Severe developmental delays, cognitive impairment and encephalopathy (which for consistency are referred to as HIV-associated Neurocognitive Disorders [HAND]) occurred in 30-50% of perinatally infected children prior to the availability of effective combination antiretroviral therapy (ART). While with ART the incidence of encephalopathy has been reduced, severe cognitive impairment is still identified in 15-20% of HIV-infected children. Additionally, although much research has been performed on HAND, the neuropathogenesis of CNS impairment remains to be elucidated. The research proposed will apply state-of-the-art exome sequencing technology to identify the host genetic factors associated with HAND in children.
The specific aims of this proposal are:
Aim 1 : Apply whole exome sequencing (WES) to identify novel candidate genetic variants associated with HAND in a discovery cohort of perinatally infected children. In this aim, WES will be used to identify novel genetic locus variants and pathways that are associated with HAND in children. The hypothesis to be tested is that by examining all protein-coding sequences (exomes) in addition to HLA and killer Ig-like receptor (KIR) alleles in 500 HIV-infected children equally divided between subjects with HAND and those with normal neurocognitive and neurodevelopmental function gene locus variants will be identified which are associated with CNS disease.
Aim 2 : Evaluate the associations of the genetic variants with CNS disease in replication cohorts of HIV-infected children in the U.S. Having identified novel genetic variants that are associated with HAND in Aim 1, the association of ~500 variants and specific HLA/KIR genotypes of highest significance in the discovery cohort will be tested for association in two U.S. replication cohorts with similar ethnic and socioeconomic backgrounds as the discovery cohort. Targeted exome sequencing and genotyping of specific HLA and KIR SNPs will be performed.
Aim 3 : Examine the genetic variants identified in Aims 1 and 2 associated with CNS disease of children in the U.S. for association of these polymorphisms with CNS disease in a cohort of HIV-infected children in South Africa. The hypothesis to be tested is that although a cohort of children born in South Africa differs significantly from those born in the U.S., genes carrying variants identified to alter the risk of HIV-related CNS disease in U.S. born children will also be important determinants of risk for children from South Africa. For these studies, targeted exome sequencing and specific HLA and KIR genotypes will be applied to South African HIV-infected children who have undergone extensive neuropsychometric and developmental testing. To our knowledge, our research has access to the largest cohorts of well-characterized HIV-infected children with CNS outcomes in the world, and will for the first time apply exome sequencing to large number of HIV-infected children. The findings of this research will provide insights into the pathogenesis of HAND and suggest novel strategies how to treat and to prevent the CNS disease associated with HIV.
Despite the availability of effective antiretroviral treatment, HIV-associated Neurocognitive Disorders (HAND) is still common among HIV-infected children and adults, and the neuropathogenesis of the CNS impairment remains to be elucidated. The research proposed will apply state-of-the-art exome sequencing technology to identify the host genetic factors associated with HAND in children. The findings of this research will provide insights into the pathogenesis of HAND, and suggest novel strategies how to treat and to prevent the CNS disease associated with HIV.
|Spector, Stephen A; Brummel, Sean S; Nievergelt, Caroline M et al. (2016) Genetically determined ancestry is more informative than self-reported race in HIV-infected and -exposed children. Medicine (Baltimore) 95:e4733|
|Gupta, Amita; Montepiedra, Grace; Gupte, Akshay et al. (2016) Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. PLoS One 11:e0148649|
|Singh, Kumud K; Qin, Min; Brummel, Sean S et al. (2016) Killer Cell Immunoglobulin-Like Receptor Alleles Alter HIV Disease in Children. PLoS One 11:e0151364|
|Brummel, Sean S; Singh, Kumud K; Maihofer, Adam X et al. (2016) Associations of Genetically Determined Continental Ancestry With CD4+ Count and Plasma HIV-1 RNA Beyond Self-Reported Race and Ethnicity. J Acquir Immune Defic Syndr 71:544-50|
|Moodley, Amaran; Spector, Stephen A (2015) Single high-dose vitamin D at birth corrects vitamin D deficiency in infants in Mexico. Int J Food Sci Nutr 66:336-41|
|Qin, Min; Brummel, Sean; Singh, Kumud K et al. (2014) Associations of host genetic variants on CD4âº lymphocyte count and plasma HIV-1 RNA in antiretroviral naÃ¯ve children. Pediatr Infect Dis J 33:946-52|
|Shoji-Kawata, Sanae; Sumpter, Rhea; Leveno, Matthew et al. (2013) Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494:201-6|
|Moodley, Amaran; Qin, Min; Singh, Kumud K et al. (2013) Vitamin D-related host genetic variants alter HIV disease progression in children. Pediatr Infect Dis J 32:1230-6|
|Singh, Kumud K; Wang, Yan; Gray, Kathryn P et al. (2013) Genetic variants in the host restriction factor APOBEC3G are associated with HIV-1-related disease progression and central nervous system impairment in children. J Acquir Immune Defic Syndr 62:197-203|
|Spector, Stephen A; Qin, Min; Lujan-Zilbermann, Jorge et al. (2013) Genetic variants in toll-like receptor 2 (TLR2), TLR4, TLR9, and FCÎ³ receptor II are associated with antibody response to quadrivalent meningococcal conjugate vaccine in HIV-infected youth. Clin Vaccine Immunol 20:900-6|
Showing the most recent 10 out of 13 publications