Characterization of the HIV-1 Latent Reservoir in CCR5-Delta 32 Heterozygotes

-
Investigator: Steven G. Deeks, MD
Sponsor: Blood Systems Research Institute

Location(s): United States

Description

Although the advent of Highly Active Antiretroviral Therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV-1 Infection, viral eradication is not achievable due to the persistence of latently- infected cells during treatment. Accumulating data suggest that "non-AIDS" cardiovascular, pulmonary, renal and hepatic diseases are amplified by HIV-1 Infection, and even patients with viral suppression develop premature immune senescence. These realities have created a pronounced interest in developing strategies to eradicate HIV-1 in infected individuals. Recently, three cases have been reported that suggest a cure for HIV-1 may in fact be achievable. the "Berlin Patient" and two individuals from Boston, all of whom were HIV-positive and underwent allogeneic Bone Marrow Transplantation, appear to be completely devoid of HIV-1 genetic material and exhibit waning anti-HIV-1 antibody levels. All three individuals share a common feature; they are heterozygous for the CCR5-Delta 32 mutation (CCR5-?32). This 32 base pair deletion in the CCR5 gene affects the expression and stability of the CCR5 chemokine receptor which is utilized as an entry coreceptor by most HIV-1 strains. the three putative cases of HIV-1 eradication in CCR5-Delta32 Heterozygotes warrant Investigation into this mutation within the context of the HIV-1 Reservoir and curative strategies. CCR5-Delta32 Heterozygotes express significantly less CCR5 at the cell surface, impeding the entry of CCR5- tropic (R5) HIV-1. We hypothesize that CCR5-Delta32 Heterozygotes harbor a smaller and less stable Reservoir due to this deficit. Firstly, initial colonization of the HIV-1 Reservoir is likely impeded in CCR5-Delta32 Heterozygotes due to restriction of viral entry, resulting in a smaller Reservoir before ART initiation. Secondly, the decay of the Reservoir during ART may be accelerated in CCR5-Delta32 Heterozygotes due to skewed cellular and tissue distribution of HIV-1, modulating the turnover rate, half-life and proliferative capacity of latently infected cells. This skewed distribution maybe driven in part by selection for alternative HIV-1 coreceptor usage in CCR5-Delta32 Heterozygotes, including enrichment of CXCR4-using (X4) viruses which preferentially infect CXCR4-expressing cells such as naive CD4+ T cells. in this proposal, we will use a systems biology, translational approach to examine the size, cellular distribution, and viral genetic composition of the HIV-1 Reservoir in the Blood and lymphoid tissues of HIV-1-infected CCR5-Delta32 Heterozygotes and case-matched CCR5 wildtype individuals. This study should yield valuable insights into the cellular and molecular determinants of HIV-1 persistence and eradication.
Although the advent of Highly Active Antiretroviral Therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV-1 Infection, a cure is not achievable due to the persistence of latently- infected cells during treatment. Recently, three HIV-infected individuals who carry the "CCR5-delta 32" human genetic mutation were putatively cured of their HIV disease following Bone Marrow Transplantation. Our proposed study uses cutting edge molecular techniques to investigate how the CCR5-Delta 32 mutation may predispose individuals to be cured of their HIV-1 disease, in the interest of designing effective eradication strategies for HIV-1 Infection.