Research Article: Spontaneous virologic suppression in HIV controllers is independent of delayed-type hypersensitivity test responsiveness

Date Published: April 2, 2012

Publisher: BioMed Central

Author(s): Jason F Okulicz, Greg A Grandits, Matthew J Dolan, Vincent C Marconi, Glenn Wortmann, Michael L Landrum.


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.

Partial Text

Delayed-type hypersensitivity (DTH) testing can be used as an in vivo assessment of cell-mediated immunity (CMI). Compared to HIV-seronegative individuals, patients with HIV typically have less favorable DTH responses, particularly in the setting of low CD4 cell counts where anergy is common [1,2]. Among HIV-infected persons on highly active antiretroviral therapy (HAART), DTH responsiveness has been shown to be both a predictor of treatment outcomes and a marker for improved CMI [3-5].

The NHS is a prospective observational cohort of over 5300 military members, dependents, and beneficiaries with HIV-1 infection followed in the military healthcare system since 1986 [8]. Participants providing informed consent in this IRB-approved study are evaluated approximately every 6 months at selected US military treatment facilities.

DTH testing was performed in 33 elite and 116 viremic controllers (Table 1). There were 3822 non-controllers for comparison, of which 491 also met criteria for the HAART suppressor subgroup. Both HIV controllers and non-controllers were predominantly male and approximately 29 years at HIV-1 diagnosis, but HIV controllers had a higher proportion of African Americans (P < 0.01). HIV controllers had both a later calendar year of diagnosis (1995 ± 6 years) and first DTH test (1997 ± 5) compared to non-controllers (1991 ± 5 and 1992 ± 5, respectively; P < 0.01 for both). HIV controllers had a lower log10 VL at diagnosis (3.0 ± 0.8) compared to non-controllers (4.3 ± 0.8; P < 0.01) and the HAART suppressor subgroup (4.4 ± 0.8; P < 0.01). Mean CD4 counts were also higher at HIV-1 diagnosis for HIV controllers (723 ± 234 cells/uL) compared to non-controllers (539 ± 275 cells/uL; P < 0.01) and the HAART suppressor subgroup (505 ± 243 cells/uL; P < 0.01). The number of DTH testing episodes for HIV controllers and non-controllers was similar (5.5 ± 4.8 vs. 5.5 ± 4.7; P = 0.84). HIV controllers, though defined by virologic criteria, are typically associated with elevated CD4 cell counts and improved clinical outcomes [6,7]. We determined that spontaneous virologic suppression in HIV controllers was independent of DTH responsiveness since nearly one-fifth of HIV controllers displayed partial or complete anergy at first DTH testing despite higher CD4 counts, and a similar proportion of non-anergic results were observed between HIV controllers and non-controllers when stratified by CD4 count. The authors declare that they have no competing interests. All authors participated in the design of the study and manuscript preparation. GAG performed the statistical analysis. All authors read and approved the final manuscript.   Source:


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