Development of co-selected single nucleotide polymorphisms in the viral promoter precedes the onset of human immunodeficiency virus type 1-associated neurocognitive impairment

Abstract

The long terminal repeat (LTR) regulates gene expression of HIV-1 by interacting with multiple host and viral factors. Cross-sectional studies in the pre-HAART era demonstrated that single nucleotide polymorphisms (SNPs) in peripheral blood-derived LTRs (a C-to-T change at position 3 of C/EBP site I (3T) and at position 5 of Sp site III (5T)) increased in frequency as disease severity increased. Additionally, the 3T variant correlated with HIV-1-associated dementia. LTR sequences derived by longitudinal sampling of peripheral blood from a single patient in the DrexelMed HIV/AIDS Genetic Analysis Cohort resulted in the detection of the 3T and 5T coselected SNPs before the onset of neurologic impairment, demonstrating that these SNPs may be useful in predicting HIV-associated neurological complications. The relative fitness of the LTRs containing the 3T and/or 5T co-selected SNPs as they evolve in their native patient-derived LTR backbone structure demonstrated a spectrum of basal and Tat-mediated transcriptional activities using the IIIB-derived Tat and colinear Tat derived from the same molecular clone containing the 3T/5T LTR SNP. In silico predictions utilizing colinear envelope sequence suggested that the patient's virus evolved from an X4 to an R5 swarm prior to the development of neurological complications and more advanced HIV disease. These results suggest that the HIV-1 genomic swarm may evolve during the course of disease in response to selective pressures that lead to changes in prevalence of specific polymorphisms in the LTR, env, and/or tat that could predict the onset of neurological disease and result in alterations in viral function.

Cocaine Alters Cytokine Profiles in HIV-1–Infected African American Individuals in the DrexelMed HIV/AIDS Genetic Analysis Cohort

“…22 The study was approved by the Drexel University College of Medicine Institutional Review Board under protocol 16311 (Brian Wigdahl, principal investigator) in compliance with Helsinki Declaration of 1975 as revised in 2000. All participants were required to provide informed consent.…”

“…Once a subject was enrolled, an anonymous identifier was assigned and the patient's clinical data were collected as previously described. 22 Blood samples were drawn from each patient at the initial visit and at each return visit (approximately every 6 months but at least one recall per year) to allow for longitudinal study. Patients were considered preferential nonusers (PN) if they tested negative for all drugs at all visits and never admitted to drug use.…”

Coinfection with Hepatitis C Virus among HIV-1-Infected Individuals Increases Proinflammatory Cytokines and HIV-1 Disease Severity

“…Patients in the Drexel Medicine CARES Cohort have been recruited from the Partnership Comprehensive Care Practice of the Division of Infectious Disease and HIV Medicine at Drexel University College of Medicine, which is located in Center City Philadelphia, Pennsylvania, USA as previously described [32]. The study was approved by the Drexel University College of Medicine Institutional Review Board under protocol 1201000748 (Brian Wigdahl, principal investigator) in compliance with Helsinki Declaration of 1975 as revised in 2000.…”

Genetic Variation and HIV-Associated Neurologic Disease

“…However, one must remember that these viral gene activation studies were performed with a viral regulatory region that was derived from a non-CNS tissue source and may, therefore, not be naturally compatible with respect to optimal LTR activation by a Tat protein selected for CNS replication. This is particularly important because previous studies (Burdo, Gartner, Mauger, & Wigdahl, 2004; Hogan, Nonnemacher, Krebs, Henderson, & Wigdahl, 2003; Hogan, Stauff, et al, 2003) demonstrated that LTRs derived from the CNS are likely to be structurally and functionally different from LTRs derived from other tissue sources and that colinear Tat and LTR combinations may result in more efficient LTR activation (Li et al, 2011). Nonetheless, taken together, these reports suggest that genetic diversity of HIV-1 Tat very likely contributes to the establishment and severity of HAND.…”