BackgroundMajor depressive disorder (MDD) is a common psychiatric complication of HIV/AIDS. While considerable research has been undertaken to understand the psychosocial risk factors of MDD, there is a paucity of data on its biological risk factors including immunological factors. To address this we undertook a study to investigate the association between MDD and pro-inflammatory cytokines and acute phase proteins among persons living with HIV/AIDS (PLWHA) in Uganda. We collected clinical and laboratory data on 201 PLWHA attending two HIV clinics in central and southwestern Uganda. Clinical data included DSM-IV based MDD diagnosis, while laboratory data included the concentrations of IL-6, TNF-α and CRP measured using ELISA. Multiple logistic linear regression analysis was used to determine which proteins were independently significantly associated with MDD controlling for study site, sex, age and highest educational attainment.ResultsThe prevalence of MDD was 62/201 (30.8%). Adjusting for confounders, the odds of MDD increased with increasing levels of IL-6 [each unit increase in IL-6 titres was associated with an aOR = 0.98 (95% CI, 0.97–0.99); p < 0.001]. Participants with low levels of TNF-α were at reduced risk of MDD compared to participants with no TNF-α [those with a TNF-α of 1- <50 pg/ml titres had an aOR = 0.35(95% CI,0.10–1.16)], but as the level of TNF-α increased, the risk of MDD increased, and in particular participants with high levels of TNF-α (of 500 or above) were at a significantly increased risk of MDD [e.g. those with a TNF-α of 500- < 1000 pg/ml titres had an aOR = 3.98 (95% CI,1.29–12.33)] compared to participants with no TNF-α. There was no evidence that MDD was associated with the level of CRP titres [aOR = 0.95 (0.78–1.15); p = 0.60)].ConclusionIn this study, the pro-inflammatory proteins IL-6 and TNF-α were significantly associated with MDD, while CRP was not.

A consensus on the implications of co-infection on de-worming and vaccination policies has not yet emerged. Well powered randomized trials in HIV-1-infected individuals with defined helminth infections are required to determine the benefits of anthelmintic interventions.

In Uganda, fisher folk have HIV prevalence rates, about four times higher than the national average, and are often coinfected with Schistosoma mansoni. We hypothesized that innate immune responses and HIV-specific Th1 immune responses might be downmodulated in HIV/S. mansoni-coinfected individuals compared with HIV+/S. mansoni-negative individuals. We stimulated whole blood with innate receptor agonists and analyzed supernatant cytokines by Luminex. We evaluated HIV-specific responses by intracellular cytokine staining for IFN-γ, IL-2, and TNF-α. We found that the plasma viral load and CD4 count were similar between the HIV+SM+ and HIV+SM− individuals. In addition, the TNF-α response to the imidazoquinoline compound CL097 and β-1, 3-glucan (curdlan), was significantly higher in HIV/S. mansoni-coinfected individuals compared with HIV only-infected individuals. The frequency of HIV-specific IFN-γ+IL-2–TNF-α− CD8 T cells and IFN-γ+IL-2–TNF-α+ CD4 T cells was significantly higher in HIV/S. mansoni-coinfected individuals compared with HIV only-infected individuals. These findings do not support the hypothesis that S. mansoni downmodulates innate or HIV-specific Th1 responses in HIV/S. mansoni-coinfected individuals.

Control of HIV replication through CD4(+) and CD8(+) T cells might be possible, but the functional and phenotypic characteristics of such cells are not defined. Among cytokines produced by T cells, CCR5 ligands, including macrophage inflammatory protein-1 beta (MIP-1β), compete for the CCR5 coreceptor with HIV, promoting CCR5 internalization and decreasing its availability for virus binding. Interferon (IFN)-γ also has some antiviral activity and has been used as a read-out for T cell immunogenicity. We used cultured ELISpot assays to compare the relative contribution of MIP-1β and IFN-γ to HIV-specific responses. The magnitude of responses was 1.36 times higher for MIP-1β compared to IFN-γ. The breadth of the MIP-1β response (45.41%) was significantly higher than IFN-γ (36.88%), with considerable overlap between the peptide pools that stimulated both MIP-1β and IFN-γ production. Subtype A and D cross-reactive responses were observed both at stimulation and test level, but MIP-1β and IFN-γ responses displayed different effect patterns. We conclude that the MIP-1β ELISpot would be a useful complement to the evaluation of the immunogenicity of HIV vaccines and the activity of adjuvants.

Background: Identifying immunogens that induce HIV-1-specific immune responses is a lengthy process that can benefit from computational methods, which predict T-cell epitopes for various HLA types. Methods:We tested the performance of the NetMHCpan4.0 computational neural network in re-identifying 93 Tcell epitopes that had been previously independently mapped using the whole proteome IFN-γ ELISPOT assays in 6 HLA class I typed Ugandan individuals infected with HIV-1 subtypes A1 and D. To provide a benchmark we compared the predictions for NetMHCpan4.0 to MHCflurry1.2.0 and NetCTL1.2.Results: NetMHCpan4.0 performed best correctly predicting 88 of the 93 experimentally mapped epitopes for a set length of 9-mer and matched HLA class I alleles. Receiver Operator Characteristic (ROC) analysis gave an area under the curve (AUC) of 0.928. Setting NetMHCpan4.0 to predict 11-14mer length did not improve the prediction (37-79 of 93 peptides) with an inverse correlation between the number of predictions and length set. Late time point peptides were significantly stronger binders than early peptides (Wilcoxon signed rank test: p = 0.0000005). MHCflurry1.2.0 similarly predicted all but 2 of the peptides that NetMHCpan4.0 predicted and NetCTL1.2 predicted only 14 of the 93 experimental peptides. Conclusion: NetMHCpan4.0 class I epitope predictions covered 95% of the epitope responses identified in six HIV-1 infected individuals, and would have reduced the number of experimental confirmatory tests by > 80%. Algorithmic epitope prediction in conjunction with HLA allele frequency information can cost-effectively assist immunogen design through minimizing the experimental effort.

Background: It has been hypothesised that Schistosoma co-infection exacerbates HIV progression, and hence anthelminthic intervention in co-infected individuals will delay it. We evaluated effects of high-intensity versus low-intensity praziquantel treatment of schistosomiasis on HIV disease progression among co-infected patients from fishing populations around Lake Victoria, Uganda. Methods: Between August 2012 and September 2015, we conducted an open-label randomised, controlled trial. Adults, antiretroviral therapy-naïve, CD4 counts ≥350 cells/μl, HIV and S. mansoni co-infected, were randomised 1:1 to praziquantel (40mg/kg) given quarterly (starting at enrolment) or annually (starting 12 weeks after enrolment; such that low-intensity participants were still untreated when sampled at 12 weeks). A non-randomised HIV-positive S. mansoni-negative comparison group was recruited. The primary outcome was mean change in plasma viral load at 12 and 60 weeks. Results: In total 363 participants (high-intensity 113, low-intensity 113, comparison group 137) were recruited; 96 (85.0%), 97 (85.8%) and 107 (78.1%) completed 60 weeks of follow up, respectively. Adjusting for baseline age and viral load, the geometric mean ratio (aGMR [95%CI]) viral load for high-intensity vs low-intensity groups at 12 weeks was 0.90 [0.65, 1.25] p=0.55 and at 60 weeks 1.88 [0.78, 4.53] p=0.16. Results in the comparison group were similar to trial arms. High-intensity, compared to low-intensity, treatment resulted in substantially lower S. mansoni prevalence at all follow up visits (p<0.05). Conclusions: In communities with a high burden of both S. mansoni and HIV infection, high-intensity treatment of S. mansoni does not delay HIV progression despite relevant benefit for parasite clearance. Trial registration: ISRCTN15371662 (17/11/2016)

Background: It has been hypothesised that Schistosoma co-infection exacerbates HIV progression, and hence anthelminthic intervention in co-infected individuals will delay it. We evaluated effects of high-intensity versus low-intensity praziquantel treatment of schistosomiasis on HIV disease progression among co-infected patients from fishing populations around Lake Victoria, Uganda. Methods: Between August 2012 and September 2015, we conducted an open-label randomised, controlled trial. Adults, antiretroviral therapy-naïve, CD4 counts ≥350 cells/μl, HIV and S. mansoni co-infected, were randomised 1:1 to praziquantel (40mg/kg) given quarterly (starting at enrolment) or annually (starting 12 weeks after enrolment; such that low-intensity participants were still untreated when sampled at 12 weeks). A non-randomised HIV-positive S. mansoni-negative comparison group was recruited. The primary outcome was mean change in plasma viral load at 12 and 60 weeks. Results: In total 363 participants (high-intensity 113, low-intensity 113, comparison group 137) were recruited; 96 (85.0%), 97 (85.8%) and 107 (78.1%) completed 60 weeks of follow up, respectively. Adjusting for baseline age and viral load, the geometric mean ratio (aGMR [95%CI]) viral load for high-intensity vs low-intensity groups at 12 weeks was 0.90 [0.65, 1.25] p=0.55 and at 60 weeks 1.88 [0.78, 4.53] p=0.16. Results in the comparison group were similar to trial arms. High-intensity, compared to low-intensity, treatment resulted in substantially lower S. mansoni prevalence at all follow up visits (p<0.05). Conclusions: In communities with a high burden of both S. mansoni and HIV infection, high-intensity treatment of S. mansoni does not delay HIV progression despite relevant benefit for parasite clearance. Trial registration: ISRCTN15371662 (17/11/2016)

Background: Identifying immunogens that induce HIV-1-specific immune responses is a lengthy process that can benefit from computational methods, which predict T-cell epitopes for various HLA types. Methods: We tested the performance of the NetMHCpan4.0 computational neural network in re-identifying 93 T-cell epitopes that had been previously independently mapped using the whole proteome IFN-g ELISPOT assays in 6 HLA class I typed Ugandan individuals infected with HIV-1 subtypes A1 and D. To provide a benchmark we compared the predictions for NetMHCpan4.0 to MHCflurry1.2.0 and NetCTL1.2. Results: NetMHCpan4.0 performed best correctly predicting 88 of the 93 experimentally mapped epitopes for a set length of 9-mer and matched HLA class I alleles. Receiver Operator Characteristic (ROC) analysis gave an area under the curve (AUC) of 0.928. Setting NetMHCpan4.0 to predict 11-14mer length did not improve the prediction (37-79 of 93 peptides) with an inverse correlation between the number of predictions and length set. Late time point peptides were significantly stronger binders than early peptides (Wilcoxon signed rank test: p =0.0000005). MHCflurry1.2.0 similarly predicted all but 2 of the peptides that NetMHCpan4.0 predicted and NetCTL1.2 predicted only 14 of the 93 experimental peptides. Conclusion: NetMHCpan4.0 class I epitope predictions covered 95% of the epitope responses identified in six HIV-1 infected individuals, and would have reduced the number of experimental confirmatory tests by >80%. Algorithmic epitope prediction in conjunction with HLA allele frequency information can cost-effectively assist immunogen design through minimizing the experimental effort. Keywords: HIV-1, epitope mapping, T-cell, artificial neural network, in-silico , NetMHCpan4.0., MHCflurry1.2.0 and NetCTL1.2.