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Simple affordable interventions are needed to reduce vertical human immunodeficiency virus (HIV) transmission in developing countries. The efficacy of 2 low doses (4 mg/kg, subcutaneously) or 1 high dose (30 mg/kg, subcutaneously) of the reverse-transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) to protect newborn macaques against simian immunodeficiency virus (SIV) infection was investigated. Thirteen newborn macaques were inoculated orally with virulent SIVmac251. The 4 placebo-treated animals (group A) became persistently infected. Groups B and C (n=4 in each group) received 2 4-mg/kg doses of PMPA, either 4 h before and 20 h after (group B) or 1 and 25 h after SIV inoculation (group C). One animal (group D) received a single 30-mg/kg dose of PMPA 1 h after SIV inoculation. Despite evidence of an initial transient infection, 3 group B animals, 2 group C animals, and the group D animal were SIV negative and seronegative at ages 19–23 months. Immune activation with recall antigens or pharmacologic immunosuppression with corticosteroids failed to reactivate viral replication. These data suggest that 1 or 2 doses of PMPA may protect human newborns against intrapartum HIV infection

Simian immunodeficiency virus (SIV) infection of infant macaques is a useful animal model to determine whether topical (oral) administration of antiviral compounds to the nursing infant could reduce human immunodeficiency virus transmission through breast-feeding. The reverse-transcriptase inhibitor tenofovir was selected because of previous demonstrations that systemic drug levels are effective in preventing SIV infection. To mimic the multiple exposures to virus during breast-feeding, 14 infant macaques were fed 15 low doses of SIVmac251 without chemical restraint. Six animals were treated with placebo, and 2 groups of 4 animals received oral topical doses of tenofovir disoproxil fumarate (DF; equivalent to 0.037 mg of tenofovir/day). About half the animals of each group became infected. In a subsequent study, 2 oral inoculations of 4 juvenile macaques with a mixture of tenofovir DF and SIVmac251 induced persistent infection. Topical administration of low doses of tenofovir DF did not protect against oral SIV infection

Despite antiretroviral medications, the rate of pediatric HIV-1 infections through breast-milk transmission has been staggering in developing countries. Therefore, the development of a vaccine to protect vulnerable infant populations should be actively pursued. We previously demonstrated that oral immunization of newborn macaques with vesicular stomatitis virus expressing simian immunodeficiency virus genes (VSV-SIV) followed 2 weeks later by an intramuscular boost with modified vaccinia ankara virus expressing SIV (MVA-SIV) successfully induced SIV-specific T and B cell responses in multiple lymphoid tissues, including the tonsil and intestine [13]. In the current study, we tested the oral VSV-SIV prime/systemic MVA-SIV boost vaccine for efficacy against multiple oral SIVmac251 challenges starting two weeks after the booster vaccination. The vaccine did not prevent SIV infection. However, in vaccinated infants, the level of SIV-specific plasma IgA (but not IgG) at the time of challenge was inversely correlated with peak viremia. In addition, the levels of SIV-specific IgA in saliva and plasma were inversely correlated with viral load at euthanasia. Animals with tonsils that contained higher frequencies of SIV-specific TNF-α- or IFN-γ-producing CD8+ T cells and central memory T cells at euthanasia also had lower viremia. Interestingly, a marked depletion of CD25+FoxP3+CD4+ T cells was observed in the tonsils as well as the intestine of these animals, implying that T regulatory cells may be a major target of SIV infection in infant macaques. Overall, the data suggest that, in infant macaques orally infected with SIV, the co-induction of local antiviral cytotoxic T cells and T regulatory cells that promote the development of IgA responses may result in better control of viral replication. Thus, future vaccination efforts should be directed towards induction of IgA and mucosal T cell responses to prevent or reduce virus replication in infants.

In a previously developed infant macaque model mimicking HIV infection by breast-feeding, we demonstrated that intramuscular immunization with recombinant poxvirus vaccines expressing simian immunodeficiency virus (SIV) structural proteins provided partial protection against infection following oral inoculation with virulent SIV. In an attempt to further increase systemic but also local antiviral immune responses at the site of viral entry, we tested the immunogenicity of different orally administered, replicating vaccines. One group of newborn macaques received an oral prime immunization with a recombinant vesicular stomatitis virus expressing SIVmac239 gag, pol and env (VSV-SIVgpe), followed 2 weeks later by an intramuscular boost immunization with MVA-SIV. Another group received two immunizations with live-attenuated SIVmac1A11, administered each time both orally and intravenously. Control animals received mock immunizations or non-SIV VSV and MVA control vectors. Analysis of SIV-specific immune responses in blood and lymphoid tissues at 4 weeks of age demonstrated that both vaccine regimens induced systemic antibody responses and both systemic and local cell-mediated immune responses. The safety and immunogenicity of the VSV-SIVgpe+MVA-SIV immunization regimen described in this report provide the scientific incentive to explore the efficacy of this vaccine regimen against virulent SIV exposure in the infant macaque model.

To determine if passively acquired antiviral antibodies modulate virus transmission and disease progression in human pediatric AIDS, the potential of pre- and postexposure passive immunization with hyperimmune serum to prevent oral simian immunodeficiency virus (SIV) infection or disease progression in newborn rhesus macaques was tested. Untreated neonates became infected after oral SIV inoculation and had high viremia, and most animals developed fatal AIDS within 3 months. In contrast, SIV hyperimmune serum given subcutaneously prior to oral SIV inoculation protected 6 newborns against infection. When this SIV hyperimmune serum was given to 3 newborns 3 weeks after oral SIV inoculation, viremia was not reduced, and all 3 infants died within 3 months of age due to AIDS and immune-complex disease. These results suggest that passively acquired antihuman immunodeficiency virus (HIV) IgG may decrease perinatal HIV transmission. However, anti-HIV IgG may not impart therapeutic benefit to infants with established HIV infection.

Research on macaques found that a deletion mutant of simian immunodeficiency virus used as a vaccine in adults caused AIDS in newborn macaques. Other research on simian AIDS and the implications of the research for human AIDS vaccination are discussed.

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Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a rapid, sensitive animal model of human pediatric AIDS. Newborn macaques were readily infected by uncloned SIVmac following oral-conjunctival exposure and had persistently high viremia and rapid development of AIDS. In contrast, when 3 pregnant macaques were vaccinated against SIV, 2 of the newborns that had transplacentally acquired antiviral antibodies were protected against mucosal SIV infection at birth. These results suggest that intervention strategies such as active immunization of human immunodeficiency virus (HIV)-infected pregnant women and anti-HIV immunoglobulin administration may decrease the rate of perinatal HIV infection.