Background:  HAART has dramatically decreased morbidity and mortality in HIV-infected children. However, not all patients on HAART have suppression of viremia. From our previous studies, we found that some HIV-infected children had suppression of plasma viremia to undetectable level on HAART, whereas others were persistently viremic despite HAART. HIV-drug resistance was considered to be the major reason for non-response to HAART, however immune factors may also be important in effective response to HAART. To determine whether immune factors are involved in response to HAART, we examined the host gene expression in peripheral blood mononuclear cells (PBMC) from HIV-suppressed and -non-suppressed children on HAART.

Methods:  PBMC were collected from perinatally HIV-infected children (age 10 to 12) on HAART for 7 to 9 years, including 3 children on HAART with undetectable plasma HIV virus for ≥3 years and 3 children on HAART with persistent HIV viremia 10³ to 10⁵ for ≥ 8 years. We focused on the gene expression relevant to HIV pathogenesis and host immune response using a microarray containing 114 genes (SuperArray Inc., OHS-051). Microarray data was analyzed with GEArray analyzer. Data were normalized by housekeeping genes, GAPDH and β-actin. Gene expression levels were confirmed by quantitative real-time polymerase chain reaction (RT-PCR).

Results:  Between the groups, 8 genes showed significantly differential expression (≥2-fold). These genes are associated with host defense, immune dysregulation, and innate immune response. BCL11B and APEX1 showed 4.5-fold and 10-fold higher expression, respectively, in HIV-suppressed children compared with -non-suppressed children. BCL11B and APEX1 have been found to be related to inhibition of HIV infectivity. Interestingly, the other HIV inhibition genes, such as APOBEC3G and TRIM5, did not show any significantly different gene expression between groups. CCR5 expression was strongly up-regulated by ≥10-fold in HIV-non-suppressed children than with normal controls and suppressed children on HAART. Incomplete suppression of viral replication during HAART may be correlated with increased CCR5 expression.

Conclusions:  This pilot study revealed that perinatally HIV-infected children with specific gene expression pattern in PBMC may have better response to HAART. Regulation of some gene expression—such as CCR5, BCL11B, and APEX1—may influence the effectiveness of HAART. A better understanding of molecular mechanism of HIV infected children’s immune responses may lead to the new therapy.