Relationship between HIV-specific Immune Response, T Cell Activation, and CD4+ T Cell Depletion in HIV-infected Patients with Undetectable Plasma HIV RNA Levels in the Absence of Therapy
Peter Hunt*1, E Sinclair1, H Hatano1, J McCune1, B Emu1, Q Tan1, P Norris2, M Busch2, J Martin1, and S Deeks1
1Univ of California, San Francisco, US and 2Blood Systems Res Inst, San Francisco, CA, US
Background: While most HIV-infected elite
controllers with undetectable viremia (<75 copies/mL) in the absence of
therapy have strong immune responses to HIV, likely contributing to the control
of viral replication, it is unclear whether these responses may also result in
generalized T cell activation, contributing to CD4+ T cell depletion.
Methods: We sampled 58 elite controllers, 66 untreated non-controllers
(>10,000 copies HIV RNA/mL plasma), and 127 HIV+ patients with
undetectable viremia on HAART from a clinic-based cohort (SCOPE), and 38 exposed
but HIV– individuals, and assessed relationships between measures of
adaptive HIV-specific immune responses, the percentage of activated (CD38+HLA-DR+)
T cells, and CD4+ T cell count.
Results: Elite controllers had a higher median percentage of
Gag-specific interferon (IFN)+ interleukin (IL) -2+ CD4+
T cells than non-controllers (p <0.001), HAART-suppressed (p <0.001),
and HIV– (p <0.001). Elite controllers also had the
highest percentage of Gag-specific IFN+IL-2+ CD8+
T cells of all the groups (p <0.001). Compared to HIV–, elite
controllers had an abnormally high median percentage of activated CD4+
T cells (3.7% vs 1.6%, p <0.001) and CD8+ T cells (15% vs
4%, p <0.001). Elite controllers also had a higher percentage of
activated CD8+ T cells than the HAART-suppressed (15% vs 9%, p =0.001).
Among elite controllers, higher Gag-specific CD4+ T cell responses
were associated with higher HIV-specific antibody levels (ρ 0.56, p =
0.004), but also higher CD4+ T cell activation (ρ 0.34, p =
0.01) and CD8+ T cell activation levels (ρ 0.51, p <0.001).
While the median CD4+ T cell count in elite controllers was 683
cells/mm3, 9 (16%) had CD4+ T cell counts <350
cells/mm3 and 4 (7%) had AIDS. Among elite controllers, higher CD4+
and CD8+ T cell activation was strongly associated with lower CD4+
T cell counts (ρ –0.59, p <0.001 and –0.44, p <0.001,
respectively). The extent of low-level viremia below 75 copies/mL—as estimated with
ultra-sensitive methods (TMA)—was not associated with HIV-specific T cell
responses, T cell activation, or CD4 cell counts (p >0.2 for all
Conclusions: Vigorous HIV-specific immune responses observed in most
elite controllers, while likely contributing to the control of virus
replication, are associated with abnormally high generalized T cell activation
levels, potentially contributing to CD4+ T cell depletion even in
the absence of readily detectable viremia.