Longitudinal assessment of human immunodeficiency virus type 1 (HIV-1)-specific gamma interferon responses during the first year of life in HIV-1-infected infants

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection results in different patterns of viral replication in pediatric compared to adult populations. The role of early HIV-1-specific responses in viral control has not been well defined, because most studies of HIV-1-infected infants have been retrospective or cross-sectional. We evaluated the association between HIV-1-specific gamma interferon (IFN-gamma) release from the cells of infants of 1 to 3 months of age and peak viral loads and mortality in the first year of life among 61 Kenyan HIV-1-infected infants. At 1 month, responses were detected in 7/12 (58%) and 6/21 (29%) of infants infected in utero and peripartum, respectively (P = 0.09), and in approximately 50% of infants thereafter. Peaks of HIV-specific spot-forming units (SFU) increased significantly with age in all infants, from 251/10(6) peripheral blood mononuclear cells (PBMC) at 1 month of age to 501/10(6) PBMC at 12 months of age (P = 0.03), although when limited to infants who survived to 1 year, the increase in peak HIV-specific SFU was no longer significant (P = 0.18). Over the first year of life, infants with IFN-gamma responses at 1 month had peak plasma viral loads, rates of decline of viral load, and mortality risk similar to those of infants who lacked responses at 1 month. The strength and breadth of IFN-gamma responses at 1 month were not significantly associated with viral containment or mortality. These results suggest that, in contrast to HIV-1-infected adults, in whom strong cytotoxic T lymphocyte responses in primary infection are associated with reductions in viremia, HIV-1-infected neonates generate HIV-1-specific CD8+-T-cell responses early in life that are not clearly associated with improved clinical outcomes.

FIG. 1.

Assays of CMV- and HIV-specific tetramer staining and IFN-γ ELISPOT responses. Responses detected from an HIV-1-infected infant at 9 (upper panels) and 12 (lower panels) months of age. PBMC were stained with anti-CD8 monoclonal antibody (y axes) and with the relevant HLA class I/peptide tetramer (x axes) or stimulated with peptides in an overnight ELISPOT assay to detect IFN-γ secretion. A2-CMVpp65-NLVPMVATV (left panels) and B8-HIV-1 nef-FLKEDGGL (right panels) responses were detected by both assays. The tetramer-positive CD8⁺ T cells, as percentages of total lymphocytes, are indicated adjacent to each plot. The antigen-specific IFN-γ ELISPOT assay results are shown above each plot.

FIG. 2.

Spectrum of HIV-1-specific peptide responses in HIV-1-infected infants with measurements at every time point to 1 year (A) or death (B). Individual graphs present HIV-1-specific SFU/10⁶ PBMC (stacked colored bars) and HIV-1 RNA copies/ml plasma (closed circles) as functions of age. The numbers above each bar or above the horizontal axes indicate the numbers of peptides tested at each time point, while the heights of each of the colored sections of the bars indicate the strengths of the peptide-specific responses. The number of peptides was the lowest at month 1, due to limitations in cell numbers, and remained constant from month 3 to 1 year or death. The notation of death indicates the infant died 1 to 3 months after the last measurement.

FIG. 2.

Spectrum of HIV-1-specific peptide responses in HIV-1-infected infants with measurements at every time point to 1 year (A) or death (B). Individual graphs present HIV-1-specific SFU/10⁶ PBMC (stacked colored bars) and HIV-1 RNA copies/ml plasma (closed circles) as functions of age. The numbers above each bar or above the horizontal axes indicate the numbers of peptides tested at each time point, while the heights of each of the colored sections of the bars indicate the strengths of the peptide-specific responses. The number of peptides was the lowest at month 1, due to limitations in cell numbers, and remained constant from month 3 to 1 year or death. The notation of death indicates the infant died 1 to 3 months after the last measurement.

FIG. 3.

HIV-1-specific IFN-γ responses increase with age in HIV-1-infected infants. Individual peak HIV-1 SFU responses are plotted on the y axis with respect to age of the infant, which is plotted on the x axis. Infants infected with HIV-1 in utero are represented by triangles; those infected peripartum are represented by circles. The linear mixed-effect regression lines are shown for changes in peak HIV-1 SFU numbers over time for infants infected in utero(dotted) and peripartum (solid) and are not significantly different from each other.

FIG. 4.

HIV-1 RNA plasma viral loads during the first year of life in infants with or without HIV-1-specific IFN-γ responses detected at 1 month of age. (A) Twelve infants infected with HIV-1 in utero: 7 with month 1 HIV-1-specific IFN-γ early responses, 5 without. (B) Twenty infants infected peripartum: 6 with HIV-1-specific IFN-γ responses, 14 without. Open symbols/dashed lines represent individuals who lacked detectable HIV-1-specific IFN-γ responses at 1 month of life. Closed symbols/solid lines represent those who had month 1 HIV-1-specific IFN-γ responses. The mean log₁₀s of HIV-1 RNA copies per ml plasma for infants with month 1 HIV-1-specific IFN-γ responses are indicated by bold solid lines; the mean log₁₀s of HIV-1 RNA copies/ml plasma for infants without month 1-specific responses are represented by bold dashed lines.