APOBEC3G-Augmented Stem Cell Therapy to Modulate HIV Replication: A Computational Study

PMC3661658The interplay between the innate immune system restriction factor APOBEC3G and the HIV protein Vif is a key host-retrovirus interaction. APOBEC3G can counteract HIV infection in at least two ways: by inducing lethal mutations on the viral cDNA; and by blocking steps in reverse transcription and viral integration into the host genome. HIV-Vif blocks these antiviral functions of APOBEC3G by impeding its encapsulation. Nonetheless, it has been shown that overexpression of APOBEC3G, or interfering with APOBEC3G-Vif binding, can efficiently block in vitro HIV replication. Some clinical studies have also suggested that high levels of APOBEC3G expression in HIV patients are correlated with increased CD4+ T cell count and low levels of viral load; however, other studies have reported contradictory results and challenged this observation. Stem cell therapy to replace a patient's immune cells with cells that are more HIV-resistant is a promising approach. Pre-implantation gene transfection of these stem cells can augment the HIV-resistance of progeny CD4+ T cells. As a protein, APOBEC3G has the advantage that it can be genetically encoded, while small molecules cannot. We have developed a mathematical model to quantitatively study the effects on in vivo HIV replication of therapeutic delivery of CD34+ stem cells transfected to overexpress APOBEC3G. Our model suggests that stem cell therapy resulting in a high fraction of APOBEC3G-overexpressing CD4+ T cells can effectively inhibit in vivo HIV replication. We extended our model to simulate the combination of APOBEC3G therapy with other biological activities, to estimate the likelihood of improved outcomes.JH Libraries Open Access Fun

Length of Endoprosthetic Reconstruction in Revision Knee Arthroplasty Is Associated With Complications and Reoperations

BackgroundComplex revision total knee arthroplasty (TKA) often calls for endoprosthetic reconstruction to address bone loss, poor bone quality, and soft tissue insufficiency. Larger amounts of segmental bone loss in the setting of joint replacement may be associated with greater areas of devascularized tissue, which could increase the risk of complications and worsen functional results.Questions/purposesAre longer endoprosthetic reconstructions associated with (1) higher risk of deep infection; (2) increased risk of reoperation and decreased implant survivorship; or (3) poorer ambulatory status?MethodsThis is a single-institution retrospective case series of nononcologic femoral endoprosthetic reconstructions for revision TKA from 1995 to 2013 (n = 32). Cases were categorized as distal (n = 17) or diaphyseal (n = 15) femoral reconstructions based on extension to or above the supracondylar metaphyseal-diaphyseal junction, respectively. Five patients from each group were lost to followup before 2 years (distal mean 4 years [range, 2-8 years]; diaphyseal mean = 6 years [range, 2-16 years]), and one of the 12 distal reconstructions and two of the 10 diaphyseal reconstructions had not been evaluated within the past 5 years. Clinical outcomes and ambulatory status (able to walk or not) were assessed through chart review by authors not involved in any cases. Prior incidence of periprosthetic joint infection was high in both groups (distal = seven of 12 versus diaphyseal = four of 10; p = 0.670).ResultsPatients with diaphyseal femoral replacements were more likely to develop postoperative deep infections than patients with distal femoral replacements (distal = three of 12 versus diaphyseal = nine of 10; p = 0.004). Implant survivorship (revision-free) for diaphyseal reconstructions was worse at 2 years (distal = 100%, 95% confidence interval [CI], 100%-100% versus diaphyseal = 40%, 95% CI, 19%-86%; p = 0.001) and 5 years (distal = 90%, 95% CI, 75%-100% versus diaphyseal = 30%, 95% CI, 12%-73%; p = 0.001). Infection-free, revision-free survival (retention AND no infection) was worse for diaphyseal femoral replacing reconstructions than for distal femoral replacements at 2 years (distal = 70%, 95% CI, 48%-100% versus diaphyseal = 20%, 95% CI, 6%-69%; p = 0.037) and 5 years (distal = 70%, 95% CI, 48%-100% versus diaphyseal = 10%, 95% CI, 2%-64%; p = 0.012). There was no difference with the small numbers available in proportion of patients able to walk (distal reconstruction = eight of 11 versus diaphyseal = seven of 10; p = 1.000), although all but one patient in each group required walking aids.ConclusionsEndoprosthetic femoral reconstruction is a viable salvage alternative to amputation for treatment of failed TKA with segmental distal femoral bone loss. In our small series even with substantial loss to followup and likely best-case estimates of success, extension proximal to the supracondylar metaphyseal-diaphyseal junction results in higher infection and revision risk. In infection, limb salvage remains possible with chronic antibiotic suppression, which we now use routinely for all femoral replacement extending into the diaphysis.Level of evidenceLevel III, therapeutic study

Length of Endoprosthetic Reconstruction in Revision Knee Arthroplasty Is Associated With Complications and Reoperations

BACKGROUND: Complex revision total knee arthroplasty (TKA) often calls for endoprosthetic reconstruction to address bone loss, poor bone quality, and soft tissue insufficiency. Larger amounts of segmental bone loss in the setting of joint replacement may be associated with greater areas of devascularized tissue, which could increase the risk of complications and worsen functional results. QUESTIONS/PURPOSES: Are longer endoprosthetic reconstructions associated with (1) higher risk of deep infection; (2) increased risk of reoperation and decreased implant survivorship; or (3) poorer ambulatory status? METHODS: This is a single-institution retrospective case series of nononcologic femoral endoprosthetic reconstructions for revision TKA from 1995 to 2013 (n = 32). Cases were categorized as distal (n = 17) or diaphyseal (n = 15) femoral reconstructions based on extension to or above the supracondylar metaphyseal-diaphyseal junction, respectively. Five patients from each group were lost to followup before 2 years (distal mean 4 years [range, 2–8 years]; diaphyseal mean = 6 years [range, 2–16 years]), and one of the 12 distal reconstructions and two of the 10 diaphyseal reconstructions had not been evaluated within the past 5 years. Clinical outcomes and ambulatory status (able to walk or not) were assessed through chart review by authors not involved in any cases. Prior incidence of periprosthetic joint infection was high in both groups (distal = seven of 12 versus diaphyseal = four of 10; p = 0.670). RESULTS: Patients with diaphyseal femoral replacements were more likely to develop postoperative deep infections than patients with distal femoral replacements (distal = three of 12 versus diaphyseal = nine of 10; p = 0.004). Implant survivorship (revision-free) for diaphyseal reconstructions was worse at 2 years (distal = 100%, 95% confidence interval [CI], 100%–100% versus diaphyseal = 40%, 95% CI, 19%–86%; p = 0.001) and 5 years (distal = 90%, 95% CI, 75%–100% versus diaphyseal = 30%, 95% CI, 12%–73%; p = 0.001). Infection-free, revision-free survival (retention AND no infection) was worse for diaphyseal femoral replacing reconstructions than for distal femoral replacements at 2 years (distal = 70%, 95% CI, 48%–100% versus diaphyseal = 20%, 95% CI, 6%–69%; p = 0.037) and 5 years (distal = 70%, 95% CI, 48%–100% versus diaphyseal = 10%, 95% CI, 2%–64%; p = 0.012). There was no difference with the small numbers available in proportion of patients able to walk (distal reconstruction = eight of 11 versus diaphyseal = seven of 10; p = 1.000), although all but one patient in each group required walking aids. CONCLUSIONS: Endoprosthetic femoral reconstruction is a viable salvage alternative to amputation for treatment of failed TKA with segmental distal femoral bone loss. In our small series even with substantial loss to followup and likely best-case estimates of success, extension proximal to the supracondylar metaphyseal-diaphyseal junction results in higher infection and revision risk. In infection, limb salvage remains possible with chronic antibiotic suppression, which we now use routinely for all femoral replacement extending into the diaphysis. LEVEL OF EVIDENCE: Level III, therapeutic study