Fully differentiated HIV-1 specific CD8+ T effector cells are more frequently detectable in controlled than in progressive HIV-1 infection.

BACKGROUND: CD8+ T cells impact control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. In HIV-1 infection, persistent HIV-1 specific IFN-gamma+ CD8+ T cell responses are detected in the setting of disease progression, consistent with functional impairment in vivo. Recent data suggest that impaired maturation, as defined by the lineage markers CD45RA and CCR7, may contribute to a lack of immune control by these responses. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the maturation phenotype of epitope-specific CD8+ T cell responses directed against HIV-1 in 42 chronically infected, untreated individuals, 22 of whom were "Controllers" (median 1140 RNA copies/ml plasma, range<50 to 2520), and 20 "progressors" of whom had advanced disease and high viral loads (median 135,500 RNA copies/ml plasma, range 12100 to >750000). Evaluation of a mean of 5 epitopes per person revealed that terminally differentiated CD8+ T cells directed against HIV-1 are more often seen in HIV-1 Controllers (16/22; 73%) compared to HIV-1 progressors (7/20; 35%)(p = 0.015), but the maturation state of epitope-specific responses within a given individual was quite variable. Maturation phenotype was independent of the HLA restriction or the specificity of a given CD8+ T cell response and individual epitopes associated with slow disease progression were not more likely to be terminally differentiated. CONCLUSIONS/SIGNIFICANCE: These data indicate that although full maturation of epitope-specific CD8+ T cell responses is associated with viral control, the maturation status of HIV-1 specific CD8+ T cell responses within a given individual are quite heterogeneous, suggesting epitope-specific influences on CD8+ T cell function.

Demographic, risk factor, and knowledge differences between Latinas and non-Latinas referred to colposcopy.

OBJECTIVE: Disparities occur in the incidence and mortality of cervical cancer among minority women in the US. Screening lowers cervical cancer incidence. Screening rates are lower for minority women than for White women in the US. This study sought to identify demographic, risk factor, and perception of the role of Pap smears between Latinas and non-Latinas. METHODS: A written survey was administered to 150 Latinas and 150 non-Latinas attending a colposcopy unit. Data on demographics, risk factors, screening rates, knowledge about cervical cancer screening, and perceived barriers to participation in screening programs were collected. RESULTS: A total of 140 Latinas and 146 non-Latinas completed the survey. Marital status and health insurance status were similar in the two groups. 30% of Latinas and 73.3% of non-Latinas reported completing college (p<0.0001). Only 55.7% of Latinas were employed, compared to 82.2% of non-Latinas (p<0.0001). 21% of Latinas and 53.4% of non-Latinas reported an annual income greater than 35,000 dollars (p<0.0001). Among Latinas, women with 1-5 lifetime Pap smears were less likely to have completed college than those with more than 5 lifetime Pap smears (OR=2.11; 95% CI 1.05-4.22) and to have an annual income of less than 35,000 dollars (OR=3.81; 95% CI 1.64-8.87). Latinas were less likely to have > or =6 lifetime sexual partners, use tobacco, and have a history of sexually transmitted infections. Latinas more commonly reported fear of test results (OR, 0.04; 95% CI 0.02-0.09) and inability to communicate with their provider in Spanish (p<0.0001) as barriers to screening than the non-Latina respondents. CONCLUSIONS: Several of the barriers limiting access to cervical cancer screening programs are also present among screened Latinas undergoing further evaluation for abnormal Pap smears.

Constraints on HIV-1 evolution and immunodominance revealed in monozygotic adult twins infected with the same virus.

The predictability of virus-host interactions and disease progression in rapidly evolving human viral infections has been difficult to assess because of host and genetic viral diversity. Here we examined adaptive HIV-specific cellular and humoral immune responses and viral evolution in adult monozygotic twins simultaneously infected with the same virus. CD4 T cell counts and viral loads followed similar trajectories over three years of follow up. The initial CD8 T cell response targeted 17 epitopes, 15 of which were identical in each twin, including two immunodominant responses. By 36 months after infection, 14 of 15 initial responses were still detectable in both, whereas all new responses were subdominant and remained so. Of four responses that declined in both twins, three demonstrated mutations at the same residue. In addition, the evolving antibody responses cross-neutralized the other twin's virus, with similar changes in the pattern of evolution in the envelope gene. These results reveal considerable concordance of adaptive cellular and humoral immune responses and HIV evolution in the same genetic environment, suggesting constraints on mutational pathways to HIV immune escape.

Impact of intrapeptide epitope location on CD8 T cell recognition: implications for design of overlapping peptide panels.

BACKGROUND: Antigen-specific CD8 T cells following infection or immunization are typically assessed by measuring interferon-gamma production after stimulation with overlapping peptides spanning the region of interest. The effect of epitope location within such peptides is not known but may influence recognition. OBJECTIVE: To examine if peptides containing the appropriate C-terminal anchor amino acid residue would provide more sensitive detection of T cell responses. The impact was examined of epitope location within overlapping peptides on recognition of epitope-specific CD8 T cell responses. METHODS: C-terminal amino acid residues were analyzed in well-defined optimal epitopes for HIV, Epstein-Barr virus, cytomegalovirus and influenza and in peptide-binding motifs. Recognition of known epitopes within longer synthesized peptides by peripheral blood mononuclear cells or CD8 T cell lines was tested using interferon-gamma Elispot at various peptide concentrations. RESULTS: Only 9 of 20 amino acids served as the C-terminal anchor position in 96% of described optimal epitopes and in 95% of peptide-binding motifs. A CD8 T cell response to an epitope within a longer peptide is best detected when the epitope is situated at the C-terminal end of the longer peptide, both when using peptides designed to include the optimal epitope at every possible position and when comparing responses towards optimal epitopes and corresponding overlapping peptides in a larger group of subjects. CONCLUSION: When using overlapping peptides to screen for CD8 T cell responses, more sensitive detection will be achieved using known C-terminal anchor amino acid residues at the C-terminus.

Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection.

Mutations within cytotoxic T lymphocyte (CTL) epitopes impair T cell recognition, but escape mutations arising in flanking regions that alter antigen processing have not been defined in natural human infections. In human histocompatibility leukocyte antigen (HLA)-B57+ HIV-infected persons, immune selection pressure leads to a mutation from alanine to proline at Gag residue 146 immediately preceding the NH2 terminus of a dominant HLA-B57-restricted epitope, ISPRTLNAW. Although N-extended wild-type or mutant peptides remained well-recognized, mutant virus-infected CD4 T cells failed to be recognized by the same CTL clones. The A146P mutation prevented NH2-terminal trimming of the optimal epitope by the endoplasmic reticulum aminopeptidase I. These results demonstrate that allele-associated sequence variation within the flanking region of CTL epitopes can alter antigen processing. Identifying such mutations is of major relevance in the construction of vaccine sequences.