Intestinal CD4 Depletion in HIV / SIV Infection

Abstract

Among the most significant findings in the pathogenesis of HIV infection was the discovery that almost total depletion of intestinal CD4+ T cells occurs rapidly after SIV or HIV infection, regardless of the route of exposure, and long before CD4+ T cell losses occur in blood or lymph nodes. Since these seminal discoveries, we have learned much about mucosal and systemic CD4+ T cells, and found several key differences between the circulating and intestinal CD4+ T cell subsets, both in phenotype, relative proportions, and functional capabilities. Further, specific subsets of CD4+ T cells are selectively targeted and eliminated first, especially cells critically important for initiating primary immune responses, and for maintenance of mucosal integrity (Th1, Th17, and Th22 cells). This simultaneously results in loss of innate immune responses, and loss of mucosal integrity, resulting in mucosal, and systemic immune activation that drives proliferation and activation of new target cells throughout the course of infection. The propensity for the SIV/HIV to infect and efficiently replicate in specific cells also permits viral persistence, as the mucosal and systemic activation that ensues continues to damage mucosal barriers, resulting in continued influx of target cells to maintain viral replication. Finally, infection and elimination of recently activated and proliferating CD4+ T cells, and infection and dysregulation of Tfh and other key CD4+ T cell results in hyperactive, yet non-protective immune responses that support active viral replication and evolution, and thus persistence in host tissue reservoirs, all of which continue to challenge our efforts to design effective vaccine or cure strategies.

Granzyme B + CD4 T cells accumulate in the colon during chronic HIV-1 infection

“…In contrast, LP GZB + CD4 T cells were readily detected at significantly higher frequencies in PWH versus controls, both as a fraction of total CD4 T cells (PWH: 9.8%, 3.6–22.3; P < .001) ( Figure 1b ) and per area of LP tissue (PWH: 39/mm 2 , 16–104; Controls: 17/mm 2 , 6–33; P = .005) ( Figure 1c ). As expected, percentages of LP CD4 T cells as a fraction of total LP CD3 + T cells, and as the number of CD4 T cells per area of LP tissue, were significantly lower in PWH consistent with gut CD4 T cell depletion 3 (PWH: 17.7%, 12.5–25.7 versus Controls: 72.7%, 62.2–82.7, P < .001; PWH: 400/mm 2 , 226–622 versus Controls: 930/mm 2 , 517–1090, P < .001) ( Figure 1d , e).…”

“… 1 , 2 Early in infection, HIV-1 replicates to high levels in intestinal CD4 T cells, resulting in the massive depletion of T helper (Th) 17 and Th22 subsets that play critical roles in maintaining intestinal homeostasis. 3 Disruption of gut homeostasis leads to mucosal inflammation and epithelial barrier damage, culminating in increased microbial translocation of enteric bacteria and their inflammatory products into the underlying tissue and systemic circulation. 4 Furthermore, numerous studies, including our own, have demonstrated an altered intestinal microbiome (dysbiosis) among people with HIV-1 (PWH), with dysbiotic profiles correlating with local and systemic immune activation, inflammation and microbial translocation (reviewed in 5 ), metabolic syndrome, 6 and various inflammation-associated comorbidities.…”

Inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection: a prospective cohort study and immunological network analysis

“…24 Profound depletion of IL-17-producing T-helper (Th)17 cells is observed at mucosal barriers early after HIV-1 infection, leading to chronic immune activation. 25 The combi nation of ongoing mucosal inflammation, HIV-1 replication, and M tuberculosis co-infection could result in heightened immune activation leading to constant triggering of the remaining IL-17A-producing cell populations during HIV-tuberculosis co-infection. This possibility is exemplified by findings of upregulated Th17 polarising cytokines and transcription factors in pleural fluid of patients with HIV-tuberculosis co-infection with tuberculosis pleurisy, despite numeric depletion of Th17 cells.…”

T cells and their function in the immune response to viruses

“…Th1, Th17, and Th22 cells are critically important for initiating primary immune responses and for maintenance of mucosal integrity. Infection and dysregulation of Tfh and other key CD4+ T cell results in hyperactive, yet non-protective immune responses that supports active viral replication and evolution, and thus persistence in host tissue reservoirs (Veazey, 2019). Chronic HIV infection is characterized by Th1 and Th2 production (Gorenec et al, 2016).…”