Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy

Abstract

Primary HIV-1 infection causes extensive immune activation, during which CD4(+) T cell activation supports massive HIV-1 production. We tested the safety and the immune-modulating effects of combining cyclosporin A (CsA) treatment with highly active antiretroviral therapy (HAART) during primary HIV-1 infection. Nine adults with primary HIV-1 infection were treated with CsA along with HAART. At week 8, all patients discontinued CsA but maintained HAART. Viral replication was suppressed to a comparable extent in the CsA + HAART cohort and in 29 control patients whose primary infection was treated with HAART alone. CsA restored normal CD4(+) T cell levels, both in terms of percentage and absolute numbers. The increase in CD4(+) T cells was apparent within a week and persisted throughout the study period. CsA was not detrimental to virus-specific CD8(+) or CD4(+) T cell responses. At week 48, the proportion of IFN-gamma-secreting CD4(+) and CD4(+)CCR7(-) T cells was significantly higher in the CsA + HAART cohort than in the HAART-alone cohort. In conclusion, rapid shutdown of T cell activation in the early phases of primary HIV-1 infection can have long-term beneficial effects and establish a more favorable immunologic set-point. Appropriate, immune-based therapeutic interventions may represent a valuable complement to HAART for treating HIV infection.

Figures

Figure 1

Mean changes from baseline in plasma HIV-1 RNA levels in patients receiving either HAART only (n = 29) or CsA + HAART (n = 9). CsA was discontinued in all patients at week 8. Data are presented as mean ± SEM. No significant differences between the two treatment cohorts were observed over time. Plasma HIV-1 RNA levels are expressed as log10 copies/ml.

Figure 2

(a) Changes from baseline in CD4+ T cell percentages during the first 28 days of follow-up in patients belonging to the CsA + HAART cohort (n = 9) and to the HAART only cohort (n = 29). Student t test P values of comparisons between the two treatment cohorts were: P = 0.048 at day 7, P = 0.018 at day 14, and P = 0.009 at day 28. (b) Changes from baseline in CD4+ T cell counts (cells/μl) during the first 28 days of follow-up in patients of the two treatment cohorts. Student t test P values of comparisons between the two treatment cohorts were: P = 0.027 at day 7, P = 0.05 at day 14, and P = 0.017 at day 28. Data are presented as mean ± SEM, and a two-tailed P value less than 0.05 was considered significant (a and b). (c) Changes over time in CD4+Ki-67+ T cell percentages during the first 28 days of follow-up in two representative patients belonging to the CsA + HAART cohort. (d) Correlation between baseline plasma HIV-1 RNA levels and changes from baseline in CD4+ T cell counts at week 2 in the nine patients in the CsA + HAART cohort (r = 0.85, P = 0.004). Plasma HIV-1 RNA levels are expressed as log10 copies/ml, and the number of CD4+ T cells is expressed in cells/μl. The regression line is shown. A two-tailed P value less than 0.05 was considered significant.

Figure 3

Mean CD4+ T cell counts over 64 weeks of follow-up in patients belonging to the HAART only cohort (n = 29) and to the CsA plus HAART cohort (n = 9). CsA was discontinued in all patients at week 8. Student t test P values of comparisons between the two treatment cohorts were: P = 0.01 at week 1, P = 0.04 at week 2, P = 0.02 at week 4, P = 0.07 at week 8, P = 0.04 at week 16, P = 0.05 at week 24, P = 0.015 at week 32, P = 0.02 at week 40, P = 0.03 at week 48, and P = 0.007 at week 64. Data are presented as mean ± SEM. A two-tailed P value less than 0.05 was considered significant. The number of CD4+ T cells is expressed in cells/μl.

Figure 4

(a) Analysis of expression of HIV-1– and CMV-specific, CD8+tetramer+ T cells in one representative patient at baseline, and after 1 week and 24 weeks of therapy. Patient 1007 was treated with CsA + HAART, and with HAART only from week 8 onward. PBMCs were stained with anti-CD8 peridinin chlorophyll (PerCP) and with either the HIV-1–specific B7-TPGPGVRYPL tetramer PE (upper panel) or the CMV-specific B7-TPRVTGGGAM tetramer PE (lower panel). The data are expressed as the percentage of cells coexpressing CD8 and the tetrameric HLA molecule within CD3+ T cell populations. (b) Analysis of HIV-1– and CMV-specific CD4+ T cells within different populations of memory cells, defined by the expression of CCR7 in two representative patients after 48 weeks of therapy. Patient 1009 was treated with CsA + HAART, while Control 2 was treated with HAART only. PBMCs were stimulated with HIV-1 p55 gag protein and CMV lysates and analyzed for the expression of CD4, CCR7, CD69, and IFN-γ (intracellular expression). The data show the expression of CD69 and IFN-γ within CD4+CCR7– T cell populations. Negative control: unstimulated PBMCs. Positive controls: PBMCs stimulated with SEB. The cluster of events shown in blue correspond to the responder CD4+ T cells coexpressing CD69 and IFN-γ, while the cluster of events in red correspond to the nonresponder CD4+ T cells. The data are expressed as the percentage of cells coexpressing CD69 and IFN-γ within CD4+CCR7– T cell populations.