Immunity to Human Immunodeficiency Virus (HIV) in Children with Chronic HIV Infection Receiving Highly Active Antiretroviral Therapy

Abstract

Our objective was to describe the CD4-mediated human immunodeficiency virus (HIV)-specific cell-mediated immunity (CMI) and its virologic and immunologic correlates in children with chronic HIV infection on highly active antiretroviral therapy (HAART). Twelve HIV-infected children on stable antiretroviral therapy with a median level of CD4؉ lymphocytes (CD4%) of 25.5% and a median viral load (VL) of 786 HIV RNA copies/ml were enrolled in this study. Nine of these children were also cytomegalovirus (CMV) seropositive. Blood mononuclear cells, stimulated with HIV and CMV antigens, were used to measure lymphocyte proliferation and to enumerate gamma interferon (IFN-␥)-producing CD4 ؉ cells. HIV CMI and CMV CMI were detected in similar proportions of patients and correlated with each other, although the HIV responses were less robust. HIV lymphocyte proliferation significantly increased with lower HIV VL and showed a trend to increase with higher CD4% and longer time on HAART. The in vitro IFN-␥ response to HIV or CMV was not affected by CD4%, VL, or HAART. Pediatric patients with established HIV infection on HAART frequently exhibit HIV CMI despite undetectable HIV replication. We concluded that the association between HIV CMI and CMV CMI indicates that the same factors govern responsiveness to either antigen. Human immunodeficiency virus (HIV) preferentially destroys CD4ϩ T lymphocytes and interferes with the functioning of the immune system, weakening defenses against infectious agents. Highly active antiretroviral therapy (HAART) restores CD4 ϩ cell numbers and greatly decreases the incidence of opportunistic infections, indicating that significant immune recovery occurs in treated patients (17,23,28). Furthermore, individuals who previously met AIDS diagnostic criteria recover cytomegalovirus (CMV)-, Mycobacterium avium-, Mycobacterium intracellulare-, and Candida-specific cell-mediated immunity (CMI) while on HAART (8,15,18).AIDS-associated impairment of the immune system includes the inability of the host to mount a protective response against HIV (21, 27). Although HIV-specific CD8-mediated cytotoxicity as detected in HIV-infected patients plays a protective role against the progression of infection (6, 13, 25), CD4-mediated immunity has been difficult to identify. Long-term nonprogressors and patients treated soon after primary infection display HIV-specific CD4-dependent lymphocyte proliferation (1, 20), but most chronically infected adults, including HAART recipients, do not (24, 29).The objective of this study was to compare the HIV-and CMV-specific CD4-mediated responses of HIV-infected children on HAART by using two recently developed and highly sensitive immunological assays, the enzyme-linked immunospot (ELISPOT) assay (32) and intracellular cytokine flow enumeration (ICCK) (34), coupled with an inactivated whole-HIV antigen preparation (3, 26).(Part of this study was presented at the 9th Conference on Retroviruses and Opportunistic Infections, 2002.) MATERIALS AND METHODS Patients.The study enrolled...

Continuous improvement in the immune system of HIV-infected children on prolonged antiretroviral therapy

“…Our study was not designed to address this question, and the analysis of HIV CD4 ELISPOT was exploratory. However, our findings, together with previous ones [14], support pursuing this question in future studies. Finding a positive association between control of viral replication and CD4 + T-cell-mediated responses to HIV may change the currently accepted paradigm that HAART has a deleterious effect on HIV-specific immune defenses.…”

“…Candida-specific immunity is one of the earliest to recover, which is consistent with the disappearance of clinical signs in response to HAART [12,13]. HIV-specific CD8-cell-mediated responses tend to decline with HAARTwhereas CD4-cell-mediated responses have infrequently been demonstrated in chronic HIV infection [14-16]. Both CD4 + and CD8 + T-cell-mediated anti-HIV responses have been associated with control of viral replication in different stages of HIV infection [17-19].…”

“…Enzyme-linked immunospot (ELISPOT) assays were performed as previously described [14] using candida antigen (Greer), aldithriol-inactivated HIV-1 antigens [29] (which measured predominantly CD4 + T-cell-mediated responses), and HIV-1 Gag, Pol, Nef and Env peptide pools [National Institute of Health (NIH) reagent repository], which measured predominantly CD8 + T-cell responses. The peptide pools consisted of 15-mer overlapping by 11 at final concentrations of 2 μg/ml.…”

Cytomegalovirus-Specific Cell-Mediated Immunity in HIV-Infected Children on HAART

“…Overall, low HIV VL was significantly associated with detectable CMV RCF, but not with CMV IFN-␥ production. This finding, which is in accordance with previous reports, 17,23 suggests that active HIV replication impairs antigen-driven PBMC proliferation more vigorously than IFN-␥ secretion and might bear on the higher frequency of CMV IFN-␥ responses compared with RCF that we detected. Neither CMV IFN-␥ nor RCF varied with CD4 ϩ cell percentages measured before or during HAART.…”

Relationship of Reconstituted Adaptive and Innate Cytomegalovirus (CMV)–Specific Immune Responses with CMV Viremia in Hematopoietic Stem Cell Transplant Recipients

“…Results, expressed as spot-forming cells (SFC)/1 ϫ 10 6 PBMC, were calculated by subtracting the median SFC in control antigen-stimulated wells from the median SFC in CMV-stimulated wells. A positive ELISPOT result was defined by у20 SFC/1 ϫ 10 6 PBMC (mean +3 standard deviation response of CMV-seronegative healthy donors) [23], provided that the mean SFC of CMVstimulated wells was у2-fold higher than the mean SFC of mockinfected control-stimulated wells.…”