Function of AminoglycosideArginine Conjugates AACs as inhibitors of HIV1 replication'

1

• Function of AminoglycosideArginine Conjugates
  (AACs) as inhibitors of HIV-1 replication.

2

• Dr. Cristina Rodriguez-Padilla
• Dr. Humberto H. Lara Villegas
• Immunology and Virology Department. ( LIV).
  Biosecurity Laboratory level 3 ( BSL-3)
• Biology Faculty. ( FCB)
• Universidad Autonoma de Nuevo Leon
• (UANL). MEXICO.
• e-mail dr_lara_at_lycos.com

3
Aminoglycosidearginine conjugates (AACs) inhibit
HIV-1 replication and act as Tat antagonists
4
Learning objectives

• To learn about a new potential fusion inhibitor
  in HIV
• To learn the phases for replication of HIV
• the fusion step
• Tat - Tar complex
• Pathophisiology of ADC
• The potential neuroprotective funtion of Neor6

5

• AACs compete with monoclonal antibody binding to
  CXCR4
• Compete with SDF-1 a and HIV-1 gp120 cellular
  uptake.

6

• We found in the NeoR6-resistant isolates of HIV,
  the following mutations in gp120 and in gp41.
• These findings strongly suggest that NeoR6
  obstructs HIV-1 replication by interfering with
  the fusion step

7

• The AACs may thus represent a novel family of
  fusion inhibitors.

8
(No Transcript)
9
Schematic representation of the AACs
10
Novel HIV-1 Tat Antagonists
Model of the HIV-1 Tat -TAR complex
11

• Targeted against transcription transactivator
  protein (Tat ) - (AACs) are being studied with
  the aim of understanding the mechanisms of
  inhibition of the diversity functions of Tat
  protein, which might be critical for anti-AIDS
  strategies.
• ( Lapidot A. and cols. )

12

• This AACs revealed antiviral activity in cell
  cultures and inhibited viral-host cell fusion, as
  well as binding to TAR-RNA (with G. Borkow ,
  Lapidot A. in Israel, J. Este, Spain, C.
  Rodriguez and H.Lara , Mexico).

13

• Other anti-Tat functions in cell
  cultures and animal models are being studied. As
  well, are animal models for Kaposis Sarcoma
  ( B. Ensoli, Italy).

14
Plausible structure of the TAR-RNA complex
with NeoR.
15
Pathophysiology of ADC
Photomicrograph from a patient with AIDS dementia
complex (ADC) shows perivascular and parenchymal
infiltrates of lymphocytes and macrophages.
These often form microglial nodules.
16
1 )
Gp120
, may be shed by an infected
macrophage in the brain, causing damage
to nerve cells.



2 ) The
HIV TAT
gene, a protein that
helps in the production of new virus,
detaches from HIV and circulates in the
blood, causing toxic effects in nerve cells

(neurotoxic).





17

• Nerve cell "suicide" (black dots) in HIV-infected
  huma brain cultures (left). Nerve cells in
  uninfected cultures appear healthy (right).
• (Courtesy of Dr.
  Gabuzda.)

18
(No Transcript)
19

• Human neuroblastoma cells express CXCR4 and CCR5
  chemokine receptors and that interaction between
  gp-120 and these receptors contributes to
  cytotoxicity elicited by the protein.
• It has been showen the neuroprotective potential
  of neomycin B hexa-arginine conjugate (NeoR), a
  recently synthesized compound with anti-HIV
  activity. ( Melino et al )

20
FUNTIONS OF AACs SUMMARY

• Inhibits HIV-1 replication
• Tat antagonists
• Bind CxCR4
• Compete with SDF-1 a and gp120 celluar utake .
• NeoR6 interfere with the fusion step of HIV

21

• The AACs may represent a novel family of fusion
  inhibitors
• The NeoR6 has neuroprotective potential against
  gp120 triggered death
• NeoR6 cross blood brain barrier

22
REFERENCES
23
REFERENCES

• M.V.Catani, M.T.Corasaniti, M.Ranalli, D.Amantea,
  A.Litovchick, A.Lapidot and G.Melino, The Tat
  antagonist neomycin B hexa-arginine conjugate
  inhibits gp120-induced death of human
  neuroblastoma cells, J. Neurochem. 84, 1237-1245
  (2003).
• A.Lapidot, A.Litovchick, M.Eisenstein,
  A.Kalinkovich, G.Borkow, Neomycin B-arginine
  conjugate, a novel HIV-1 Tat antagonist
  synthesis and anti-HIV activities, Antivir. Res.
  53 (3) 26 Sp. Iss. (2002).