Combination of Antiretroviral Drugs and Radioimmunotherapy Specifically Kills Infected Cells from HIV-Infected Individuals.

Eliminating virally infected cells is an essential component of any HIV eradication strategy. Radioimmunotherapy (RIT), a clinically established method for killing cells using radiolabeled antibodies, was recently applied to target HIV-1 gp41 antigen expressed on the surface of infected cells. Since gp41 expression by infected cells is likely downregulated in patients on antiretroviral therapy (ART), we evaluated the ability of RIT to kill ART-treated infected cells using both in vitro models and lymphocytes isolated from HIV-infected subjects. Human peripheral blood mononuclear cells (PBMCs) were infected with HIV and cultured in the presence of two clinically relevant ART combinations. Scatchard analysis of the 2556 human monoclonal antibody to HIV gp41 binding to the infected and ART-treated cells demonstrated sufficient residual expression of gp41 on the cell surface to warrant subsequent RIT. This is the first time the quantification of gp41 post-ART is being reported. Cells were then treated with Bismuth-213-labeled 2556 antibody. Cell survival was quantified by Trypan blue and residual viremia by p24 ELISA. Cell surface gp41 expression was assessed by Scatchard analysis. The experiments were repeated using PBMCs isolated from blood specimens obtained from 15 HIV-infected individuals: 10 on ART and 5 ART-naïve. We found that 213Bi-2556 killed ART-treated infected PBMCs and reduced viral production to undetectable levels. ART and RIT co-treatment was more effective at reducing viral load in vitro than either therapy alone, indicating that gp41 expression under ART was sufficient to allow 213Bi-2556 to deliver cytocidal doses of radiation to infected cells. This study provides proof of concept that 213Bi-2556 may represent an innovative and effective targeting method for killing HIV-infected cells treated with ART and supports continued development of 213Bi-2556 for co-administration with ART toward an HIV eradication strategy.

A fully human antibody to gp41 selectively eliminates HIV-infected cells that transmigrated across a model human blood brain barrier.

OBJECTIVE: Many HIV patients on combined antiretroviral therapy exhibit HIV-associated neurocognitive disorders because the brain becomes a viral reservoir. There is a need for therapeutics that can enter the central nervous system (CNS) and eradicate the virus. DESIGN: Radiolabeled human mAb 2556 to HIV gp41 selectively kills HIV-infected cells in vivo and in vitro. Here we tested the ability of 213Bi-2556 to cross a tissue culture model of the human blood brain barrier and kill HIV-infected peripheral blood mononuclear cells (PBMCs) and monocytes on the CNS side of the barrier. METHODS: 2556 mAb isoelectric point was determined with isoelectric focusing. The ability of radiolabeled 2556 to penetrate through the barrier was studied by adding it to the upper chamber of the barriers and its penetration into the CNS side was followed for 5 h. To assess the ability of Bi-2556 to kill the HIV-infected cells on the CNS side of barrier, the HIV-infected and uninfected PBMCs and monocytes were allowed to transmigrate across the barriers overnight followed by application of Bi-2556 or control mAb Bi-1418 to the top of the barrier. Killing of cells was measured by TUNEL and Trypan blue assays. The barriers were examined by confocal microscopy for overt damage. RESULTS: The isoelectric point of Bi-2556 was 9.6 enabling its penetration through the barrier by transcytosis. Bi-2556 killed significantly more transmigrated HIV-infected cells in comparison to Bi-1418 and uninfected cells. No overt damage to barriers was observed. CONCLUSION: We demonstrated that Bi-2556 mAb crossed an in-vitro human blood brain barrier and specifically killed transmigrated HIV-infected PBMCs and monocytes without overt damage to the barrier.

Role of nuclear medicine in neuroHIV: PET, SPECT, and beyond.

HIV-associated neurocognitive disorders (HAND) remain among the most common clinical disorders encountered in people infected with HIV despite widespread use of antiretroviral therapy. There is an enormous need for further evaluation and early diagnosis of HAND. The variety of PET agents such as FDG, C-PiB and [C]-R-PK11195 as well as SPECT agents Tc-HMPAO, I-FP-CIT and I-IBZM have been investigated for the diagnosis of HAND, for distinguishing between demented and nondemented HIV patients, for differentiation between HAND and nonHIV related dementia, as well as for assessing the influence of coinfection with the other viral pathogens on the brain functionality. In spite of some interesting results, none of these tracers have been specifically created for HAND and none can be recommended for HAND diagnosis. Specialized tracers need to be developed for better diagnosis and management of HAND. The potential role of therapeutic nuclear medicine as part of the curative strategies for HIV is also discussed.

Cleft palate, bilateral external auditory canal atresia, and other midline defects associated with Diamond-Blackfan anemia: case report.

Diamond-Blackfan anemia (DBA) is associated with congenital anomalies especially of the midline. When present, facial anomalies are reminiscent of Treacher-Collins syndrome, and both DBA and Treacher-Collins syndrome are disorders of ribosomal biogenesis. Herein, we describe a female infant with multiple midline defects associated with DBA and reaffirm the absence of RPS-19 mutations in DBA patients with facial anomalies.