Different Immunological Phenotypes Associated with Preserved CD4+ T Cell Counts in HIV-Infected Controllers and Viremic Long Term Non-Progressors

BACKGROUND: HIV-infected controllers control viral replication and maintain normal CD4+ T cell counts. Long Term Non-Progressors (LTNP) also maintain normal CD4+ T cell counts, but have on-going viral replication. We hypothesized that different immunological mechanisms are responsible for preserved CD4+ T cell counts in controllers and LTNP. METHODS: 25 HIV-infected controllers and 14 LTNP were included in this cross-sectional study. For comparison, 25 progressors and 34 healthy controls were included. Production and destruction of T cells were addressed by determination of T cell receptor excision circles (TREC), recent thymic emigrants, naïve cells, immune activation, senescence and apoptosis. Furthermore, telomere length was determined, and the amount of lymphoid tissue in tonsil biopsies was quantified. RESULTS: Controllers presented with partly preserved thymic output, preserved expression of the IL-7 receptor and IL-7 receptor density, and lower levels of destruction of cells than progressors resembling HIV-negative healthy controls. In contrast, LTNP appeared much like progressors, and different from controllers in immune activation, senescence, and apoptosis. Interestingly, CD8+ RTE, TREC and telomere length were partly preserved. Finally, both controllers and LTNP displayed decreased amounts of lymphoid tissue compared to healthy controls. CONCLUSIONS: Controllers presented with an immunological profile different from LTNP. While controllers resembled healthy controls, LTNP were similar to progressors, suggesting different immunological mechanisms to be responsible for preserved CD4+ T cell counts in LTNP and controllers. However, both controllers and LTNP presented with reduced amounts of lymphoid tissue despite preserved CD4+ T cell counts, indicating HIV to cause damage even in non-progressors

Data on production and destruction of CD4+ and CD8+ T cells.

<p>Data are given as median and (interquartile ranges) in percentages (%) of CD4+ or CD8+ T cells, respectively. LTNP: long term non-progressors, PR: progressors, HIV−: healthy controls, MFI: Mean Flouroscence Intensinty.</p

Activated, senescent and apoptotic T cells.

<p>Fig. 4A and 4B shows activated and apoptotic CD4+ T cells, respectively, while Fig. 4C,D and E shows activated, senescent and apoptotic CD8+ T cells, respectively, in healthy controls (HIV−, n = 34), controllers (n = 25), long-term non-progressors (n = 14) and progressors (n = 25). Values are presented as percentages (%) of CD4 and CD8+ T cells, respectively. In all cell populations HIV-infected patients displayed elevated percentages compared to healthy controls. Furthermore, in all cell populations controllers resembled healthy controls, while LTNP resembled progressors. *indicates p values <0.05, **indicates p values <0.001, ***indicates p values <0.0001, ns indicates not significant.</p

Clinical characteristics of the full study population and of those having a tonsil biopsy made.

<p>Data are given as median and (interquartile) ranges. HIV− = healthy controls, LTNP = Long Term Non Progressors.</p

Associations between HIVRNA and parameters examined in Long term Non-Progressros (LTNP), controllers and progressors.

<p>Cell populations are given as percentages of CD4+ or CD8+ T cells, respectively. Only significant results are given. Ns indicates not significant.</p

Data on lymphoid tissue in tonsil biopsies.

<p>In 8 healthy controls (HIV-), 8 progressors, 9 controllers and 5 long term non-progressors (LTNP) tonsil biopsies were performed. In both controllers and LTNP more patients appeared to have a disrupted lymphoid architecture with reduced amounts of lymphoid tissue compared to healthy controls (p = 0.0263 and p = 0.0570, respectively), while progressors were comparable to healthy controls. Fig. 2A shows the lymphoid score. Each box represents one biopsy. Histological characteristics of the lymphoid tissue were scored as stage I (no lymphocyte depletion with prominent germinal centres, green), stage II (partial lymphocyte depletion with >10% lymphocytes, with or without small follicles, no germinal centres, yellow) or stage III (lymphocyte depletion with <10% lymphocytes, no germinal centres or follicles, red). Fig. 2B, 2C and 2D show representative pictures of stage I, II and III, respectively.</p

T cell receptor excision circles (TREC) and telomere length.

<p>Fig. 3A shows median (interquartile range) TREC content in DNA in healthy controls (HIV−, n = 18), controllers (n = 9), long term non-progressors (LTNP, n = 14) and progressors (n = 19) were 0.0011 (0.0004–0.0023), 0.001 (0.0004–0.0022) 0.0009 (0.0004−0.0014) and 0.0005 (0.0003−0.0009), respectively. Fig. 3B shows median (interquartile range) telomere length in healthy controls (n = 12), controllers (n = 9), LTNP (n = 11) and progressors (n = 12) were 1.09 (0.40−1.32), 0.39 (0.03−1.36), 0.55 (0.24−0.66) and 0.36 (0.15−0.89), respectively. Values are given relative to healthy controls. Both TREC and telomere length were partly preserved in controllers and LTNP compared to healthy controls (all p values >0.05), while progressors displayed both reduced TREC content and telomere length (p = 0.046 and p = 0.035, respectively). *indicates p values <0.05, ns indicates not significant.</p