Impaired CD4 T Cell Memory Response to Streptococcus pneumoniae Precedes CD4 T Cell Depletion in HIV-Infected Malawian Adults

Abstract

ObjectiveInvasive pneumococcal disease (IPD) is a leading cause of morbidity and mortality in HIV-infected African adults. CD4 T cell depletion may partially explain this high disease burden but those with relatively preserved T cell numbers are still at increased risk of IPD. This study evaluated the extent of pneumococcal-specific T cell memory dysfunction in asymptomatic HIV infection early on in the evolution of the disease.MethodsPeripheral blood mononuclear cells were isolated from asymptomatic HIV-infected and HIV-uninfected Malawian adults and stained to characterize the underlying degree of CD4 T cell immune activation, senescence and regulation. Pneumococcal-specific T cell proliferation, IFN-γ, IL-17 production and CD154 expression was assessed using flow cytometry and ELISpot.ResultsWe find that in asymptomatic HIV-infected Malawian adults, there is considerable immune disruption with an increase in activated and senescent CD4+CD38+PD-1+ and CD4+CD25highFoxp3+ Treg cells. In the context of high pneumococcal exposure and therefore immune stimulation, show a failure in pneumococcal-specific memory T cell proliferation, skewing of T cell cytokine production with preservation of interleukin-17 but decreased interferon-gamma responses, and failure of activated T cells to express the co-stimulatory molecule CD154.ConclusionAsymptomatic HIV-infected Malawian adults show early signs of pneumococcal- specific immune dysregulation with a shift in the balance of CD4 memory, T helper 17 cells and Treg. Together these data offer a mechanistic understanding of how antigen-specific T cell dysfunction occurs prior to T cell depletion and may explain the early susceptibility to IPD in those with relatively preserved CD4 T cell numbers.

Low antigen-specific CD4 T-cell immune responses despite normal absolute CD4 counts after long-term antiretroviral therapy an African cohort

“…Our findings are consistent with previous reports that despite sustained HIV-RNA viral suppression and restoration of circulating CD4+ T-cell numbers to levels above 450 cells/μl, specific immune responses among ART-treated adults remain dependent upon the pre-ART CD4 counts [15]. Functional defects in pneumococcal-specific T-cell memory and regulation were previously reported during the course of HIV disease [16]. Our study participants initiated ART at advanced stages of HIV disease which makes complete restoration of their immune responses very difficult.…”

“…A major strength was using two complimentary methods for determining antigen-specific CD4 T-cell immune responses to common antigens in this setting [16,26,27]. Many studies have looked at proliferation and discontinuation of prophylaxis without analysis of cytokine production profiles [28,29].…”

Alterations in memory B cell subsets upon immunization against Streptococcus pneumoniae in HIV-1 infected adults

“…Moreover, despite few studies describing higher levels of isotype switched B cells in treated patients compared to naive [27] and differentiate from HIV negative individuals [28], our study confirmed more recent authors [29], underlining the need for further investigation on this specific memory subset.…”

Incomplete Recovery of Pneumococcal CD4 T Cell Immunity after Initiation of Antiretroviral Therapy in HIV-Infected Malawian Adults

“…We have previously shown that in asymptomatic HIV-infected individuals (WHO Stage I), the proportion of naive T cells is comparable to healthy HIV-negative persons but memory cells are proportionally decreased [11]. We now show no change in the proportion of naive CD4 + T cells (CCR7 + CD45RA + )[21], [22] between 0 and 6 months ART-mediated immune reconstitution but that this subset had further increased by 12 months ( Figure 1B , p = 0.0001), to levels even higher to those seen in HIV–uninfected individuals (median 35.73% vs 19.36%, p = 0.0234).…”