Simian immunodeficiency virus infection in neonatal macaques

Abstract

Children with human immunodeficiency virus infection often have higher viral loads and progress to AIDS more rapidly than adults. Since the intestinal tract is a major site of early viral replication and CD4(+) T-cell depletion in adults, we examined the effects of simian immunodeficiency virus (SIV) on both peripheral and intestinal lymphocytes from 13 neonatal macaques infected with SIVmac239. Normal neonates had more CD4(+) T cells and fewer CD8(+) T cells in all tissues than adults. Surprisingly, neonates had substantial percentages of CD4(+) T cells with an activated, memory phenotype (effector CD4(+) T cells) in the lamina propria of the intestine compared to peripheral lymphoid tissues, even when examined on the day of birth. Moreover, profound and selective depletion of jejunum lamina propria CD4(+) T cells occurred in neonatal macaques within 21 days of infection, which was preceded by large numbers of SIV-infected cells in this compartment. Furthermore, neonates with less CD4(+) T-cell depletion in tissues tended to have higher viral loads. The persistence of intestinal lamina propria CD4(+) T cells in some neonates with high viral loads suggests that increased turnover and/or resistance to CD4(+) T-cell loss may contribute to the higher viral loads and increased severity of disease in neonatal hosts.

FIG. 1.

Viral loads in plasma of neonatal macaques infected with SIVmac239 as determined by real-time reverse transcription-PCR. Note that viral loads stay relatively high in pediatric macaques throughout the course of infection.

FIG. 2.

In situ hybridization for SIV in the intestine of neonatal macaques 7 days (mm103-97) (A), 14 days (mm136-97) (B), and 21 days (mm191-97) (C) after intravenous SIVmac239 infection. Note that in early infection, large numbers of SIV-infected cells are detected throughout the lamina propria of the jejunum (A). By 14 days of infection, when intestinal CD4⁺ T cells are being depleted (B), there are fewer SIV-infected cells in the lamina propria of the ileum but large numbers remain in the inductive lymphoid tissues (Peyer's patches and organized lymphoid tissue). Finally, by 21 days of infection (a period of maximal lamina propria CD4⁺ T-cell depletion), very few infected cells are observed in the lamina propria of the ileum and most of the SIV-infected cells are observed in the inductive sites (C). Also note that the ileum (B and C) contains both effector lymphoid issues (lamina propria) and inductive lymphoid tissues (organized lymphoid follicles), whereas the jejunum lacks organized lymphoid tissues (A).

FIG. 3.

Lymphocyte phenotypes in the blood of newborn macaques. Flow cytometry dot plots demonstrate lymphocyte subsets in the blood of two different newborn macaques (mm196-99 and mm100-99). Plots were generated by gating through lymphocytes.

FIG. 4.

Expression patterns of CD45RA and CD62L (L-selectin) on CD4⁺ and CD8⁺ T cells from various tissues of a newborn macaque. Plots were generated by gating first on lymphocytes and then through CD4⁺ (top panels) or CD8⁺ (bottom panels) T cells. Data are representative of three of four newborn macaques examined (see text).

FIG. 5.

Coexpression of HLA-DR on CD4⁺ cells (black bars) and CD8⁺ cells (white bars) from various tissues of a newborn macaque. Bars represent means of four neonates examined on the day of birth ± the standard deviation. LN, lymph node.

FIG. 6.

Changes in CD4⁺ T-cell levels in various tissues of uninfected and SIV-infected neonatal macaques. Each bar reflects the mean of at least two animals ± the standard deviation. Data indicate the percentage of CD3⁺ T cells coexpressing CD4. Data from uninfected newborn neonates are displayed at day 0.

FIG. 7.

Dot plots comparing T-cell subsets from intestinal (top panels) and peripheral (bottom panels) lymphoid tissues of a normal, age-matched, uninfected neonatal macaque (mm103-98; 50 days old) (left) with those from an SIVmac239-infected neonate (mm296-97; 50 days p.i.) (right). Plots were generated by gating through lymphocytes and then through CD3⁺ T cells. Thus, the CD4⁺ T-cell loss is accompanied by an increased percentage of CD8⁺ T cells remaining in the T-cell gate.