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.
Breast Neoplasms/*BLOOD/ENZYMOLOGY Human Monocytes/*ENZYMOLOGY
RNA-Directed DNA Polymerase/*ANTAGONISTS & INHIB/BIOSYNTHESIS
Tamoxifen/*PHARMACOLOGY Tetradecanoylphorbol Acetate/PHARMACOLOGY