Recurrent Viremia in Persons with Evidence of Spontaneous Control of HCV

<p>Serial HCV VL determinations were performed in persons demonstrating spontaneous control of HCV. Data were censored at the last available time point. Six of 25 participants experienced recurrent HCV viremia in the HIV+ group, while 0 of 16 HIV− participants experienced recurrence. The median time of follow-up did not differ between groups.</p

Relationship of CD4⁺ T cell Proliferation against HCV Antigens to CD8⁺ IFN-γ Responses

<p>Total CD8⁺ IFN-γ response was determined via a comprehensive ELISpot assay against the entire HCV-expressed polyprotein. In HIV+ participants who control HCV spontaneously, the magnitude of IFN-γ responses mediated by CD8⁺ T cells is significantly higher in participants with LP responses against HCV (<i>p</i> = 0.0014, Wilcoxon rank-sum test).</p

HCV Viremia Is Associated with Decreased Lymphoproliferation against HCV Antigens But Not against HIV or CMV

<div><p>(A) The cumulative SI against HCV antigens core, NS3, NS4, and NS5. Four of 60 coinfected participants and three of 34 monoinfected participants could not be tested due to lack of fresh PBMCs, thus 87 of 94 of the total cohort were tested.</p> <p>(B) Responses against HIV-1 p24 antigen. Of 60 coinfected participants, 53 were tested.</p> <p>(C) Responses against CMV in coinfected participants, including the 42 participants confirmed as seropositive for CMV.</p></div

HCV-Specific T Cell Responses before and after HCV Recurrence in HIV+ Participants with Prior Spontaneous Control

<div><p>(A) LP responses before and after HCV recurrence. Responses to c33c (NS3) and NS5 declined after the establishment of viremia. By contrast, stimulation indices to HIV-1 p24 antigen and phytohemagglutinin (positive control) increased.</p> <p>(B–E) The degree of viremia is shown in shaded gray for four participants. IFN-γ measurements are in spot-forming cell (SFC)/10⁶ PBMCs. The cumulative HCV CD8⁺ T cell response is represented by the solid red lines. In three participants who demonstrated decline in HCV-specific CD8⁺ T cell responses, Epstein–Barr virus (EBV) response to the lytic A2 epitope (GLCTLVAML) is shown by the blue dashed lines.</p></div

LP Responses to HCV Antigens Are Associated with Spontaneous Control of Viremia Regardless of HIV Status

<p>Stimulation indices to HCV proteins are plotted per subgroup. The two plots on the left represent responses in HIV− persons; the two on the right in HIV+. Cutoff of significance for lymphoproliferation was an SI of 5, shown by horizontal dotted line. Median values are also shown.</p

Rate of Detection of LP Responses against HCV Antigens by Subgroup, Stratified by HIV Status and HCV Viremia

<p><i>p</i>-Values represent comparison of proportions per Fisher's exact test. HIV− persons with spontaneous control of viremia had the highest rate of detection (86%). By comparison, HIV+ persons with spontaneous control of viremia exhibited a 35% rate of LP responses. Both groups of controllers demonstrated significantly higher rates of detection than did their viremic counterparts. Fresh cells were not available for analysis of four of 30 HIV-1/HCV controllers.</p

LP Responses in HIV+ Participants Who Spontaneously Control HCV

<p>No participant with a history of CD4⁺ T cell depletion (nadir CD4 < 300 cell/μl) displayed LP response to HCV antigens (A), contrasting with responses to CMV in which responses were detected in individuals with a history of significant CD4⁺ T cell depletion (B). Those marked with * are CMV−, and values are therefore not shown</p

Different HLA Class I Alleles Differ in Their Contribution to the Total HIV-1-Specific CD8⁺ T Cell Response

<p>The percentage contribution of HIV-1-specific CD8⁺ T cell responses restricted by each individual HLA class I allele to the total HIV-1-specific CD8⁺ T cell response in individuals expressing the respective allele is shown. HLA class I alleles are listed according to their contribution from left to right. HLA-B57 and HLA-B27 contributed 66% and 65.4%, respectively, to the total HIV-1-specific CD8⁺ T cell response in individuals expressing these alleles.</p

Figure 1

<div><p>Immunodominance Patterns for HIV-1-Specific CD8⁺ T Cell Responses Restricted by Individual HLA Class I Alleles</p> <p>Peptides corresponding to described optimal HIV-1-specific CD8⁺ T cell epitopes were tested in all study participants expressing the respective HLA class I allele. The average magnitude of CD8⁺ T cell responses specific for each tested peptide, given as SFCs per million input PBMCs (SFC/Mill PBMC), are shown as bars in the left part of each graph. The percentage of participants expressing the respective allele that had a detectable peptide-specific CD8⁺ T cell response are shown as bars on the right part of each graph. Epitopes are aligned for each HLA class I allele according to their frequency of recognition from top to bottom. The peptide number corresponds to the peptide sequence listed for each HLA allele and number in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030403#pmed-0030403-t002" target="_blank">Table 2</a>. Data are shown only for HLA class I alleles that were expressed in at least three individuals, and for which at least three HIV-1-specific optimal CD8⁺ T cell epitopes had been defined.</p></div

Immunodomination of HLA-B57- and HLA-B27-Restricted HIV-1-Specific CD8⁺ T Cell Responses

<p>The percent contribution (left graphs) and the absolute magnitude (right graphs, given as SFCs per million input PBMCs [SFC/Mill PBMC]) of HLA-A1-, -A2-, -A3-, and -A24-restricted HIV-1-specific CD8⁺ T cell responses in individuals expressing these HLA class I alleles alone, or in conjunction with HLA-B57 or HLA-B27, are shown. Each dot represents data for one individual. The contribution, as well as the absolute magnitude, of HIV-1-specific CD8⁺ T cell responses directed against HLA-A1-, -A2-, and -A24-restricted CD8⁺ T cell epitopes was significantly lower in participants that also coexpressed HLA-B57 or HLA-B27. The same trend was observed for HLA-A3, but did not reach statistical significance. HLA-A1-, -A2-, -A3-, and -A24-restricted HIV-1-specific CD8⁺ T cell response did not differ between individuals expressing other frequent HLA class B alleles, such as HLA-B7, -B8, -B35, or -B44 (unpublished data).</p