Pediatric HIV-1–Specific Cytotoxic T-Lymphocyte Responses Suggesting Ongoing Viral Replication Despite Combination Antiretroviral Therapy

Abstract

Human immunodeficiency virus-1 (HIV-1)-specific cytotoxic T-lymphocyte (CTL) responses are common in infected adults and usually exhibit rapid decay after combination antiretroviral therapy (ART). CTLs develop later in the first year of life, and the fate of HIV-1-specific responses in perinatally infected children after ART is less well described. HIV-1-specific CTL responses were measured in 17 perinatally infected children and adolescents (ages 3-20 y) receiving combination ART. Seven had prolonged viral suppression (Ͻ400 copies/mL) for 2.5-5.3 y and 10 had persistent viremia (median, 77,550 copies/mL). HIV-1-specific CTL responses were tested by interferon (IFN)-␥ enzyme-linked immunospot (ELISpot) assays using 53 overlapping peptide pools spanning the entire HIV-1 proteome. HIV-1-specific CTL responses were detected in 14 of 17 individuals. Responses to one to four viral proteins were found in eight of 10 individuals with persistent viremia and six of seven with prolonged viral suppression. The magnitude and breadth of CTL responses were similar between groups. HIV-1-specific CTL responses were present in the majority of perinatally infected subjects, irrespective of viremia at evaluation. Because ART-treated infected adults usually have rapid decay of responses, these data suggest viral replication below the limits of detection is more persistent in combination ART-treated perinatally infected pediatric subjects. The long-term clinical implications of these findings remain to be determined. (Pediatr Res 61: 692-697, 2007)

Multiple T-Cell Responses to Human Immunodeficiency Virus Type 1 Are Enhanced by Dendritic Cells

“…Many studies of HIV-1-specific T-cell immunity have used pools containing from 2 to over 100 HIV-1 synthetic peptides of 8 to 20 aa in length (3,7,9,14,17,24,25,31,32,34,37,49). These peptides have been added directly to the PBMC or purified T cells to gauge peptide-specific immune responses in persons with HIV-1 infection or in anti-HIV-1 drug treatment and vaccine trials.…”

“…There is little information, however, as to whether these professional APC can similarly enhance other T-cell functions that could be critical to control of HIV-1 infection, particularly their proliferative capacity and ability to produce multiple immune mediators. Moreover, many current approaches for measuring the magnitude and breadth of T-cell responses use pools of various numbers of synthetic peptides, usually 15 or 20 amino acids (aa) in length, which overlap by 10 to 11 aa (1,3,7,9,13,14,17,24,25,27,32,37,45,48,49), developed by Kern et al (26) and Maecker et al (31). Such studies have not accounted for a role of APC in processing that is required to reduce these peptides to their optimal, 8-to 10-mer length for presentation by MHC class I molecules to CD8 ϩ T cells (43), or to 13-to 17-mers for presentation by MHC class II to CD4 ϩ T cells (46).…”

Supranormal thymic output up to 2 decades after HIV-1 infection

“…We note that the persistence of broad antiviral responses to HIV during cART has previously been observed in other perinatally-infected persons and contrasts with the situation in older adults, in whom complete decay of these responses is common. [37, 42-45]…”

Modeling HIV persistence, the latent reservoir, and viral blips

“…A number of studies have suggested that residual viral replication continues in patients under potent combination therapy even when the viral loads have been suppressed to below the limit of detection for a long time [17, 28, 29, 62, 115, 168]. This low-level ongoing virus replication involves generation of new infected cells through de novo infection from the virus released from other infected cells.…”