Nabatanzi et al. AIDS Res Ther (2018) 15:7 https://doi.org/10.1186/s12981-018-0194-y AIDS Research and Therapy REVIEW Open Access Efects of HIV infection and ART on phenotype and function of circulating monocytes, natural killer, and innate lymphoid cells Rose Nabatanzi1* , Stephen Cose2, Moses Joloba1, Sarah Rowland Jones3 and Damalie Nakanjako4,5 Abstract HIV infection causes upregulation of markers of infammation, immune activation and apoptosis of host adaptive, and innate immune cells particularly monocytes, natural killer (NK) and innate lymphoid cells (ILCs). Although antiretro- viral therapy (ART) restores CD4 T-cell counts, the persistent aberrant activation of monocytes, NK and ILCs observed likely contributes to the incomplete recovery of T-cell efector functions. A better understanding of the efects of HIV infection and ART on the phenotype and function of circulating monocytes, NK, and ILCs is required to guide devel- opment of novel therapeutic interventions to optimize immune recovery. Keywords: HIV, Innate immunity, Monocytes, Natural killer cells, Innate lymphoid cells, Antiretroviral therapy Background towards a T helper 1 (T1) response [8, 9]. ILCs rapidly Te human innate immune system is comprised of a secrete immunoregulatory cytokines which makes them complex network of cellular and soluble proteins that provide protective immunity early on during infection work together to provide the frst-line of defense against [10] and also maintain intestinal homeostasis by directly common invading pathogens prior to involvement of the regulating T cells through the presentation of peptide adaptive immune response [1–3]. Innate immune cells antigens on major histocompatibility complex II [11]. including monocytes, natural killer cells (NK), innate During HIV infection, the adaptive immune system lymphoid cells (ILCs), and other antigen presenting cells is directly afected through the rapid infection of CD4 (APCs) play a crucial role in the ushering in the adaptive T-cells [12] but the efects on the innate immune sys- arm of the immune response [4, 5]. In particular, mono- tem are more indirect through microbial translocation, cytes are precursor cells to professional APCs involved in infammation, and immune activation [13]. Immune acti- immune surveillance [6]. In addition, they have pattern- vation and infammation cause a reduction in the num- recognition receptors (PRRs) that detect conserved path- bers of monocytes, NK and ILCs, consequently leading ogen-associated molecular patterns (PAMPs) which lead to poor innate and adaptive immune responses, all which to the induction of infammatory responses that com- result in suboptimal response to infecting antigens [14]. bat invading pathogens [7]. Natural killer cells produce Antiretroviral therapy (ART) suppresses HIV replica- cytokines; particularly interferon-gamma (IFN-ɣ) which tion, restores CD4 T-cell numbers, reduces microbial activates phagocytic cells and primes APCs for interleu- translocation, infammation, and aberrant T-cell activa- kin 2 (IL-2) secretion thus shaping adaptive immunity tion [15–17]. Te net efect of this is the near restoration of the immune system to pre-infection status and control/ prevention of opportunistic infections and other AIDS- *Correspondence: [email protected] associated ailments [18, 19]. Several studies have how- 1 Department of Immunology and Molecular Biology, Makerere University College of Health Sciences, P. O. Box 7072, Kampala, Uganda ever demonstrated incomplete recovery of the adaptive Full list of author information is available at the end of the article immune responses including ours which showed lower © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nabatanzi et al. AIDS Res Ther (2018) 15:7 Page 2 of 8 CD4 T-cell proliferation among ART-treated adults (with therapeutic intervention to optimize recovery of host CD4 counts restored to 500 cells/µl and more), relative to immune responses. their HIV-negative counterparts [19–21]. Innate immune cells; in particular NK cells, ILCs and monocytes, par- HIV infection and innate immune cells ticipate in the initiation and development of adaptive Monocytes immune responses although little is known about their In the frst few weeks of HIV infection, there is a mas- recovery during ART. Tis review discusses the recovery sive accumulation of CD8 T-cells and a massive deple- of monocytes, NK and ILCs during ART, because of their tion of CD4 T-cells in the gut, followed by increased gut respective contributions to the regulation of the adaptive permeability and translocation of microbial products immune response. into circulation [23, 24]. Microbial translocation con- Figure 1 summarises the efects of HIV infection and tributes to increased monocyte activation as evidenced ART on monocytes, NK cells, ILCs, and other innate by the rapid shift in the circulating monocyte pool from cells. Persistent infammation and activation of mono- the classical phagocytic monocytes (CD14++CD16−) to cytes, NK cells, and ILCs is likely associated with the per- the intermediate infammatory monocyte subpopula- sistent T-cell activation and impaired efector functions tion (CD14++CD16+) in the frst 2 weeks of HIV infec- observed among ART-treated adults [20–22]. Tere is tion [25]. Subsequently, monocyte subsets are disrupted, likely a unique phenomenon of innate immune cell recov- leading to suboptimal efector functions of phagocytosis, ery during ART, among residents in sub-Saharan Africa intracellular killing, chemotaxis and cytokine produc- (SSA) where several endemic infections activate the tion [26]. HIV infection, both through direct infection immune systems. A better understanding of innate cell and indirectly through microbial translocation, leads to dysfunctions and their efects on the adaptive responses monocyte activation and aberrant release of pro-infam- during ART would guide the development of innovative matory cytokines including TNF-α, IL-1β and IL-6, Fig. 1 The efects of HIV infection and ART on monocytes, NK cells, ILCs Nabatanzi et al. AIDS Res Ther (2018) 15:7 Page 3 of 8 thereby activating the immune system [17]. In addition to to still have elevated levels of the infammatory monocyte aberrant cytokine production, HIV-associated monocyte subset (CD14++CD16+) and a downregulated expression activation leads to increased release of chemokines, lead- of phagocytic monocyte subset (CD14++CD16−), result- ing to non-specifc movement of monocytes into various ing in the reduced ability of monocytes to process and tissue sites [23]. Direct HIV infection of the monocytes present antigens to T cells [34, 37]. Similarly, phagocytic down regulates MHCII expression, inhibits MHCII-anti- activity and oxidative burst of neutrophils and mono- gen complex formation and reduces the monocyte abil- cytes remained impaired among HIV-1 infected patients, ity to take up antigens for processing and presentation to in Athens general hospital after 3 months of ART [26, T cells [27]. In a study conducted in Beijing, Chen et al. 38]. However, there is paucity of data on monocyte acti- [28] demonstrated that acute HIV-1 infected individu- vation and functional recovery beyond 2 years of ART, als had signifcantly increased proportions of infamma- particularly in sub-Saharan Africa (SSA) where monocyte tory monocyte subsets and upregulated expression of the frequency and functional recovery has not been widely HLA-DR and CD163 receptors when compared with HIV studied in HIV treatment cohorts. Given the increasing negative individuals. Tese acquired defects in monocyte numbers of individuals receiving ART, for 7 years and function cause the inability of monocytes to present anti- over, a better understanding of the efects of long-term gens [27]. ART on infammation and monocyte activation would be We postulate that the observed increase in infamma- relevant to inform innovations against chronic infamma- tory monocytes and immune activation markers could tion and its complications among adults living with HIV. further impair monocyte responsiveness to antigens making the HIV infected individuals more susceptible to Natural killer cells opportunistic infections. After several months to years Natural killer (NK) cells have an important role in con- of HIV infection, viral load levels gradually increase, trolling acute HIV infection, through rapid division while CD4 T-cells continue to reduce in number and and production of huge amounts of IFN-γ cytokine [8]. function [29–31]. Similarly, there is dysregulation of Strong NK cell activity and cytotoxic receptor expression monocyte subsets with higher populations of infam- are associated with preservation of CD4 T cells and lower matory (CD14+CD16+) monocytes than phagocytic viral set point [39]. HIV infection is associated with sev- (CD14+CD16−) populations. Monocytes in circulation eral changes in the NK cell compartment, including phe- become functionally anergic due to continued activation notypic and functional abnormalities