Specific sequence configurations of HIV-1 LTR G/C box array result in altered recruitment of Sp isoforms and correlate with disease progression.

Basal and activated human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) activity, and in return, viral replication is partly dependent on interactions of the G/C box array with the Sp family of transcription factors. Analysis of LTR Sp binding site sequence variants revealed a C-to-T change at position 5 within Sp site III that increased in frequency and a 5T mutation within Sp site II, which decreased in frequency during the course of HIV disease. These results suggest LTR Sp binding site sequence variants may prove useful as viral molecular markers indicative of progressive HIV-1-induced disease.

High-affinity interaction between HIV-1 Vpr and specific sequences that span the C/EBP and adjacent NF-kappaB sites within the HIV-1 LTR correlate with HIV-1-associated dementia.

Numerous host and viral factors likely participate in the onset and progression of HIV-1-associated dementia (HIVD). Previous studies have suggested that viral gene expression in resident central nervous system (CNS) cells of monocyte/macrophage lineage play a central role in the production of neurotoxic viral proteins and infectious virus, deregulation of cellular gene expression, and/or dysfunction of glial and neuronal cell populations. HIV-1 replication is regulated, in part, by interactions between cellular transcription factors and the viral trans-activators, Tat and viral protein R (Vpr), with cis-acting promoter elements within the LTR. We have previously demonstrated that Vpr binds with high affinity to selected sequence configurations within CCAAT/enhancer binding protein (C/EBP) site I and downstream sequences immediately adjacent to this site. Studies reported herein establish a correlation between the diagnosis of HIVD and the increased prevalence of HIV-1 LTRs containing a C/EBP binding site I that exhibits high affinity for Vpr. To this end, the interaction of Vpr with C/EBP site I variants in 47 LTRs from three nondemented patients and 96 LTRs from seven demented patients was examined. Competition electrophoretic mobility shift (EMS) analyses were utilized to examine Vpr binding to oligonucleotide probes containing C/EBP site I variants. We demonstrated that 89% of LTRs derived from patients exhibiting clinical dementia contained C/EBP site I configurations that displayed a high relative affinity for Vpr, while only 11% of LTRs contained C/EBP site I configurations that exhibited a low relative affinity Vpr binding phenotype. In contrast, examination of LTRs derived from patients lacking clinically evident dementia revealed that only 53% of brain-derived LTRs contained C/EBP site I configurations that displayed a high relative affinity for Vpr, while 47% of LTRs contained C/EBP site I configurations that exhibited a low relative affinity Vpr binding phenotype. We propose that sequence-specific interactions between cis-acting elements in the LTR, members of the C/EBP family of transcription factors, and the virion-associated trans-activator protein Vpr play important roles in the pathogenesis of HIVD.

Genetic variation and HIV-associated neurologic disease.

HIV-associated neurologic disease continues to be a significant complication in the era of highly active antiretroviral therapy. A substantial subset of the HIV-infected population shows impaired neuropsychological performance as a result of HIV-mediated neuroinflammation and eventual central nervous system (CNS) injury. CNS compartmentalization of HIV, coupled with the evolution of genetically isolated populations in the CNS, is responsible for poor prognosis in patients with AIDS, warranting further investigation and possible additions to the current therapeutic strategy. This chapter reviews key advances in the field of neuropathogenesis and studies that have highlighted how molecular diversity within the HIV genome may impact HIV-associated neurologic disease. We also discuss the possible functional implications of genetic variation within the viral promoter and possibly other regions of the viral genome, especially in the cells of monocyte-macrophage lineage, which are arguably key cellular players in HIV-associated CNS disease.

Molecular Mechanisms of Neurodegenerative Diseases Induced by Human Retroviruses: A Review.

PROBLEM STATEMENT: Infection with retroviruses such as human immunodeficiency virus type 1 (HIV-1) and human T cell leukemia virus type 1 (HTLV-1) have been shown to lead to neurodegenerative diseases such as HIV-associated dementia (HAD) or neuroAIDS and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), respectively. APPROACH: HIV-1-induced neurologic disease is associated with an influx of HIV-infected monocytic cells across the blood-brain barrier. Following neuroinvasion, HIV-1 and viral proteins, in addition to cellular mediators released from infected and uninfected cells participate in astrocytic and neuronal dysregulation, leading to mild to severe neurocognitive disorders. RESULTS: The molecular architecture of viral regulatory components including the Long Terminal Repeat (LTR), genes encoding the viral proteins Tat, Vpr and Nef as well as the envelope gene encoding gp120 and gp41 have been implicated in 'indirect' mechanisms of neuronal injury, mechanisms which are likely responsible for the majority of CNS damage induced by HIV-1 infection. The neuropathogenesis of HAM/TSP is linked, in part, with both intra-and extracellular effectors functions of the viral transactivator protein Tax and likely other viral proteins. Tax is traditionally known to localize in the nucleus of infected cells serving as a regulator of both viral and cellular gene expression. CONCLUSION/RECOMMENDATIONS: However, recent evidence has suggested that Tax may also accumulate in the cytoplasm and be released from the infected cell through regulated cellular secretion processes. Once in the extracellular environment, Tax may cause functional alterations in cells of the peripheral blood, lymphoid organs and the central nervous system. These extracellular biological activities of Tax are likely very relevant to the neuropathogenesis of HTLV-1 and represent attractive targets for therapeutic intervention.