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

Abstract

Background CD4 counts guide antiretroviral therapy (ART) initiation and prophylaxis for opportunistic infections. It is unclear whether normal CD4 counts translate to normalized immune responses among ART-treated adults. We compared antigen-specific CD4 T-cell immune responses among ART-treated adults with CD4 ≥ 500 cells/μl, optimal immune responders (O-IR), and their age-matched healthy HIV-negative counterparts. Methods In a sample-based case–control study, cryopreserved peripheral blood mononuclear cells from 15 O-IR after 7 years of ART and 15 healthy controls, were analyzed for CD4+ T-cell proliferation using CFSE dye and cytokine production. Results CD4 T-cell proliferation, upon stimulation with PPD and pneumococcal polysaccharide antigen, was lower among O-IR relative to HIV-negative controls; p = 0.016 and p = 0.016 respectively. CD4 T-cell production of IL-2 was lower among O-IR relative to HIV-negative control p = 0.002. CD4 T-cell proliferation upon stimulation with SEB and CMV antigens was similar among O-IR and HIV-negative controls p = 0.971 and p = 0.480, respectively, and so was IL-4 and IFN γ production; p = 0.528 and p = 0.892, respectively. Conclusion Seven years of suppressive ART caused partial CD4 T-cell function recovery in an African HIV treatment cohort, despite restoration of CD4 T-cell counts to levels ≥ 500 cells/μl. The role innate immunity in the recovery of immune function during long-term ART should be investigated to guide decisions on continued prophylaxis against opportunistic infections.

Aberrant natural killer (NK) cell activation and dysfunction among ART-treated HIV-infected adults in an African cohort

“…Of the 30 healthy HIV-uninfected individuals, 63% (19/30) were female, their median age was 36 IQR (33–42) years, median Body Mass Index (BMI) 25.95(22, 30), 8% were hypertensive and 4% were diabetic. All participants had no fevers at the time of enrolment in the study [ 18 ].…”

“…HIV RNA viral loads, complete blood counts and CD4 lymphocyte counts were measured 6 monthly [ 21 ]. Optimal responders, consecutively enrolled into this immune recovery study, were individuals in the highest quartile of CD4 increase (a quartile with mean CD4 increase of 823 cells/μl) who did not have any opportunistic infection in the six months preceding immune recovery study [ 18 ]. These were compared with 30 age-matched HIV-uninfected adults within the communities served by Mulago National referral hospital routine HIV testing program.…”

“…We hypothesized that innate immune dysfunction, for example, NK cell dysfunction may not recover fully during ART, thereby affecting recovery of adaptive T-cell responses. Incomplete recovery of NK cell repertoire could contribute to the persistent T-cell function abnormalities previously described in our cohort of ART-treated adults, even when CD4 counts were restored to levels above 500 cells/μl [ 18 ]. With emerging evidence that NK cell function is key to protection against progression from latent Mtb infections to active tuberculosis, understanding recovery of NK cell function during ART is essential to the control of Mtb infection among ART-treated HIV-infected adults in sub-Saharan Africa where Tb remains a leading opportunistic infection and a leading cause of death [ 19 , 20 ].…”

Effects of HIV infection and ART on phenotype and function of circulating monocytes, natural killer, and innate lymphoid cells

“…Figure 1 summarises the effects of HIV infection and ART on monocytes, NK cells, ILCs, and other innate cells. Persistent inflammation and activation of monocytes, NK cells, and ILCs is likely associated with the persistent T-cell activation and impaired effector functions observed among ART-treated adults [ 20 – 22 ]. There is likely a unique phenomenon of innate immune cell recovery during ART, among residents in sub-Saharan Africa (SSA) where several endemic infections activate the immune systems.…”

Cell-Mediated Immunity to the Pneumococcus

“…Incidence rates of pneumococcal infection are much higher in individuals with HIV infection [12]. There is evidence that although B cell recovery takes longer than normalization of circulating T and B cell numbers [13], aspects of CD4 1 and CD8 1 T cell function fail to normalize even after prolonged treatment [14,15]. The consequent immunodysregulation-again-has profound consequences for both T and B cell immunity.…”