
interferon, able to recognize nucleic acids and viruses into cytoplasm
and to induce pro‐inflammatory response.
• We hypothesized the involvement of inflammasome in the early
defence against HIV‐1 and in the fully maturation of dendritic cells
• We evaluated the response of dendritic cells pulsed with HIV‐1 in
terms of inflammasome activation in 20 healthy donors.
• Moreover inflammasome response to HIV was evaluated in 20 HIV
infected subjects

14. • In HC‐DC, HIV‐1 induced
higher NLRP3/NALP3 mRNA
expression compared to
other inflammasome genes
such as NALP1/NLRP1 or
IPAF/NLRC4 (p<0.001)
• This augmented expression
was accompanied by CASP1
and IL1B increased mRNA
levels and by a significant
increment of IL‐1 secretion
(p<0.05).
• Otherwise HIV‐1 failed to
activate inflammasome and
cytokine production in HIV‐
DC.

15. 45 papers published average IF 3.9
3 +1 PhD Thesis
3+ 2 Masters
3 grants from CNPq (Brazil)

16. Networking
HIV‐Latin America Network
Brazil: Recife, Sao Paulo,
Rio de Janeiro, Porto Alegre
Argentina: Buenos Aires
Bolivia: La Paz
MEEGID Quito 2014
Other countries will join
The network

18. Immunogenetics and Immunobiology Research Labs
IRCCS Burlo Garofolo

19. Europe US networking
Michel Tibayrenc, MD, PhD
Infectious Diseases and Vectors,Ecology, Genetics, Evolution and Control
MIVEGEC/IDVEGEC (IRD 224‐CNRS 5290‐UM1‐UM2)
IRD Center BP 64501
34394 Montpellier Cedex 5 France
Alfredo Garzino‐Demo Ph.D
Laboratory of Virus‐Host Interactions, Division of Basic Science
Institute of Human Virology
University of Maryland, Baltimore, US
Ernesto T.A. Marques Jr., MD, PhD
Infectious Diseases and Microbiology
Center for Vaccine Research
9022 BST3 3501 Fifth Avenue
Pittsburgh, Pennsylvania 15261

20. Exome‐CHIPS the new frontier

21. DNAH17
MDN1
CDH23
OR5D14
PINK1
RERGL
OR5V1
CST2
MYH7B
FAT3
RNF213
ADAM30
PTCD1
ATP5J2‐PTCD1
COL12A1
TNS1
THSD7A
MTMR3
KIAA1107
OR12D3
MEGF11
NLRP8
MKNK1
ZNF616
SYNE1
DSP
EPYC
NEW TALENTS
UPCOMING…

22. TO BE CONTINUED…