PURPOSE OF THE STUDY.
HIV-infected, nonprogressing adults appear to control viremia with effective adaptive immune responses. In contrast, the natural primate hosts of simian immunodeficiency viruses (SIVs), such as sooty mangabeys, remain disease-free despite ongoing viral replication. The purpose of this study was to examine the immunologic features and the degree of immune activation in nonprogressing, HIV-infected children (pediatric nonprogressors [PNPs]).
170 HIV-infected children >5 years of age who met the following criteria were studied: antiretroviral (ART) naïve, maintaining normal-for-age CD4+ T-cell counts, and clinically nonprogressing. At the time of enrollment, ART was limited to patients whose CD4+ T-cells declined to a specified threshold that the subjects in this study had not reached (CD4+ T-cells <500). These nonprogressing children were compared with children with HIV disease who were clinically and immunologically progressing.
Levels of plasma HIV RNA were measured longitudinally, and flow cytometric measurements of multiple lymphocyte subsets were made. Also addressed were circulating levels of iFABP (intestinal fatty-acid binding protein) and soluble CD14 (sCD14) as measures of intestinal damage and microbial translocation, HIV neutralizing antibody levels, and anti–HIV-specific CD8+ cytotoxic T-cell functions.
PNPs maintained normal CD4+ T-cell counts despite a plasma viral load set point of 20 000 to 30 000 viral nucleic acid copies per mL of plasma. PNP CD4+ T-cells expressed very low levels of activation markers (CD38 and DR). Levels of iFABP and sCD14 were lower in PNPs than in progressors, indicating less intestinal damage and reduced microbial translocation into the systemic circulation. Relatively high numbers of naïve T-cells, lower effector memory T-cells, and reduced T-cell PD1 expression were noted as previously reported. Increased T-cell differentiation, exhaustion, and dysfunction in T-cells were apparent in progressors. PNPs generated broadly neutralizing antibodies and HIV-specific CD8+ cytotoxic T-cell responses, but these were not associated specifically with nonprogression. Finally, long-lived T-cells in PNPs expressed reduced CCR5 levels, indicating a reduction in the susceptibility to infection.
Once again, children are not down-sized adults. The mechanisms of maintaining nonprogression in PNPs share common immunologic features with nonpathogenic SIV infection in natural primate hosts rather than with nonprogressing human adults.
Great strides have been made in the treatment of HIV disease. However, the ability to induce clinical nonprogression of the disease remains elusive, and this primarily rests on the inability to eliminate the viral reservoir present in the secondary lymphoid tissues of infected individuals. The first of two strategies that have been proposed to address the latent viral reservoir has been called “kick and kill.” This approach holds that by activating latently infected cells, the resulting viremia will then be susceptible to an antiviral drug attack. A second method of addressing the latent virus includes “soothe and snooze,” which aims to inhibit the pathways that lead to reactivation of latent virus.
Chronic immunologic activation drives HIV pathobiology. As demonstrated in the current study, the ability of a select group of HIV-infected children to remain disease free rests in their ability to ignore the presence of the virus, control immune activation, and maintain normal immune functions. Perhaps a third approach to inducing long-term nonprogression would be the maintenance of “blissful ignorance.”