Mechanisms for decreased HIV transcription in CCR5 delta-32 heterozygotes on ART

Emory University, Atlanta GA

Investigators

Abstract

? DESCRIPTION (provided by applicant): Although antiretroviral treatment (ART) is extremely effective in reducing the mortality associated with human immunodeficiency virus (HIV) infection, it cannot eradicate the virus. Therefore, there is profound interest in developing curative strategies for HIV infection. To date, the only example of HIV eradication is the cure of the Berlin Patient in 2009. This HIV-positive individual was transplanted with bone marrow from an individual homozygous for a 32-base pair deletion in the gene CCR5 (CCR5-d32), a mutation that prevents cell surface expression of CCR5. Since CCR5 is the main coreceptor used for HIV entry into target cells, the donor marrow is believed to be the primary cause for eradication. This has led to great clinical interest in the role and manipulation of CCR5 in recent years. Several groups have performed maraviroc intensification clinical trials and multiple groups are actively investigating the silencing of CCR5 using zinc-finger nuclease or CRISPRs in HIV-infected individuals in an attempt to control HIV replication and viremia in the absence of ART. The CCR5-d32 mutation has been reported to have protective effects against HIV. CCR5-d32 heterozygosity is associated with reduced HIV RNA levels during untreated HIV disease and reduced rates of progression, while CCR5-d32 homozygosity protects against HIV acquisition. We recently reported that CCR5-d32 heterozygosity results in decreased HIV transcription during treated disease, the first report to detail the impact of CCR5-d32 in the setting of ART. To date, no studies have examined the impact of CCR5 cell surface concentration or CCR5 signaling on HIV transcription. We aim to determine mechanisms by which CCR5 limitation modulates HIV transcription under ART. We hypothesize that: (1) decreased CCR5 cell surface expression leads to decreased HIV transcription through loss of CCR5-mediated signaling, and/ or (2) decreased CCR5 cell surface expression leads to a reduction in ongoing residual replication. Understanding the role of CCR5 in HIV transcription will further the field's understanding of host pressures on viral replication and build a foundation for interpreting results of novel eradication therapies seeking to modulate CCR5 expression.