13th International AIDS Conference Durban, South Africa - July 9-July 14, 2000

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. TuOrA343)

Morris L, Trkola A, Ketas T, Bures R, Cilliers T, Maddon P, Montefiori DC, Moore JP
L. Morris, Private Bag X4, Sandringham, Johannesburg, 2131, South Africa, Tel.: +27 11 321 4232, Fax: +27 11 882 0596, E-mail: lynnm@niv.ac.za

BACKGROUND: Entry of HIV-1 into cells is dependent on the interaction of the envelope glycoprotein with both CD4 and a coreceptor, most frequently CCR5. Agents that inhibit viral entry include small molecule inhibitors, antibodies and chemokines. Knowledge of the effectiveness of these compounds against subtype C viruses is necessary to design appropriate therapeutic agents as well as HIV-1 vaccines.

METHODS: The sensitivity of primary HIV-1 subtype C isolates from nine acutely infected individuals and eighteen AIDS patients to various anti-CCR5 agents was explored. Of the twenty-seven isolates, twenty-three used CCR5 only (R5) and four used both CCR5 and CXCR4 (R5X4). Isolates from acutely infected individuals were also assessed using sera from subtype B and C infected individuals.

RESULTS: Twenty R5 isolates were highly sensitive (100% inhibition) to the CCR5 inhibitor TAK779 (5 and 1 uM), the anti-CCR5 monoclonal antibody PA14/PRO (168 and 33 nM) and the CCR5 ligand RANTES (0.5 and 0.1 ug/ml). Two R5 and four R5X4 isolates showed less than 80% inhibition to one or more agents at the lower concentration, but were effectively inhibited by all three agents when used at higher concentrations. One R5X4 virus was not inhibited by any of these agents. Five of six isolates tested from acutely infected individuals were inhibited by serum antibodies from subtype B infected individuals that was equivalent to, and in some cases more sensitive than, that seen with subtype B viruses. Two of these isolates, which included the DU151 vaccine strain, were potently neutralized with later autologous serum samples within the first year of infection.

CONCLUSIONS: These data indicate that subtype C isolates can be inhibited by serum antibodies, including those to subtype B, and that the CCR5-using isolates are sensitive to compounds that prevent viral entry via CCR5, suggesting that therapies developed using subtype B isolates would also be effective against viruses from subtype C.

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