Less than 1% of people living with HIV (PLHIV) spontaneously control HIV-1. Characterization of immune drivers eliciting this spontaneous control remain important. Monocytes can undergo long-term functional reprogramming after exposure to certain stimuli such as b-glucan, a process called trained immunity (TI), which confers heterologous protection against multiple pathogens. We hypothesized that spontaneous controllers show enhanced innate immune responsiveness and TI compared with noncontrolling PLHIV. Immune stimulations in the 1st degree relatives of both groups were used as surrogates of the immune reactivity without HIV.
In a double case control design, HIV-1 elite controllers (EC; Nf31) and non-controlling PLHIV on suppressive antiretroviral therapy (ART) (non-EC; Nf30) were recruited, as well as relatives from both groups (Nf23 and Nf22, respectively). Groups were similar in age, sex, BMI and vaccination history. EC were subdivided into non-viremic (N = 17) and viremic (Nf14), based on viral load cutoffs < 75 and < 10,000 copies/mL, respectively. Adherent monocytes were exposed ex vivo to 1 ug/ml b-glucan (trained) or RPMI (control) for 24 hours at 37⁰C. After 24 hours, the cells were washed and left to rest for 5 days, followed by stimulation with 10 ng/mL LPS on day 6. TNF, IL-6 and IL-1RA were measured in supernatant at day 7 by ELISA.
EC relatives had stronger TNF, IL-6 and IL-1RA production capacity of control monocytes after LPS stimulation than non-EC relatives (P = 0.0013, P = 0.013 and P = 0.013, respectively, Fig 1A). Induction of trained immunity was also stronger in EC relatives after b-glucan exposure and LPS stimulation (P = 0.0021, P = 0.078 and P = 0.0056 for TNF, IL-6 and IL-1RA, respectively, Fig 1B). Control monocytes responses of EC and non-EC PLHIV were similar after LPS stimulation (P = 0.54, P = 0.63 and P = 0.063 for TNF, IL-6 and IL-1RA, respectively). However, trained monocytes of EC showed greater induction of TNF, IL-6 and IL-1RA production (P = 0.047, P = 0.0054 and P = 0.043, respectively, Fig 1C). Both trained and control monocytes of non-viremic EC produced more TNF than viremic EC (P = 0.012 and P = 0.012, respectively, Fig 1D).
Elite controllers and their first-degree relatives show both increased innate immune responses and trained innate immunity compared to non-controlling PLHIV on ART and their first-degree relatives. Further studies on the role of trained innate immunity to control HIV-1 are warranted.