Suppression of Maternal Virus Load With Zidovudine, Didanosine, and Indinavir Combination Therapy Prevents Mother-to-Fetus HIV Transmission in Macaques

Abstract

Recently, we developed a maternal-fetal macaque model using a highly pathogenic HIV-2 strain, HIV-2287, to study the time course of HIV transmission in utero. Most pregnant macaques (Macaca nemestrina) infected with HIV-2287 (10-103 infective doses) transmitted HIV to their fetuses, as verified by positive identification of virus-infected mononuclear cells and free viral RNA in fetal blood. To determine whether an antiretroviral drug combination therapy composed of two dideoxynucleosides, azidothymidine (15 mg/kg) and dideoxyinosine (15 mg/kg), and a protease inhibitor, indinavir (25 mg/kg), could completely inhibit mother-to-fetus HIV transmission, we administered these drugs orally through gastric catheters to five pregnant macaques infected with 10 infective doses of HIV-2287. Beginning 30 minutes after HIV inoculation, the dams were given the combination antiviral therapy three times daily until delivery by cesarean section. Drug treatment reduced the maternal virus load to a minimally detectable level but did not prevent primary HIV-2287 infection. All fetal and infant blood samples were virus negative by internally controlled RNA polymerase chain reaction (QC-RNA-PCR) and virus coculture assays. Fetal and infant CD4+ T-cell levels remained normal throughout the experiment. These findings strongly suggest that combination chemotherapy with azidothymidine, dideoxyinosine, and indinavir can suppress maternal viral load enough to prevent mother-to-fetus transmission of HIV.

Systemic and Intestinal Immune Responses to HIV-2287Infection inMacaca nemestrina

“…48 The HIV-2 287 nonhuman primate model of human HIV infection was proved valuable for the study of the events leading to lentivirus-induced immunodeficiency during an abbreviated time course. [18][19][20][21][22][23] We report consistent virus isolation from PBMCs by day 4 postinfection ( Table 1) and peak virus levels between days 10 and 14. We also found that cell-associated virus loads peaked in the ileum (Table 2 and Fig.…”

“…[30][31][32][33][34][35] To more closely examine acute intestinal response to a highly pathogenic virus, we now report on a series of macaques infected by HIV-2 287 . [18][19][20][21][22][23] We found a clear correlation between local CD4 1 cell depletion and a drop in local antibody production. Moreover, the intestinal events in the intravenously infected macaques preceded CD4 1 cell depletion in the peripheral circulation by several days.…”

“…Characteristically, infected macaques seroconvert and develop peak virus loads during the initial 2 weeks postinfection, experience CD4 1 T cell depletion within 2 months, and progress to AIDS by 6 to 12 months postinfection. [18][19][20][21][22][23] In contrast, the majority of macaques infected with SIV isolates experience CD4 1 cell declines within 4 to 12 months and AIDS within 1 to 3 years after infection. 48 The HIV-2 287 nonhuman primate model of human HIV infection was proved valuable for the study of the events leading to lentivirus-induced immunodeficiency during an abbreviated time course.…”

“…These PBMC virus load data together with that from the mesenteric nodes support previous observations that HIV-2 287 disseminates rapidly after intravenous inoculation and that peak virus loads occur during the first 2 weeks of infection. [20][21][22][23] Cell-associated virus loads in the intestinal mucosa were monitored by in situ hybridization. Control ileum tissue from a sham-inoculated age-matched macaque was examined in conjunction with the ileum of the infected macaques and no evidence of HIV-2 infection was seen (not shown).…”

“…CD4 1 T cells play an essential role in the regulation of IgA responses to pathogenic agents at mucosal sites [15][16][17] and it may be expected that changes in intestinal CD4 levels during HIV infection would alter local mucosal surface immunity. Macaque infection models, particularly those utilizing a rapidly progressing and consistently pathogenic viruses such as HIV-2 287 , [18][19][20][21][22][23] offer the opportunity to determine the sequence of events leading to clinical AIDS in a short time period.…”