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Anti-HIV-1 combination therapy in monocyte/macrophages.
Rusconi S; Chow Y; Merrill D; Hirsch M; Infectious Disease Unit,
December 30, 1995
Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:133.

Monocyte/macrophages represent an important reservoir for HIV-1 infection, especially in the CNS. Therefore successful anti-retroviral therapy should also be effective in these cells. To assess the anti-retroviral therapeutic efficacy of various combinations of drugs against HIV-1 infections of monocytes, we compared regimens inhibiting different steps in retroviral replication (conventional or divergent combination therapy) versus combinations that attack the same target (convergent combination therapy). The site targeted was reverse transcriptase (RT). HIV-1 Ba-L monocytotropic strain was used to infect 7 day adherent monocytes. The in vitro treatment conditions were varied to assess efficacy during both prophylaxis and acute infection. Convergent RT inhibitor combinations AZT+ddI(or ddC)+ Nevirapine+/-Foscarnet or AZT+ddI(or ddC)+ pyridinone+/- Foscarnet or AZT+ddI(or ddC)+Foscarnet, were compared to divergent combinations AZT+the protease inhibitor RO31- 8959+Interferon alpha A (IFN) or AZT+RO31-8959+rsCD4 or AZT+rsCD4+IFN or AZT+RO31-8959+ the Tat inhibitor RO24-7429 or AZT+RO31-8959+RO24-7429+rsCD4. Drugs were tested at individually inhibitory concentrations of IC99, IC95, IC90, IC75 and IC50. Cultures were passaged in medium and drugs twice weekly and cell-free supernates were tested for HIV-1 p24 antigen production. In some experiments drugs were removed from subsequent medium changes at various times after infection. All regimens completely inhibited HIV-1 replication in prophylactic settings at IC99 concentrations. Breakthrough was not observed once p24 became undetectable, even after drug removal. As drug concentrations were reduced, differences between regimens became more apparent. Regimens that acted at both single and multiple targets were effective in inhibiting virus replication in prophylactic settings and less so in acute therapy.