IAVI Report - July / September 2001

Emily Bass

One of the biggest puzzles in understanding mother-to-child transmission of HIV is why the majority of babies born to HIV-infected women remain uninfected in utero, at birth and-perhaps most remarkably-during breastfeeding. It's even more remarkable in view of studies suggesting that cell-free viral load in breast milk can vary from undetectable to more than 200,000 copies per ml, meaning that a breastfeeding infant may ingest up to millions of viral copies each day (see J Infect Dis 1998 Jan;177(1):34-9).

This apparent resistance puts infants in the compelling category of exposed, seronegative (ESN) individuals (see article, page 9) who can repel or effectively control HIV despite repeated exposures. Katharine Lazuriaga and Sarah Rowland-Jones have both documented cases of infants apparently clearing a transient HIV infection. It is these immune defenses which vaccine researchers seek to boost, or mimic, with a neonatal vaccine. But there is little hard data on just what they are and how this apparent protection works.

New research by Marta Marthas (California Regional Primate Research Center, University of California, Davis) could help fill in the picture. Marthas showed earlier that subcutaneously administered SIV hyper-immune serum protects newborn monkeys against infection by orally delivered SIV-mac 251 (J Infect Dis 1998 May;177(5):1247-59). This spring, she returned to the issue with a multiple low-dose challenge study designed to approach conditions of breast milk transmission-the first primate study to tackle this problem.

Working with 40 neonatal macaques, Marthas is using oral challenges in groups of animals. The challenges, given three times daily, five days a week, are 10-100 fold lower than the standard single oral challenge. So far, she says, the majority of the animals are getting infected, including all four given the highest dose and one out of four (so far) in the lowest-dose group. The uninfected animals wil be sacrificed after three months and autopsied to look for signs of latent SIV infection (since cultures from a few animals yielded virus after 8-12 weeks) and SIV-specific immune responses in the tissues. Similar studies done on adult female macaques who remained seronegative after a single, low-dose vaginal challenge showed signs of SIV infection and SIV-specific proliferative responses upon autopsy two years later (J Virol 1998 Dec;72(12):10029-35).

In one sub-study, Marthas will evaluate immune responses and protection against low-dose challenge in infant rhesus monkeys vaccinated with an SIV-MVA (made by Pat Earle and Bernie Moss at the National Institute of Allergy and Infectious Diseases) or an SIV-ALVAC construct (a simian version of ALVAC vCP205 containing env, gag and pol from SIV-MAC 239, made by Aventis Pasteur). She is keen to find out whether the responses to these vaccines will be different with a repeated low-dose compared with the standard single, high dose challenge. "If you give multiple challenges after vaccination and get transient or abortive replication, can you boost the immune responses that were induced by the vaccine? Perhaps," says Marthas. Based on what she's seen so far, including late viremia or compete protection of some vaccinated infants, Marthas thinks this model could be a better way to test vaccines. "It's made me think we might be throwing out some vaccine candidates prematurely based on results of high-dose challenge studies."

In human studies, cord blood samples provide a valuable window into immune defenses that develop in utero, when the fetus is exposed to viral particles and proteins that cross the placenta. It's here that Louise Kuhn (Columbia University) and her collaborators Anna Coutsoudis (University of Natal), Glenda Gray (Chris Hani Baragwanath Hospital, Johannesburg) and Mario Clerici (University of Milan) found striking evidence that T-helper cell responses correlate with protection against MTCT.

Kuhn collected cord blood samples from 86 infants in a vitamin A supplementation trial in South Africa. Of the 86, 33 (38%) had HIV-specific CD4+ T-helper responses at birth. Three of these responding infants were born HIV-positive, 28 were negative, and 2 were lost to follow-up. Significantly, none of the infants with T-helper cell responses at birth became infected during breastfeeding. In contrast, 6 out of 53 infants (11%) lacking CD4+ responses were infected prior to delivery and 17% were infected during labor or at delivery.

In a provocative follow-up study, Kuhn looked for HIV-specific CD4+ T-helper cells in infants born to mothers who received AZT/3TC before and after delivery. Surprisingly, none of the infants in this study showed these responses, an outcome that did not correlate with maternal viral load. Kuhn speculates that this may be due to some other interaction between the antiretrovirals and co-stimulatory factors, such as cytokines or antigen-presenting cells, needed for an anti-HIV immune response. The possibility that short-course antiretrovirals for the mother could influence the infant's ability to mount immune responses is yet another argument for interventions to protect infants during breastfeeding. Kuhn and others emphasize that the helper responses reappear in infants, and that these findings do not imply that ARVs should be withheld from HIV-positive pregnant women.

As for why some infants develop these T-cell responses and others do not is, Kuhn calls this "the million dollar question." Their presence does not appear to correlate with maternal viral load, CD4+ T-cell count or gestational age at delivery. "It might have something to do with the way the virus is presented in utero, with the presence of specific epitopes, or with some kind of interaction between the mother and the child genetically," says Kuhn, adding that "it's all just speculation." She is now following up with a closer look at neonatal correlates of protection, and with a study of nevirapine and its effects on T-helper immune responses.

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©2001. The IAVI Report.

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