Pathogenesis and disease progression subsequent to human immunodeficiency virus type 1 (HIV-1) infection of the immune system, brain, and other end organs is dependent on viral entry and replication in specific cell populations within these compartments that cause celular dysfunction or death by a variety of direct and/or indirect mechanisms. These virus-host interactions can be regulated by numerous factors, including viral binding and entry, host cell proliferation and activation, cellular differentiation, antiretroviral therapy status, substances of abuse, and the action of viral and cellular proteins that interface with the long terminal repeat (LTR) and to each other to regulate viral expression. The capacity of HIV-1 to replicate is further affected by the evolution of viral quasispecies. Studies have indicated that naturally-occurring sequence variation within the LTR influences the ability of the viral promoter to drive viral expression by altering functional interactions with cellular and viral trans-activators. Recent studies have suggested the possibility that genetic alterations within the HIV-1 genome may correlate with either the stage of HIV-1 disease, neurologic status, and/or organ compartmentalization. However, many of these studies involved cross population analyses of clinical samples from a small number of patients in the pre-HAART era, rather than from longitudinal studies with sufficient patient numbers in the HAART era. The proposed studies will utilize a continually expanding DREXELMED HIV- 1-infected patient cohort for cross-population and longitudinal studies for sequencing and structure/function analyses to examine the working hypothesis that binding site signatures within the LTR and viral envelope can be used as molecular markers to identify HIV-1-infected individuals more prone to developing advanced stage disease with end-organ involvement that may be exacerbated by specific co-morbidities such as cocaine or cannabinoid abuse The specific aims of this application are to continue to: (1) construct a HIV-1 (subtype B) LTR and Env polymerase chain reaction (PCR) product sequence database and clone bank derived from peripheral blood mononuclear cells (PBMCs) from HIV-1-infected peripheral blood (PB) collected longitudinally from patients with comprehensive clinical histories with respect to social and clinical demographics (initial and all return visits), (2) identify LTR and Env single nucleotide polymorphisms (SNPs) and co-selected SNPs (csSNPs) detected in LTRs derived from PBMCs [and, in selected circumstances, purified PB sub-populations, plasma virus, CNS tissues (NNTC) and other cellular compartments] obtained from a large well studied HIV-1- infected cohort using bioinformatic tools to examine SNPs at any of the 634 nucleotides of the HIV-1 LTR, within the HIV-1 gp120, or within the HIV-1 gp41, (3) construct a parallel PCR product sequence database and define specific LTR and Env SNPs and csSNPs from brain tissues with varying degrees of HIV-1-associated neurologic disorders obtained from the National Neuro-AIDS Tissue Consortium (NNTC)], and (4) determine the ability of HIV-1 LTR clones containing specific csSNPs to support transcription and viral replication studies.
The proposal represents a significant and innovative approach involving the use of specific LTR and Env signature sequences to predict and track HIV-1 disease progression, the development of HIV-associated neurocognitive disorders, study the impact of substance abuse (cocaine and cannabinoids) on these processes, and potentially help guide the therapeutic management of HIV disease. The studies will also identify co-selected genetic elements within and between the HIV-1 LTR and Env that are associated with cell type-specific entry and control of viral gene expression and likely involved in viral pathogenesis and HIV disease.
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