Evolution of Viral Load and CD4+ T Cell Counts during STI

<div><p>(A) Survival curves of time to virologic failure during the first three supervised treatment interruptions. Virologic failure was defined as having a viral load of greater than 5,000 copies RNA/ml plasma for 3 wk or greater than 50,000 copies once. Patients still achieving viral control at the last visit and individuals restarting therapy without meeting criteria or lost in follow-up are censored at the last evaluable time point. The horizontal axis represents the time off therapy since the beginning of the treatment interruption, the vertical axis corresponds to the number of patients maintaining control of viremia. The curves for first, second, and third STIs do not differ significantly from each other (log-rank test, <i>p ></i> 0.05).</p> <p>(B) Evolution of CD4+ T cell counts during the longest treatment interruption. Slopes of CD4+ T cell counts during the first year of the longest treatment interruption are shown for patients who experienced a cessation of therapy of at least 12 mo (all except AC13, AC25, and AC45), compared to the natural decline of CD4+ T cell counts in untreated patients of the MACS cohort with early chronic HIV-1 infection (CD4+ counts of >350 cells/mm³). CD4+ T cell losses were calculated on a regression line based on least squares fit. The two groups differed significantly from each other (Mann-Whitney <i>U</i> test, <i>p =</i> 0.02).</p> <p>(C) CD4+ T cell count at intercept and CD4+ T cell slopes during the longest treatment interruption. The CD4+ T cell slopes of the same 11 patients shown in (B) and of untreated patients of the MACS cohort are represented according to the CD4+ T cell count at the intercept of the regression line based on least squares fit with the vertical axis (day 0 of treatment interruption).</p></div

HIV-1 Viral Loads and CD4+ T Cell Counts in the 14 Study Participants

<p>Time zero corresponds to first institution of highly active antiretroviral therapy (HAART). Closed squares, HIV-1 plasma viral loads; open circles, CD4+ T cell counts; shaded areas, treatment with HAART according to protocol; diagonally shaded areas, patient restarted therapy without meeting criteria of virological failure; vertical dotted lines, virological failure without reinstitution of HAART. Patients are ordered by increasing number of supervised treatment interruptions.</p

Evolution of HIV-1-Specific CD4+ and CD8+ T Cell Responses during STI

<div><p>(A–D) Magnitude and breadth of increase of HIV-specific CD8+ T cells during supervised treatment interruptions.</p> <p>(A and B) Magnitude (A) and breadth (B) of HIV-specific CD8+ responses at the first day of treatment interruption (black bars) and at the last day off therapy (white bars). Data represent the mean and standard deviation.</p> <p>(C and D) Correlation between the increase of the magnitude (C) or breadth (D) of CD8+ T cell responses and the time off therapy during the first treatment interruption.</p> <p>(E and F) Evolution of CD4+ T helper cell responses during supervised treatment interruptions.</p> <p>(E) Magnitude of CD4 T helper cell responses at baseline and at the first day of treatment interruption (closed circles) and last day off therapy (open circles). Horizontal bars correspond to median values. An stimulation index greater than five was considered significant.</p> <p>(F) Correlation between the magnitude of p24-specific lymphocyte proliferative responses at the beginning of the first treatment interruption and the time patients were able to remain off therapy during the subsequent STI.</p></div

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

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

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

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

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 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

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