Cross-reactivity between HLA-A2-restricted FLU-M1:58–66 and HIV p17 GAG:77–85 epitopes in HIV-infected and uninfected individuals

BACKGROUND: The matrix protein of the influenza A virus and the matrix and capsid proteins of the human immunodeficiency virus (HIV) share striking structural similarities which may have evolutionary and biological significance. These similarities led us to hypothesize the existence of cross-reactivity between HLA-A2-restricted FLU-M1:58–66 and HIV-1 p17 GAG:77–85 epitopes. METHODS: The hypothesis that these two epitopes are cross-reactive was tested by determining the presence and extent of FLU/GAG immune cross-reactivity in lymphocytes from HIV-seropositive and seronegative HLA-A2(+ )donors by cytotoxicity assays and tetramer analyses. Moreover, the molecular basis for FLU/GAG cross-reactivity in HIV-seropositive and seronegative donors was studied by comparing lymphocyte-derived cDNA sequences corresponding to the TCR-β variable regions, in order to determine whether stimulation of lymphocytes with either peptide results in the expansion of identical T-cell clonotypes. RESULTS: Here, we report evidence of cross-reactivity between FLU-M1:58–66 and HIV-1 p17 GAG:77–85 epitopes following in vitro stimulation of PBMC derived from either HIV-seropositive or seronegative HLA-A2(+ )donors as determined by cytotoxicity assays, tetramer analyses, and molecular clonotyping. CONCLUSION: These results suggest that immunity to the matrix protein of the influenza virus may drive a specific immune response to an HLA-A2-restricted HIV gag epitope in HIV-infected and uninfected donors vaccinated against influenza

Increased Loss of CCR5+ CD45RA− CD4+ T Cells in CD8+ Lymphocyte-Depleted Simian Immunodeficiency Virus-Infected Rhesus Monkeys▿

Previously we have shown that CD8+ T cells are critical for containment of simian immunodeficiency virus (SIV) viremia and that rapid and profound depletion of CD4+ T cells occurs in the intestinal tract of acutely infected macaques. To determine the impact of SIV-specific CD8+ T-cell responses on the magnitude of the CD4+ T-cell depletion, we investigated the effect of CD8+ lymphocyte depletion during primary SIV infection on CD4+ T-cell subsets and function in peripheral blood, lymph nodes, and intestinal tissues. In peripheral blood, CD8+ lymphocyte-depletion changed the dynamics of CD4+ T-cell loss, resulting in a more pronounced loss 2 weeks after infection, followed by a temporal rebound approximately 2 months after infection, when absolute numbers of CD4+ T cells were restored to baseline levels. These CD4+ T cells showed a markedly skewed phenotype, however, as there were decreased levels of memory cells in CD8+ lymphocyte-depleted macaques compared to controls. In intestinal tissues and lymph nodes, we observed a significantly higher loss of CCR5+ CD45RA− CD4+ T cells in CD8+ lymphocyte-depleted macaques than in controls, suggesting that these SIV-targeted CD4+ T cells were eliminated more efficiently in CD8+ lymphocyte-depleted animals. Also, CD8+ lymphocyte depletion significantly affected the ability to generate SIV Gag-specific CD4+ T-cell responses and neutralizing antibodies. These results reemphasize that SIV-specific CD8+ T-cell responses are absolutely critical to initiate at least partial control of SIV infection

Heterologous Plasmid DNA Prime-Recombinant Human Adenovirus 5 Boost Vaccination Generates a Stable Pool of Protective Long-Lived CD8+ T Effector Memory Cells Specific for a Human Parasite, Trypanosoma cruzi▿†

Recently, we described a heterologous prime-boost strategy using plasmid DNA followed by replication-defective human recombinant adenovirus type 5 as a powerful strategy to elicit long-lived CD8+ T-cell-mediated protective immunity against experimental systemic infection of mice with a human intracellular protozoan parasite, Trypanosoma cruzi. In the present study, we further characterized the protective long-lived CD8+ T cells. We compared several functional and phenotypic aspects of specific CD8+ T cells present 14 or 98 days after the last immunizing dose and found the following: (i) the numbers of specific cells were similar, as determined by multimer staining or by determining the number of gamma interferon (IFN-γ)-secreting cells by enzyme-linked immunospot (ELISPOT) assay; (ii) these cells were equally cytotoxic in vivo; (iii) following in vitro stimulation, a slight decline in the frequency of multifunctional cells (CD107a+ IFN-γ+ or CD107a+ IFN-γ+ tumor necrosis factor alpha positive [TNF-α+]) was paralleled by a significant increase of CD107a singly positive cells after 98 days; (iv) the expression of several surface markers was identical, except for the reexpression of CD127 after 98 days; (v) the use of genetically deficient mice revealed a role for interleukin-12 (IL-12)/IL-23, but not IFN-γ, in the maintenance of these memory cells; and (vi) subsequent immunizations with an unrelated virus or a plasmid vaccine or the depletion of CD4+ T cells did not significantly erode the number or function of these CD8+ T cells during the 15-week period. From these results, we concluded that heterologous plasmid DNA prime-adenovirus boost vaccination generated a stable pool of functional protective long-lived CD8+ T cells with an effector memory phenotype