Development of an HIV vaccine is a global priority. A major roadblock to a vaccine is an inability to induce protective broadly neutralizing antibodies (bnAbs). HIV gp41 bnAbs have characteristics that predispose them to be controlled by tolerance. We used gp41 2F5 bnAb germline knock-in mice and macaques vaccinated with immunogens reactive with germline precursors to activate neutralizing antibodies. In germline knock-in mice, bnAb precursors were deleted, with remaining anergic B cells capable of being activated by germline-binding immunogens to make gp41-reactive immunoglobulin M (IgM). Immunized macaques made B cell clonal lineages targeted to the 2F5 bnAb epitope, but 2F5-like antibodies were either deleted or did not attain sufficient affinity for gp41-lipid complexes to achieve the neutralization potency of 2F5. Structural analysis of members of a vaccine-induced antibody lineage revealed that heavy chain complementarity-determining region 3 (HCDR3) hydrophobicity was important for neutralization. Thus, gp41 bnAbs are controlled by immune tolerance, requiring vaccination strategies to transiently circumvent tolerance controls.
The phenotype of T cells therapeutically effective in immunotherapy of advanced Friend virus-induced (FBL) leukemia in vivo and cytotoxic to FBL in vitro was determined. Mice bearing disseminated FBL leukemia were successfully treated by a combination of cyclophosphamide and adoptive transfer of syngeneic immune lymphocytes. Therapeutic efficacy was largely dependent on the presence of Lyt-1+2- T cells in the transferred cells, whereas cells cytotoxic to FBL tumor in vitro were derived from the Lyt-1+2+ and Lyt-1-2+ subsets. Thus, the predominate cell required to eradicate tumor in adoptive chemoimmunotherapy was not cytolytic to tumor in vitro. Potentially, the Lyt-1+2- cell may operate in vivo as an amplifier cell rather than by a direct anti-tumor effect. Elimination of the Lyt-1+ population with alpha-Lyt-1 and complement prevented the generation of significant cytotoxic responses during both primary in vitro sensitization to alloantigens and in vitro sensitization of tumour-primed cells. The capacity of Lyt-1+ cell-depleted population to generate cytotoxic responses was partially reconstituted by addition, at the initiation of culture, of interluekin 2, a T cell growth factor derived from Lyt-1+2- cells, which contain the CTL and CTL precursors, were nearly as effective in vitro as unseparated immune cells. If the remaining effector cells (i.e., Lyt-1+2- T cells) function in vivo predominantly as amplifier cells, than the tumour-bearing host must be capable of making a positive contribution to the outcome of therapy.
Protection from cytomegalovirus (CMV) disease in immunocompromised hosts has been shown to correlate with recovery of the host virus- specific CD8+ T-cell response. The administration of ganciclovir to immunosuppressed transplant recipients as antiviral prophylaxis has reduced the early risk of CMV disease, but late disease is observed with increased frequency, suggesting that recovery of the CMV-specific T-cell responses necessary for protective immunity may be delayed in these patients. Therefore, we evaluated reconstitution of CMV-specific T-cell responses in 47 bone marrow transplant (BMT) recipients entered on a randomized placebo-controlled study of ganciclovir. The study drug was initiated at a mean of 24 days after BMT. At day 30 to 40, a minority of patients had recovery of T-cell immunity to CMV and the frequency of reconstitution was equivalent in patients randomized to ganciclovir or placebo. The failure of ganciclovir to effect early reconstitution may reflect the short duration of treatment. Early recovery was associated with the infusion of BM from a CMV seropositive donor (P = .07 for CD8+ cytotoxic T cell (CTL), P = .04 for CD4+ Th). Between day 40 and day 90, recovery of deficient CD8+ and CD4+ CMV- specific T-cell responses occurred in the majority of individuals that received placebo, but in a minority of ganciclovir recipients. Two cases of late-onset CMV disease occurred in ganciclovir recipients. In all patients, the presence of a CTL response to CMV conferred protection from subsequent CMV disease (P = .005), and these protective CTL responses are shown to be specific for structural virion proteins similar to the responses in immunocompetent CMV seropositive individuals. These data confirm the importance of CMV-specific T-cell responses and suggest that a delay in recovery of these responses as a result of ganciclovir prophylaxis may contribute to the occurrence of late CMV disease.
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