HIV-Specific CD8+ T Cell Function in Children with Vertically Acquired HIV-1 Infection Is Critically Influenced by Age and the State of the CD4+ T Cell Compartment

Abstract

The immunology of vertical HIV transmission differs from that of adult infection in that the immune system of the infant is not fully matured, and the factors that influence the functionality of CD8+ T cell responses against HIV in children remain largely undefined. We have investigated CD8+ T cell responses in 65 pediatric subjects with vertically acquired HIV-1 infection. Vigorous, broad, and Ag dose-driven CD8+ T cell responses against HIV Ags were frequently observed in children who were older than 3 years of age and maintained CD4+ T cell counts >400 cells/μl. In contrast, younger age or a CD4+ T cell count <400 cells/μl was associated with poor CD8+ T cell responses and high HIV loads. Furthermore, subjects with a severely depleted and phenotypically altered CD4+ T cell compartment had circulating Gag-specific CD8+ T cells with impaired IFN-γ production. When viral load was not suppressed by antiviral treatment, subjects that fell below the putative age and CD4+ T cell count thresholds had significantly reduced CD8+ T cell responses and significantly higher viral loads. Thus, the data suggest that fully effective HIV-specific CD8+ T cell responses take years to develop despite an abundance of Ag in early life, and responses are further severely impaired, independent of age, in children who have a depleted or skewed CD4+ T cell compartment. The results are discussed in relation to differences between the neonatal and adult immune systems in the ability to respond to HIV infection.

HIV-Specific Gag Responses in Early Infancy Correlate with Clinical Outcome and Inversely with Viral Load

“…Preferential targeting of Gag by CD8 + T cells has been linked to better viral control in adults and in older children with HIV infection. 4,9,11,16,17 We did not find a correlation between the magnitude of Gag-specific CD8 + T cell responses and viral load, although the magnitude of a response is not the only indicator of viral control. Studies of HIV-infected adults have indicated that the ability of antigenspecific T cells to perform multiple functions simultaneously (''polyfunctional'') is associated with control of viremia.…”

“…11,16 These observations suggest that Gag-specific CD8 + T cell responses may be associated with better viral control and survival. Our findings support this hypothesis, as we showed that infants who survived the first year of life had a significantly higher frequency of Gag-specific CD8…”

Differences in Evolution of HIV-1 Subtype C Reverse Transcriptase Between Children and Adults Likely Explained by Maturity of Cytotoxic T-Lymphocyte Responses

“…In other words, less positive selection would have been observed because the transmitted viruses may already have resistance to potential CTL responses that could develop in the child. Another possible explanation is that there are differences in CTL maturity and response between adults and children 6 and the lack of a strong CTL response in children may be due to intrauterine exposure to HIV that results in maturational or developmental abnormalities in CD4 and CD8 cells.…”

“…7 Generally, HIV-infected children usually need to be older than 3 years of age and have a sufficient number of circulating CD4 T cells to mount a strong and antigen-driven CTL response against HIV. 6 It has been suggested that this weakness of the CTL response against HIV 6 in infants is caused by antigen exhaustion and induction of Th2-like immune responses in early life. 8 Teasing out the mechanisms responsible for any differences in CTL responses between adults and children is complicated, since pediatric HIV infection results in a complex pattern of qualitative and quantitative defects in the immune system 9 and shared HLA-mediated selective pressures on the virus in a vertical transmitting mother-infant pair may undermine future HLA-mediated viral control in the child.…”

“…5 Understanding the antigenicity, immunogenicity, and evolution of CTL epitopes that incorporate antiretroviral (ART) drug resistance mutations (DRM) is perhaps a first step toward developing immune strategies against the emergence and transmission of drug-resistant HIV strains. 1,6 The ability to mount a potent CTL response differs between children and adults in that HIV-infected children have a weaker CTL response than HIV-infected adults. 7 Generally, HIV-infected children usually need to be older than 3 years of age and have a sufficient number of circulating CD4 T cells to mount a strong and antigen-driven CTL response against HIV.…”