Preexposure prophylaxis with 9-(2-phosphonylmethoxyethyl)adenine against simian immunodeficiency virus infection in macaques.

A reverse transcriptase inhibitor, 9-(2-phosphonylmethoxyethyl)adenine (PMEA), was evaluated for efficacy against acute simian immunodeficiency virus (SIV) infection in juvenile macaques (Macaca fascicularis). Macaques were pretreated subcutaneously with PMEA for 48 h before SIV inoculation. Drug treatment continued for an additional 28 days. Efficacy of PMEA was determined by detection of SIV in blood, SIV DNA in peripheral blood mononuclear cells, and SIV antibodies. Protection from acute SIV infection occurred in 83% of macaques treated with 20 mg/kg/day versus 50% of macaques treated with 10 mg/kg/day. Several PMEA-treated macaques developed mild dermatitis that disappeared when the 4-week therapy ended. The results of these experiments indicate that preexposure prophylaxis with PMEA can prevent acute SIV infection in macaques. Since PMEA demonstrates profound inhibition of retrovirus infection, it may have utility as a chemoprophylactic agent for humans exposed to SIV or human immunodeficiency virus.

Infectivity and pathogenesis of titered dosages of simian immunodeficiency virus experimentally inoculated into longtailed macaques (Macaca fascicularis).

The 50% macaque infectious dose (MID50) and pathogenesis of uncloned simian immunodeficiency virus (isolated from a pigtailed macaque, SIVmne) was determined in longtailed macaques (Macaca fascicularis). Five pairs of macaques were inoculated with 10-fold dilutions of the virus stock, and one macaque was mock-infected. The virologic and clinical status of these macaques was monitored for up to 80 weeks. The MID50 of SIVmne was determined to be 10(2) cell culture infectious dose of the original virus stock. In order to test the infectivity and pathogenesis of an established viral dose, six additional macaques were inoculated with 10x MID50 (10(3) cell culture infectious dose) of the SIVmne. The virologic and clinical status of these macaques was monitored for 40 weeks. All of the macaques inoculated with 10x MID50 or greater became infected as evidenced by seroconversion and consistent virus isolation from peripheral blood mononuclear cells. Macaques infected with SIVmne had an initial sharp decrease in CD2, CD20, CD4, CD8, and CD4CD29 lymphocyte subsets, whereas the CD4:CD8 ratio increased. Viremic macaques developed persistent slight to moderate peripheral lymphadenopathy approximately 3 to 4 weeks after inoculation. Four macaques subsequently died of AIDS-like disease at 29, 33, 42, and 80 weeks after inoculation. Data obtained from the viral titration study and the acute infection model will aid in the development of animal trials to evaluate antiretroviral therapies and preventive vaccines against human immunodeficiency virus infection.

Effect of dosing frequency on ZDV prophylaxis in macaques infected with simian immunodeficiency virus.

The effect of dosing frequency on zidovudine (ZDV) prophylaxis against simian immunodeficiency virus (SIV) infection was examined in long-tailed macaque monkeys (Macaca fascicularis). The results indicate that dosing frequency is extremely important for drug efficacy. The monkeys were divided into three groups based on dosing frequencies of 6-, 8-, or 12-h intervals. All were given a total daily dose of 100 mg/kg of ZDV. The drug was administered subcutaneously starting 24 h before SIV inoculation, and treatment continued for an additional 28 days. With the total daily dose held constant, ZDV was most therapeutic when administered at 12-h intervals, less effective at 8-h intervals, and least effective at 6-h intervals. These results indicate that early ZDV treatment based on infrequent but high dosages may increase the antiretroviral effect of the drug. These findings could serve as a model for ZDV chemoprophylaxis in humans. In cases involving accidental exposure to SIV or human immunodeficiency virus (HIV-1 or HIV-2), immediate, high-dosage therapies may be most therapeutic.