HAART in HIV-infected patients: Restoration of antigen-specific CD4 T-cell responses in vitro is correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia

Kantonsspital St. Gallen, San Gallo, Saint Gallen, Switzerland
AIDS (Impact Factor: 5.55). 11/1999; 13(14):1857-62. DOI: 10.1097/00002030-199910010-00007
Source: PubMed


To analyse prospectively the effect of highly active antiretroviral treatment (HAART) on CD4 T-cell responses in vitro and in vivo in HIV-infected patients.
Prospective study with 49 protease inhibitor-naive adult patients. Data were collected at baseline and after 3 and 6 months of HAART.
In vitro CD4 T-cell reactivity was analysed by stimulation of peripheral blood mononuclear cells with several antigens. In vivo CD4 T-cell reactivity (delayed type hypersensitivity) was assessed by Multitest Merieux. Both measurements were correlated to CD4 (memory) T-cell count and HIV-1 viraemia.
Restoration of specific CD4 T-cell proliferation was observed in most patients. The in vitro T-cell response was restored more frequently against antigens to which the immune system is constantly exposed (Candida albicans, Mycobacterium tuberculosis, M. avium) as compared with a low-exposure antigen (tetanus toxoid). Overall, delayed type hypersensitivity detection rate increased under HAART. Multivariate analysis showed improvement of antigen-specific T-cell proliferation to be significantly associated with an increase in memory CD4 T-cells, whereas improvement of the delayed type hypersensitivity response was associated with a decrease in plasma HIV-1 RNA.
HAART for 6 months restored antigen-specific CD4 T-cell response to several antigens. In vitro immune reconstitution was closely correlated with an increase in memory CD4 cells. Restoration of delayed type hypersensitivity was associated with suppression of viraemia. It appears that in addition to expansion of memory CD4 cells, suppression of viraemia following HAART may allow an improved inflammatory reaction, thus providing even stronger immune reconstitution.

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    • "DTH responses have also been studied in patients receiving HAART. In addition to immune reconstitution measured clinically by CD4 cell gains, several studies demonstrated an improvement in DTH responses after initiation of HAART [12–14]. However, despite successful treatment, DTH responsiveness remains impaired for many patients on HAART [12, 15]. "
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    ABSTRACT: Introduction Delayed-type hypersensitivity (DTH) testing is an in vivo assessment of cell-mediated immunity. Although highly active antiretroviral therapy (HAART) improves immunologic parameters, the relationship between DTH responsiveness and CD4 gains on HAART is not completely understood. We investigated CD4 reconstitution and the change in DTH responses from treatment baseline through 24 months of viral load (VL)-suppressive HAART in the U.S. Military HIV Natural History Study. Methods Treatment-naïve subjects with VL <400 copies/mL after ≥24 months on HAART were included (n=302). DTH testing consisted of ≥3 recall antigens, and responses were classified by the number of positive skin tests: anergic (0–1) or non-anergic (≥2). Pre-HAART DTH results were compared for the outcome of CD4 reconstitution at 24 months of HAART. Improvement in DTH responses was also analyzed for those anergic before HAART initiation. Results Non-anergic responses were observed in 216 (72%) participants, while 86 (28%) individuals were anergic prior to HAART initiation. Demographically there were similar distributions of age at HIV diagnosis and HAART initiation, as well as gender and race or ethnicity. There were no significant differences between non-anergic and anergic participants in pre-HAART CD4 count (409 cells/μL, interquartile range (IQR) 315–517 vs. 373 cells/μL, IQR 228–487; p=0.104) and VL (4.3 log10 copies/mL, IQR 3.4–4.9 vs. 4.4 log10 copies/mL, IQR 3.6–5.0; p=0.292). Median CD4 gains 24 months after HAART initiation were similar between the non-anergic (220 cells/μL, IQR 115–358) and anergic groups (246 cells/μL, IQR 136–358; p=0.498). For individuals anergic before HAART initiation, DTH normalization occurred at 24 months post-HAART in the majority of participants (51 of 86, 59%). Normalization of DTH responses was not associated with CD4 count at HAART initiation (OR 0.73, 95% CI 0.47, 1.09 per 100 cells; p=0.129) nor with AIDS diagnoses prior to HAART (OR 0.34, 95% CI 0.04, 2.51; p=0.283). Conclusions DTH responsiveness has been shown to predict HIV disease progression independent of CD4 count in untreated individuals. In the setting of HAART, pre-HAART anergy does not appear to impact CD4 gains or the ability to normalize DTH responses after 24 months of VL-suppressive HAART.
    Journal of the International AIDS Society 02/2014; 17(1):18799. DOI:10.7448/IAS.17.1.18799 · 5.09 Impact Factor
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    • "In addition to reconstitution of CD4 cells, HAART impacts the immune system in other ways including the improvement of serologic response to vaccinations [10], reducing immune activation [11], and enhancing DTH responses [3,12]. In one study, suppression of plasma viremia was necessary for improved DTH responsiveness on HAART [13]. For HAART-naïve individuals, lower steady-state VL has also been associated with greater DTH responsiveness [5]. "
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    ABSTRACT: Delayed-type hypersensitivity (DTH) testing, an in vivo assessment of cell-mediated immunity, is a predictor of HIV disease progression beyond CD4 cell count. We investigated whether preserved DTH responsiveness was characteristic of HIV controllers compared to non-controllers and individuals on suppressive HAART. DTH testing consisted of ≥ 3 recall antigens applied approximately every 6 months. DTH responses were classified by the number of positive skin tests: anergic (0), partial anergic (1), or non-anergic (≥ 2). HIV controllers were compared to treatment naïve non-controllers (n = 3822) and a subgroup of non-controllers with VL < 400 copies/mL on their initial HAART regimen (n = 491). The proportion of non-anergic results at first DTH testing was similar for HIV controllers compared to non-controllers (81.9% vs. 77.6%; P = 0.22), but tended to be greater in HIV controllers compared to the HAART subgroup (81.9% vs. 74.5%; P = 0.07). Complete anergy was observed in 14 (10.1%) HIV controllers with CD4 counts ≥ 400 cells/uL. For longitudinal testing, the average percentage of non-anergic DTH determinations per participant was higher in HIV controllers compared to non-controllers (81.2 ± 31.9% vs. 70.7 ± 36.8%; P = 0.0002), however this difference was eliminated with stratification by CD4 count: 200-399 (83.4 ± 35.6% vs. 71.9 ± 40.9%; P = 0.15) and > 400 cells/uL (81.2 ± 31.5% vs. 80.4 ± 32.7%; P = 0.76). Spontaneous virologic control was not associated with DTH responsiveness, and several HIV controllers were anergic despite having elevated CD4 counts. These findings suggest that cellular immunity assessed by DTH is not a principal factor contributing to spontaneous virologic suppression in HIV controllers.
    AIDS Research and Therapy 04/2012; 9:10. DOI:10.1186/1742-6405-9-10 · 1.46 Impact Factor
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    • "Following ART, a quantitative increase in peripheral T cells occurs which partially restores activity to recall antigens as a result of suppression of HIV viral replication in lymphoid tissue and reductions in immune activation [8,9]. Furthermore, restoration of in vitro responses to common infectious antigens and improvement in delayed type hypersensitivity has been significantly associated with increases in memory CD4 T cells following ART [10]. "
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    ABSTRACT: To immunophenotype CD4+ and CD8+ T cell sub-populations in HIV-associated immune reconstitution inflammatory syndrome (IRIS). Nested case-control immunological study. ART-naïve HIV-infected patients were prospectively observed for IRIS during the first 6 months of ART. Twenty-two IRIS cases and 22 ART-duration matched controls were sampled for T cell immunophenotyping. IRIS cases demonstrated significantly lower CD4 cell counts compared to controls (baseline: 79 versus 142, p = 0.02; enrollment: 183 versus 263, p = 0.05, respectively) with no differences in HIV RNA levels. Within CD4+T cells, cases exhibited more of an effector memory phenotype compared to controls (40.8 versus 27.0%, p = 0.20), while controls trended towards a central memory phenotype (43.8 versus 30.8%, p = 0.07). Within CD8+ T cells, controls exhibited more central memory (13.9 versus 7.81%, p = 0.01, respectively) and effector (13.2 versus 8.8%, p = 0.04, respectively) phenotypes compared to cases, whereas cases demonstrated more terminal effectors than controls (28.8 versus 15.1%, p = 0.05). Cases demonstrated increased activation of CD8+ T cell effector memory, terminal effector, and effector subsets than controls (p = 0.04, 0.02, and 0.02, respectively). CD4+ and CD8+ T cell subset maturational phenotypes were heterogeneous among IRIS cases and controls. However, IRIS cases demonstrated significant increases in activation of CD8+ T cell effector subpopulations.
    AIDS Research and Therapy 08/2009; 6(1):16. DOI:10.1186/1742-6405-6-16 · 1.46 Impact Factor
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