Monocytes
In the first few weeks of HIV infection, there is a massive accumulation of CD8 T-cells and a massive depletion of CD4 T-cells in the gut, followed by increased gut permeability and translocation of microbial products into circulation [
23,
24]. Microbial translocation contributes to increased monocyte activation as evidenced by the rapid shift in the circulating monocyte pool from the classical phagocytic monocytes (CD14
++CD16
−) to the intermediate inflammatory monocyte subpopulation (CD14
++CD16
+) in the first 2 weeks of HIV infection [
25]. Subsequently, monocyte subsets are disrupted, leading to suboptimal effector functions of phagocytosis, intracellular killing, chemotaxis and cytokine production [
26]. HIV infection, both through direct infection and indirectly through microbial translocation, leads to monocyte activation and aberrant release of pro-inflammatory cytokines including TNF-α, IL-1β and IL-6, thereby activating the immune system [
17]. In addition to aberrant cytokine production, HIV-associated monocyte activation leads to increased release of chemokines, leading to non-specific movement of monocytes into various tissue sites [
23]. Direct HIV infection of the monocytes down regulates MHCII expression, inhibits MHCII-antigen complex formation and reduces the monocyte ability to take up antigens for processing and presentation to T cells [
27]. In a study conducted in Beijing, Chen et al. [
28] demonstrated that acute HIV-1 infected individuals had significantly increased proportions of inflammatory monocyte subsets and upregulated expression of the HLA-DR and CD163 receptors when compared with HIV negative individuals. These acquired defects in monocyte function cause the inability of monocytes to present antigens [
27].
We postulate that the observed increase in inflammatory monocytes and immune activation markers could further impair monocyte responsiveness to antigens making the HIV infected individuals more susceptible to opportunistic infections. After several months to years of HIV infection, viral load levels gradually increase, while CD4 T-cells continue to reduce in number and function [
29‐
31]. Similarly, there is dysregulation of monocyte subsets with higher populations of inflammatory (CD14
+CD16
+) monocytes than phagocytic (CD14
+CD16
−) populations. Monocytes in circulation become functionally anergic due to continued activation and high inflammatory status [
32]. Untreated, individuals with chronic HIV-1 infection continue to have increased proportions of both the intermediate and non-classical monocytes subsets [
33]. Moreover, levels of expression of CD163, a marker of activation on inflammatory monocytes remains significantly higher among individuals with chronic HIV-1-infection than HIV negative controls [
34]. Protracted expression of the activated phenotype of monocyte subsets has a direct association with disease progression [
33].
ART down regulates the excessive production of cytokines by the inflammatory monocytes thereby reducing the levels of immune activation and inflammation [
17]. In a review by Burdo et al. [
35], it was observed that ART initiation within the first year of HIV infection reduced monocyte activation, as evidenced by a reduction in expression of activation marker CD163 and absolute numbers of inflammatory monocytes. Similarly, markers of microbial translocation [lipopolysaccharide protein (LPS), IL-6, 16S ribosomal DNA and soluble CD14], and inflammatory markers such as
d-dimer and interferon-α declined with ART initiation [
33,
36]. Although a lot of immune functions appear to be recovered during ART, some monocyte dysfunctions persist. After 1 year of therapy, ART-treated adults were reported to still have elevated levels of the inflammatory monocyte subset (CD14
++CD16
+) and a downregulated expression of phagocytic monocyte subset (CD14
++CD16
−), resulting in the reduced ability of monocytes to process and present antigens to T cells [
34,
37]. Similarly, phagocytic activity and oxidative burst of neutrophils and monocytes remained impaired among HIV-1 infected patients, in Athens general hospital after 3 months of ART [
26,
38]. However, there is paucity of data on monocyte activation and functional recovery beyond 2 years of ART, particularly in sub-Saharan Africa (SSA) where monocyte frequency and functional recovery has not been widely studied in HIV treatment cohorts. Given the increasing numbers of individuals receiving ART, for 7 years and over, a better understanding of the effects of long-term ART on inflammation and monocyte activation would be relevant to inform innovations against chronic inflammation and its complications among adults living with HIV.