Cellular immune correlates analysis of an HIV-1 preexposure prophylaxis trial.

HIV-1-specific T-cell responses in exposed seronegative subjects suggest that a viral breach of the exposure site is more common than current transmission rates would suggest and that host immunity can extinguish subsequent infection foci. The Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial provided an opportunity to rigorously investigate these responses in a case-control immunology study; 84 preinfection peripheral blood mononuclear cell samples from individuals enrolled in the iPrEx trial who later seroconverted were matched with 480 samples from enrolled subjects who remained seronegative from both the placebo and active treatment arms. T-cell responses to HIV-1 Gag, Protease, Integrase, Reverse Transcriptase, Vif, and Nef antigens were quantified for all subjects in an IFN-γ enzyme-linked immunospot (ELISpot) assay. IFN-γ responses varied in magnitude and frequency across subjects. A positive response was more prevalent in those who remained persistently HIV-1-negative for Gag (P = 0.007), Integrase (P < 0.001), Vif (P < 0.001), and Nef (P < 0.001). When correlated with outcomes in the iPrEx trial, Vif- and Integrase-specific T-cell responses were associated with reduced HIV-1 infection risk [hazard ratio (HR) = 0.36, 95% confidence interval (95% CI) = 0.19-0.66 and HR = 0.52, 95% CI = 0.28-0.96, respectively]. Antigen-specific responses were independent of emtricitabine/tenofovir disoproxil fumarate use. IFN-γ secretion in the ELISpot was confirmed using multiparametric flow cytometry and largely attributed to effector memory CD4+ or CD8+ T cells. Our results show that HIV-1-specific T-cell immunity can be detected in exposed but uninfected individuals and that these T-cell responses can differentiate individuals according to infection outcomes.

Irreversible Electroporation Can Effectively Ablate Hepatocellular Carcinoma to Complete Pathologic Necrosis.

PURPOSE: To describe full explant pathology and radiographic correlation in patients with hepatocellular carcinoma (HCC) treated with irreversible electroporation (IRE) who subsequently underwent liver transplant. MATERIALS AND METHODS: In a retrospective study, 6 patients who had undergone IRE for HCC and subsequent orthotopic liver transplant during the period 2011-2013 were evaluated. Of the 6 patients, 4 had Child-Pugh class A cirrhosis, and 2 had class B cirrhosis. Irreversible electroporation was performed for a single focal HCC with median tumor diameter of 22 mm (range, 6-26 mm). After IRE, follow-up multiphasic cross-sectional imaging was performed at 1 month and every 3 months thereafter until liver transplant. Mean time between IRE and transplant was 10 months (range, 3-17 mo). Assessment of imaging response was based on modified Response Evaluation Criteria In Solid Tumors. Liver explants were evaluated for necrosis and viable carcinoma in IRE-treated tumors. RESULTS: After IRE, all tumors showed a complete response on follow-up imaging. Five tumors showed complete pathologic necrosis without any viable carcinoma, sharply demarcated from the surrounding hepatic parenchyma. Bile ducts within the treatment area were preserved. A single tumor treated with a bipolar IRE probe had < 5% viable carcinoma cells at the periphery. CONCLUSIONS: This study demonstrates the efficacy of IRE for HCC based on pathologic evaluation and correlation to radiologic findings.

Increased expression of intrinsic antiviral genes in HLA-B*57-positive individuals.

The genetic background of HIV-1-infected subjects, particularly the HLA class I haplotype, appears to be critical in determining disease progression rates, thought to be a result of the role of HIV-1-specific CD8(+) T cell responses. The HLA-B*57 allele is strongly associated with viremic suppression and slower disease progression. However, there is considerable heterogeneity in HIV-1 disease progression rates among HLA-B*57-positive subjects, suggesting that additional factors may help to contain viral replication. In this report, we investigated the association between host restriction factors, other established immunological parameters, and HLA type in HIV-1-seronegative individuals. Our results demonstrate that healthy, uninfected HLA-B*57-positive individuals exhibit significantly higher gene-expression levels of host restriction factors, such as APOBEC3A, APOBEC3B, BST-2/tetherin, and ISG15. Interestingly, HLA-B*57 individuals have significantly lower CD4(+) T cell frequencies but harbor slightly more activated CD4(+) T cells compared with their HLA-B*35 counterparts. We detected significant correlations between CD4(+) T cell activation and expression of several APOBEC3 family members, BST-2/tetherin, SAMHD1, and TRIM5α in HLA-B*57-positive individuals. To our knowledge, this is the first report showing distinct associations between host restriction factors and HLA class I genotype. Our results provide insights into natural protection mechanisms and immunity against HIV-1 that fall outside of classical HLA-mediated effects.