Correspondence

HIV-1 in Newborns

N Engl J Med 1994; 330:1905-1906June 30, 1994

Article

To the Editor:

The study by Blanche et al. (Feb. 3 issue)1 confirms the bimodal pattern of AIDS in newborns and shows a clear correlation between the survival of the infant and the severity of disease in the mother. The authors hypothesize that advanced maternal disease could result in transmission of a larger viral inoculum, increased pathogenicity of the viral strains, or earlier transmission in utero. However, none of these explain how infection of newborns with human immunodeficiency virus type 1 (HIV-1) can evolve into AIDS over a few months.

Analysis of HIV-1-specific T-cell responses of newborns shows that fetal T cells can be primed in utero to HIV-1 determinants2. HIV-1-infected children were, however, found only among those lacking HIV-1 env-specific T-cell activity, suggesting that HIV-1-specific immunity can be protective in newborns. Besides decreasing the risk of infection, T-cell immunity seems to reduce the spread or the pathogenicity of HIV-1. Rapidly progressive AIDS in newborns correlates with an absence of HIV-1-specific humoral3 and cellular4 immunity. In the patients described, virtually no HIV-1-specific antibodies and lymphocytes were detectable, and immune responses specific for other antigens were functional. This is in accordance with the hypothesis that HIV-1-specific immunologic tolerance may directly result in rapid progression of disease3.

Forty years ago, Billingham et al. showed that exposure to antigens during early embryonic life profoundly influences the immune system5. Antigens present in the fetal thymus during early development of the organ are regarded as self-antigens, and the naive immune system learns not to respond against them. This phenomenon is called (neonatal) immunologic tolerance.

Advanced maternal disease could result in early transmission in utero, possibly of a large inoculum or of more virulent strains able to infect the fetal thymus and subsequently induce specific immunologic tolerance to HIV-1 determinants. The condition of infants rendered unable to mount efficient HIV-1-specific immune responses may progress rapidly toward AIDS, whereas functional specific responses to HIV-1 antigens resulting from later in utero or perinatal contact with viral antigens may, by contrast, prevent or slow disease progression. Future applications of immune-based therapy require precise assessments of infants' immune responses to HIV-1 antigens. For the time being, antiviral therapy started early during gestation (in the first trimester) may be able to decrease the viral load in the mother and reduce the risk of very early transmission to the fetus.

Daniel E. Speiser, M.D.
Claire-Anne Wyler, M.D.
Claire-Anne Siegrist, M.D.
Hopital Cantonal Universitaire, CH-1211 Geneva 14, Switzerland

5 References

1. 1

   Blanche S, Mayaux M-J, Rouzioux C, et al. Relation of the course of HIV infection in children to the severity of the disease in their mothers at delivery. N Engl J Med 1994;330:308-312
   Full Text | Web of Science | Medline

2. 2

   Clerici M, Sison AV, Berzofsky JA, et al. Cellular immune factors associated with mother-to-infant transmission of HIV. AIDS 1993;7:1427-1433
   CrossRef | Web of Science | Medline

3. 3

   Siegrist C-A, Wyler C-A, Gerritsen EJ, Perrin L, Speiser D, Suter S. Specific tolerance to HIV-1 antigens in an infant with rapid progression to AIDS. AIDS 1993;7:1683-1684
   CrossRef | Web of Science | Medline

4. 4

   Cheynier R, Langlade-Demoyen P, Marescot MR, et al. Cytotoxic T lymphocyte responses in the peripheral blood of children born to human immunodeficiency virus-1-infected mothers. Eur J Immunol 1992;22:2211-2217
   CrossRef | Web of Science | Medline

5. 5

   Billingham RE, Brent L, Medawar PB. `Actively acquired tolerance' of foreign cells. Nature 1953;172:603-606
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with Speiser et al. that there is still no single explanation for the very rapid progression of HIV infection in a small number of children. However, we do not share their opinion that immune tolerance might be the cause of the majority of these early severe forms. The report to which they refer1 is, in our opinion, exceptional. In our experience, all children with rapidly progressive HIV disease have at least a humoral response to the virus that can be detected by Western blotting, even if the response diminishes as cellular immunity collapses2.

In a prospective longitudinal analysis of cytotoxicity against various HIV antigenic epitopes,3 we had the opportunity to examine several children with the early severe form of HIV infection. All the cytotoxicity tests were negative at the time when severe manifestations of the disease developed; however, one child monitored since birth initially had positive results for a short period before the tests became negative, showing a rapid disappearance of specific cytotoxic response. In addition, thymic lesions observed in HIV-infected fetuses4 argue more strongly for the induction of an immune deficiency in utero than for a true state of immune tolerance.

Stephane Blanche, M.D.
Hopital Necker-Enfants Malades, 75743 Paris, France

Marie-Jeanne Mayaux, B.A.
Hopital Bicetre, 94270 Le Kremlin Bicetre, France

Christine Rouzioux, Ph.D.
Hopital Necker-Enfants Malades, 75743 Paris, France

4 References

1. 1

   Siegrist C-A, Wyler C-A, Gerritsen EJ, Perrin L, Speiser D, Suter S. Specific tolerance to HIV-1 antigens in an infant with rapid progression to AIDS. AIDS 1993;7:1683-1684
   CrossRef | Web of Science | Medline

2. 2

   Blanche S, Tardieu M, Duliege AM, et al. Longitudinal study of 94 symptomatic infants with perinatally acquired human immunodeficiency virus infection: evidence for a bimodal expression of clinical and biological symptoms. Am J Dis Child 1990;144:1210-1215
   Web of Science | Medline

3. 3

   Buseyne F, Blanche S, Schmitt D, Griscelli C, Riviere Y. Detection of HIV-specific cell-mediated cytotoxicity in the peripheral blood from infected children. J Immunol 1993;150:3569-3581
   Web of Science | Medline

4. 4

   Papiernik M, Brossard Y, Mulliez N, et al. Thymic abnormalities in fetuses aborted from human immunodeficiency virus type 1 seropositive women. Pediatrics 1992;89:297-301
   Web of Science | Medline