Innate Activation of MDC and NK Cells in High-Risk HIV-1–Exposed Seronegative IV-Drug Users Who Share Needles When Compared With Low-Risk Nonsharing IV-Drug User Controls

Abstract

Background Previous studies have described increased innate immune activation in HIV-1 exposed, sero-negative intra-venous drug users (HESN-IDU), but have not addressed the independent role of injected drugs and/or repeated injections in driving immune activation. Methods Here, we investigated innate (NK cells and dendritic cells) and adaptive (HIV-specific antibody and CD8+ T cell) immune parameters among a high-risk cohort of needle-sharing HESN-IDU subjects and compared them to low-risk non-sharing IDU subjects (NS-IDU) and non drug-user controls. Results We observed that HIV-specific antibody and CD8+ T cell responses were not detected in HESN-IDU subjects, yet innate immune cell activation was found to be significantly increased on NK cells (CD69 and CD107a upregulation) and MDCs (CD40 and CD83 upregulation) when compared to NS-IDU subjects or non drug-user controls (p<0.01, and p<0.05, respectively). HESN-IDU subjects maintained strong NK cell CD107a degranulation and cytokine (IFN-gamma, TNF-alpha and MIP-1 beta) production following target cell-incubation suggesting that constitutive innate activation does not induce functional exhaustion of innate cells in HESN-IDU subjects. NK activation in HESN-IDU subjects was independent of drug use patterns but was durable over time and correlated with plasma levels of IP-10 by Luminex analysis (rho=0.5073, p=0.0059, n=28). Conclusions Our results indicate that heightened innate immune cell activation in HESN-IDU subjects is not the result of the IV-drugs and repeated injection practice itself, but to repeated exposure to factors intrinsic to sharing needles (i.e., exposure to pathogens or heterologous cells among donor blood).

Brief Report: The Relationship Between Injection Drug Use Risk Behaviors and Markers of Immune Activation

“…Sharing of injection equipment (needles and paraphernalia) was not significantly related to the immune activation markers studied. While this differs from the results reported by Tomescu et al 3 this discrepancy may be attributed to the many differences between the studies. For example, Tomescu looked at NK cells, while our analysis used T cells; our analysis controlled for HCV viremia; and there were differences in the characteristics of the participants recruited (e.g., frequency of injection was lower in the Tomescu study- about once per day compared with an average of over 5 times per day in our sample).…”

“…3,4 Increasing our understanding of the factors contributing to this heightened immune activation, which has been associated with progression of chronic disease and disability, 5,6 can lead to better health outcomes for PWID.…”

“…1 Adding further to the mixed results regarding the influence of injection behaviors on immune activation, a recent study conducted with HIV seronegative PWID reported heightened immune activation related to needle sharing. 3 …”

Further Evidence that Human Endogenous Retrovirus K102 is a Replication Competent Foamy Virus that may Antagonize HIV-1 Replication

“…Moreover, that a state of protection is also associated with adaptive immune quiescence [ 39 ] would be consistent with our findings that PHA and IL-2 supplementation in the IMDM cultures blocked HERV-K102 particle production (data not shown). The contribution of repeated exposures presumably to other pathogens, is reminiscent of the findings reported in injection drug use HESN, where it has been shown protection related to the sharing of needles and the stimulation of innate immunity [ 41 ] and is consistent with our work showing various viruses stimulate HERV-K102 particle production in vivo [ 3 ]. Interestingly, more recent evidence in the Nairobi cohort has shown Mx2 expression, which inhibits HIV-1 integration, was associated with medroxyprogesterone use and the latter was associated with protection against HIV-1 transmission [ 42 ].…”

Increased Steady-State Memory B Cell Subsets Among High-Risk Participants in an HIV Vaccine Trial

“…Overall, the immune profile of high-risk populations is poorly resolved, although increased immune activation has been observed in high-risk men who have sex with men (MSM) 3,4 and injection drug users. [5][6][7] Immune activation, particularly increases in activated CD4 T cells, may increase susceptibility to HIV by providing additional viral targets or facilitating rapid viral dissemination. It is becoming increasingly evident that variations in the subtle qualitative aspects of the humoral HIV vaccine response may influence its efficacy.…”