Identification of HIV-1 genetic associations with coreceptor usage and neurocognitive impairment

Gregory C. Antell

doi:10.17918/etd-7451

The low fidelity of HIV-1 reverse transcriptase results in a high frequency of mutation and generates extensive genetic variation both within and between infected individuals. Importantly, many of these mutations can contribute to disease presentation and progression despite the overall efficacy of antiretroviral therapy (ART). Of particular interest to the studies herein was the relationship between HIV-1 genetic diversity, tropism, and the development of HIV-1 associated neurocognitive disorders (HAND), a comorbidity of increasing prevalence in the HIV-1 infected population. These studies explored two interrelated avenues of research: developing a strategy to identify genetic signatures of HIV-1 co-receptor utilization during entry that extends beyond proteins forming the viral envelope, and utilizing the genetic variation of the accessory HIV-1 protein Tat to assess the likelihood of neurocognitive impairment. Jensen-Shannon divergence was applied to compare multiple sequence alignments and identify signature positions that are most distinct between X4- and R5-utilizing HIV-1 genotypes or quasispecies, for the accessory proteins Tat and Vpr. Additionally, within the HIV-1 long terminal repeat (LTR), predicted transcription factor binding sites demonstrated statistically different binding affinity scores for X4 and R5 LTR sequences. Finally, we developed a statistical learning approach utilizing regularized logistic regression for the prediction of neurocognitive impairment, integrating patient-derived HIV-1 genetic information as well as standard clinical measurements such as CD4+ T cell count and viral load. Here, we demonstrated that genetic-based models of neurocognitive impairment can outperform models utilizing standard clinical data based on the analysis of receiver operating characteristic (ROC) curves. This performance provides strong support that the integration of next generation sequencing data of HIV-1 Tat and other genes may yield improvements to clinical screening tools, as well as allow the statistical inference of genetic variants associated with neurocognitive impairment. These studies have shown that the naturally occurring genetic variation that exists throughout the genome associates with coreceptor usage and hence cell phenotype. This may play a role in disease pathogenesis as macrophages are classically implicated in bringing virus to the central nervous system (CNS) and infection of the T cell compartment is classically related to worsening of disease progression. In line with this thought, viral proteins made from infected cells in the CNS, like Tat, may play a role in CNS dysfunction leading to impairment. Taken together, viral sequences found in patients may have the ability to be used as a biomarker for disease progression and neurocognitive impairment.

Identification of HIV-1 genetic associations with coreceptor usage and neurocognitive impairment

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Identification of HIV-1 genetic associations with coreceptor usage and neurocognitive impairment

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