HIV-1 Promoter Single Nucleotide Polymorphisms Are Associated with Clinical Disease Severity

Abstract

The large majority of human immunodeficiency virus type 1 (HIV-1) markers of disease progression/severity previously identified have been associated with alterations in host genetic and immune responses, with few studies focused on viral genetic markers correlate with changes in disease severity. This study presents a cross-sectional/longitudinal study of HIV-1 single nucleotide polymorphisms (SNPs) contained within the viral promoter or long terminal repeat (LTR) in patients within the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. HIV-1 LTR SNPs were found to associate with the classical clinical disease parameters CD4+ T-cell count and log viral load. They were found in both defined and undefined transcription factor binding sites of the LTR. A novel SNP identified at position 108 in a known COUP (chicken ovalbumin upstream promoter)/AP1 transcription factor binding site was significantly correlated with binding phenotypes that are potentially the underlying cause of the associated clinical outcome (increase in viral load and decrease in CD4+ T-cell count).

Designing broad-spectrum anti-HIV-1 gRNAs to target patient-derived variants

“…Recent studies have shown the patient-derived HIV-1 sequences displayed a measureable and substantial amount of genetic variation even on stable, uninterrupted HAART with region-specific as well as patient-specific mutation rates, indicating that certain regions may be more easily targeted than others 2 , 32 – 35 . As is demonstrated in the cross-sectional data analysis performed herein, the same difficulty with target variation will be encountered within a patient.…”

The sense behind retroviral anti-sense transcription

“…In addition, there is evidence of single nucleotide polymorphisms in transcription factor binding sites within the LTRs of different HIV-1 subtypes [18–21]. This sequence variation leads to subtype-specific differences in proviral gene expression, thereby imparting unique biological characteristics to a given strain.…”

Specific amino acids in HIV-1 Vpr are significantly associated with differences in patient neurocognitive status

“…Neuropsychological assessments of HIV-1-infected patients currently enrolled in the CARES Cohort at the Drexel University College of Medicine (Aiamkitsumrit et al , 2014; Dampier et al , 2016; Li et al , 2011; Nonnemacher et al , 2016; Parikh et al , 2014; Shah et al , 2014) revealed a range of neurocognitive function, as indicated by GDS. Most Cohort patients for which Vpr sequences were available had GDS ≤2 (Fig.…”