AEGiS-14IAC: Aspirin-like molecules that inhibit HIV-1 replication.

14th International AIDS Conference

Barcelona, Spain - July 7-12, 2002

Aspirin-like molecules that inhibit HIV-1 replication.

Int Conf AIDS 2002 Jul 7-12; 14:(abstract no. LbPp2207)

Pereira C, Paridaen J, Rutten K, Huigen M, Bovenkamp M, Middel J, Jastrzebski J, Schuurman R, Marnett L, Verhoef J, Nottet H
University Medical Center Utrecht, Utrecht, The Netherlands

BACKGROUND: Anti-inflammatory molecules are proposed in HIV-1-associated dementia (HAD) therapy. Some anti-inflammatory molecules are also known to possess anti-HIV activity. We found that o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS), a recently synthesized non-steroidal anti-inflammatory molecule can inhibit HIV-1 replication. Our aim is to clarify the mechanism of action of APHS and to determine whether APHS can act synergistically with other drugs.

METHODS: HIV-1 replication was quantified by p24 ELISA. Cellular viability was determined by a MTT assay. The IC50 and TC50 and Combination Index (CI) values were determined using the CalcuSyn program. HIV-1 entry efficiency and HIV-1 RT activity in PBMC in the presence of APHS was assessed using real-time PCR to quantify HIV-1 gag RNA or DNA, respectively. The replication of drug-resistant HIV-1 strains was determined with a MTT-based drug susceptibility assay.

RESULTS: When administered during the first steps of the infection APHS is capable of inhibiting the replication of several HIV-1 strains (macrophage-tropic and lymphotropic) in a dose-dependent manner in both peripheral blood mononuclear cells (PBMC), monocyte-derived macrophages (MDM) and peripheral blood lymphocytes (PBL) with IC50 values of about 10 mM. APHS TC50 values were about 100-200 mM. After provirus insertion into the cellular genome, APHS does not affect HIV-1 replication. APHS does not inhibit HIV-1 entry into host cells. APHS inhibits the RT activity in PBMC. APHS inhibits replication of all tested drug-resistant strains in a MT-2 cell line. APHS showed synergistic interactions with the RT inhibitors (RTI) AZT, 3TC and efavirenz (CI < 1), while additive interactions were found between APHS and the protease inhibitors (PI) indinavir and ritonavir (CI 3 1).

CONCLUSIONS: APHS inhibits HIV-1 RT activity in PBMC. APHS works synergistically with RTI. APHS can inhibit replication of common RTI and PI-resistant HIV-1 strains.

Keywords: AEGIS, HIV-1, Virus Replication, Aspirin, HIV-1 Reverse Transcriptase, Zidovudine, HIV Infections, Macrophages, Lymphocytes, Oxazines, efavirenz, virology

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