Description): Neonates are more susceptible than adults to infectious diseases, particularly those of viral origin. The increased susceptibility to viral infections is particularly evident in HIV children infected who have a rapid disease course and increased viral loads compared to adults. While this is well known, explanations for the increased susceptibility of children are largely speculative and involve the concept of """"""""immunologic immaturity"""""""". While this phrase is widely used, it is poorly defined. The objective of this proposal is to carefully define developmental changes in the immunophenotypic composition and function of the systemic and mucosal immune system from neonate to adult in normal and simian immunodeficiency virus (SIV)-infected macaques. In this model, SIV serves as a useful tool to determine which differences between the immature and mature immune system are responsible for the increased susceptibility to SIV. The hypothesis is that the normal neonatal immune system is compartmentalized and that, while the systemic immune system may be functionally immature, the mucosal immune system is competent at birth, containing large numbers of activated, memory T cells that serve as targets for HIV infection. Furthermore, the investigators hypothesize that these cells are geared toward the production of type 2 cytokines, which diminish the neonates capacity to generate an effective cell-mediated immune response. Finally, they hypothesize that neonatal tissues have increased expression of relevant chemokine receptors that function as cofactors for HIV infection, compared to adult tissues. To evaluate these hypotheses, the investigator will examine normal (uninfected) and SIV-infected rhesus macaques, from neonate to adult to: 1) Characterize the ontogeny of T cell development, cytokine production, and the sequential expression and development of chemokine receptors in mucosal and peripheral lymphoid tissues of neonatal macaques at various stages of development, and to compare them to those of juvenile and adult macaques and; 2) Determine the effects of SIV infection on lymphocyte immunophenotype, cytokine production and chemokine receptor expression in neonatal macaques by examining sequential changes in mucosal and peripheral lymphoid tissues at various time points after infection with both pathogenic and nonpathogenic clones of SIV. The data will be compared to data already obtained from juvenile and adult macaques infected with equal doses of the same viral stocks.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Special Emphasis Panel (ZHD1-DRG-H (02))
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Nugent, Robert
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Tulane University
Other Domestic Higher Education
New Orleans
United States
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Lifson, J D; Piatak Jr, M; Cline, A N et al. (2003) Transient early post-inoculation anti-retroviral treatment facilitates controlled infection with sparing of CD4+ T cells in gut-associated lymphoid tissues in SIVmac239-infected rhesus macaques, but not resistance to rechallenge. J Med Primatol 32:201-10
Veazey, Ronald S; Lifson, Jeffrey D; Pandrea, Ivona et al. (2003) Simian immunodeficiency virus infection in neonatal macaques. J Virol 77:8783-92
Veazey, Ronald S; Klasse, Per Johan; Ketas, Thomas J et al. (2003) Use of a small molecule CCR5 inhibitor in macaques to treat simian immunodeficiency virus infection or prevent simian-human immunodeficiency virus infection. J Exp Med 198:1551-62
Veazey, Ronald S; Lifson, Jeffrey D; Schmitz, Jorn E et al. (2003) Dynamics of Simian immunodeficiency virus-specific cytotoxic T-cell responses in tissues. J Med Primatol 32:194-200
Veazey, Ronald; Ling, Binhua; Pandrea, Ivona et al. (2003) Decreased CCR5 expression on CD4+ T cells of SIV-infected sooty mangabeys. AIDS Res Hum Retroviruses 19:227-33
Veazey, Ronald S; Marx, Preston A; Lackner, Andrew A (2003) Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection. J Infect Dis 187:769-76
Veazey, Ronald S; Shattock, Robin J; Pope, Melissa et al. (2003) Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med 9:343-6
Veazey, Ronald; Lackner, Andrew (2003) The mucosal immune system and HIV-1 infection. AIDS Rev 5:245-52
Ling, Binhua; Veazey, Ronald S; Luckay, Amara et al. (2002) SIV(mac) pathogenesis in rhesus macaques of Chinese and Indian origin compared with primary HIV infections in humans. AIDS 16:1489-96
Veazey, R S; Gauduin, M C; Mansfield, K G et al. (2001) Emergence and kinetics of simian immunodeficiency virus-specific CD8(+) T cells in the intestines of macaques during primary infection. J Virol 75:10515-9

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