Clinical Interventional Studies of HIV Reservoirs

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

My group designed new ATI protocol (NIH protocol #000277 ) to characterize the earliest events in latency reactivation in blood and tissue. We are using highly advanced Computed Tomography/Positron Emission Tomography (CT/PET) directed biopsy approach developed at the NIH Clinical Center to identify and biopsy lymph nodes with and without increased metabolic activity prior to and following a 10-day ATI. In parallel, extensive plasma and peripheral blood lymphocytes (pheresis) sampling is performed to provide clinical material for comparison. ATI may continue until viral RNA levels reach stopping criteria (1000 copies/ml) and repeat imaging and sampling takes place after conclusion of ATI when viral RNA levels return to <20 c/ml by commercial detection methods. To provide additional measure of control for variability in sampling and analysis, the study is randomized, and half of the enrolled participants undergo repeat imaging, biopsy, phlebotomy and pheresis over 10 day period without ATI. This protocol is providing a wealth of clinical material to characterize early events in HIV reactivation following ATI; samples from participants randomized to no-ATI provide valuable samples to study persistence over time. In initial analyses, we unexpectedly identified areas of elevated 18F-FDG uptake in lymphoid tissue even after prolonged ART. Although these areas of uptake are not considered pathologic, they represent useful signals to evaluate and correlate with other parameters, such as measures of inflammation and low-level HIV viremia. These new data suggest that new, more sensitive, imaging techniques may be useful to quantify immune activation in individuals undergoing prolonged ART. In order to investigate this observation, it is important to investigate imaging in HIV-uninfected individuals.18F-FDG PET and PET/CT imaging studies of lymphoid tissue from otherwise healthy individuals has not been previously performed using contemporary analysis approaches. A recently completed study by Sack and colleagues at the NIH Clinical Center (13H0065; NCT01778569), "The Psoriasis, Atherosclerosis, and Cardiometabolic Disease Initiative (PACI)" used PET and PET/CT scans to analyze 18F-FDG uptake in spleen and bone marrow in otherwise healthy individuals and in individuals with chronic inflammation from psoriasis [20]. Although uptake into other anatomic areas, such as lymphoid tissue, was not assessed, existing stored scans from a total of 65 otherwise healthy individuals contain these data. We have initiated a new secondary use protocol to evaluate these PET/CT images (Protocol IRB002399, "Secondary Use Protocol for Analysis of 18F-FDG Uptake in Positron Emission Tomography"). In collaboration with the Sereti Lab (NIAID), D. Boulware (U. Minnesota), B. Keele, (Leidos) and S. Joseph (UNC) my group has analyzed the structures of HIV populations prior to and following initiation of antiretroviral therapy in individuals with comorbid cryptococcal meningitis. Cryptococcal meningitis is a life threatening OI of the central nervous system characterized by high levels of HIV in cerebrospinal fluid (CSF), severe neurologic disruption with breakdown of the blood brain barrier (BBB). HIV populations in the CSF are genetically diverse, but their source is uncertain, and has not been studied in PWH infected aggressive subtype D HIV infections. We compared compartmentalization of HIV populations from blood (plasma and PBMC) and CSF in 10 PWH (including Subtype D) and cryptococcal meningitis prior to initiating ART. We found HIV compartmentalization in the CSF in some PWH, including subtype D, despite high concentrations of HIV RNA in both the CSF and in blood that persisted following introduction of ART. We also demonstrated that the majority of the CSF derived HIV in some PWH was macrophage-tropic. M-tropic HIV has been previously demonstrated in CSF, but has not been reported at such high levels, especially in the absence of CSF pleocytosis, overt HIV encephalitis or dementia. Instead, these data suggest active opportunistic infections may drive high levels of M-tropic HIV compartmentalized in the CNS despite evidence of BBB breakdown. These data open new areas for understanding the establishment of HIV reservoirs, and especially the role of M-tropic virus in the CNS. Similarly, we found IRIS in the setting TB resulted in profound shifts in HIV virus populations.