A recombinant vaccine containing Aventis Pasteur’s canarypox vector (ALVAC)–HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC–simian immunodeficiency virus (SIV) and gp120 alum (ALVAC–SIV + gp120) equivalent vaccine, but not an ALVAC–SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.

AbstractsBackgroundPatients with chronic viral infections including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) are at increased risk of developing malignancies. The safety and efficacy of ICI therapy in patients with both cancer and chronic viral infections is not well established as most clinical trials of ICIs excluded these patient populations.MethodsWe performed a retrospective analysis of patients with advanced-stage cancers and HIV, HBV, or HCV infection treated with ICI therapy at 5 MedStar Health hospitals from January 2011 to April 2018.ResultsWe identified 50 patients including 16 HIV, 29 HBV/HCV, and 5 with concurrent HIV and either HBV or HCV. In the HIV cohort (n = 21), any grade immune-related adverse events (irAEs) were 24% with grade ≥ 3 irAEs 14%. Among 5 patients with matched pre/post-treatment results, no significant changes in HIV viral load and CD4+ T-cell counts were observed. RECIST confirmed (n = 18) overall response rate (ORR) was 28% with 2 complete responses (CR) and 3 partial responses (PR). Responders included 2 patients with low baseline CD4+ T-cell counts (40 and 77 cells/ul, respectively). In the HBV/HCV cohort (n = 34), any grade irAEs were 44% with grade ≥ 3 irAEs 29%. RECIST confirmed ORR was 21% (6 PR). Among the 6 patients with known pre/post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation.ConclusionsOur retrospective series is one of the largest case series to report clinical outcomes among HIV, HBV and HCV patients treated with ICI therapy. Toxicity and efficacy rates were similar to those observed in patients without chronic viral infections. Viral reactivation was not observed. Tumor responses occurred in HIV patients with low CD4 T-cell counts. While prospective studies are needed to validate above findings, these data support not excluding such patients from ICI–based clinical trials or treatment.

T follicular regulatory cells (TFR) are a suppressive CD4+ T cell subset that migrates to germinal centers (GC) during antigen presentation by up-regulating the chemokine receptor CXCR5. In the GC, TFR control T follicular helper cells (TFH) expansion and modulate the development of high-affinity antigen specific responses. Here we identified and characterized TFR as CXCR5+ CCR7−-“follicular” T regulatory cells (TREG) in lymphoid tissues of healthy rhesus macaques, and we studied their dynamic throughout infection in a well-defined animal model of HIV pathogenesis. TFR were infected by SIVmac251 and had comparable levels of SIV-DNA to CXCR5− CCR7+-“T-zone” TREG and TFH. Contrary to the SIV-associated TFH expansion in the chronic phase of infection, we observed an apparent reduction of TFR frequency in cell suspension, as well as a decrease of CD3+ Foxp3+ cells in the GC of intact lymph nodes. TFR frequency was inversely associated with the percentage of TFH and, interestingly, with the avidity of the antibodies that recognize the SIV-gp120 envelope protein. Our findings show changes in the TFH/TFR ratio during chronic infection and suggest possible mechanisms for the unchecked expansion of TFH cells in HIV/SIV infection.

In the version of this article initially published online, an affiliation for Luca Schifanella was omitted and there was an error in the description of the phenotypic analyses of plasmablasts in the Online Methods. The error has been corrected for the print, PDF and HTML versions of this article.