The Hitchhiker Guide to CD4+ T-Cell Depletion in Lentiviral Infection. A Critical Review of the Dynamics of the CD4+ T Cells in SIV and HIV Infection.

Quentin Le Hingrat,Ivona Pandrea,Cristian Apetrei,Irini Sereti,Alan L Landay

doi:10.3389/fimmu.2021.695674

Abstract

CD4+ T-cell depletion is pathognomonic for AIDS in both HIV and simian immunodeficiency virus (SIV) infections. It occurs early, is massive at mucosal sites, and is not entirely reverted by antiretroviral therapy (ART), particularly if initiated when T-cell functions are compromised. HIV/SIV infect and kill activated CCR5-expressing memory and effector CD4+ T-cells from the intestinal lamina propria. Acute CD4+ T-cell depletion is substantial in progressive, nonprogressive and controlled infections. Clinical outcome is predicted by the mucosal CD4+ T-cell recovery during chronic infection, with no recovery occurring in rapid progressors, and partial, transient recovery, the degree of which depends on the virus control, in normal and long-term progressors. The nonprogressive infection of African nonhuman primate SIV hosts is characterized by partial mucosal CD4+ T-cell restoration, despite high viral replication. Complete, albeit very slow, recovery of mucosal CD4+ T-cells occurs in controllers. Early ART does not prevent acute mucosal CD4+ T-cell depletion, yet it greatly improves their restoration, sometimes to preinfection levels. Comparative studies of the different models of SIV infection support a critical role of immune activation/inflammation (IA/INFL), in addition to viral replication, in CD4+ T-cell depletion, with immune restoration occurring only when these parameters are kept at bay. CD4+ T-cell depletion is persistent, and the recovery is very slow, even when both the virus and IA/INFL are completely controlled. Nevertheless, partial mucosal CD4+ T-cell recovery is sufficient for a healthy life in natural hosts. Cell death and loss of CD4+ T-cell subsets critical for gut health contribute to mucosal inflammation and enteropathy, which weaken the mucosal barrier, leading to microbial translocation, a major driver of IA/INFL. In turn, IA/INFL trigger CD4+ T-cells to become either viral targets or apoptotic, fueling their loss. CD4+ T-cell depletion also drives opportunistic infections, cancers, and comorbidities. It is thus critical to preserve CD4+ T cells (through early ART) during HIV/SIV infection. Even in early-treated subjects, residual IA/INFL can persist, preventing/delaying CD4+ T-cell restoration. New therapeutic strategies limiting mucosal pathology, microbial translocation and IA/INFL, to improve CD4+ T-cell recovery and the overall HIV prognosis are needed, and SIV models are extensively used to this goal.

Highlights

Even before HIV was formally established as the cause of AIDS, CD4+ T-cell depletion was identified as a key feature of HIV infection
Lymphocytopenia was notably due to a depletion of CD4+ T cells and, in addition to their decrease in absolute number and percentage of total T cells, residual CD4+ T cells were dysfunctional in AIDS patients [1]
As longitudinal studies cannot access and sample all body compartments, reasonable knowledge on CD4+ T-cell dynamics during HIV infection was obtained from descriptive studies of cohorts of HIV-1 infected patients and experimental studies of simian immunodeficiency virus (SIV) infection in nonhuman primates (NHP)

Summary

INTRODUCTION

Even before HIV was formally established as the cause of AIDS, CD4+ T-cell depletion was identified as a key feature of HIV infection. Lower levels of immune activation and apoptosis of the CD4+ T cells from the LNs and circulation may help protect the immune system of the natural SIV hosts from the immune exhaustion described in the late-stage diseases of pathogenic HIV/SIV infections [92, 140, 145] This might be partly due to difference in the dynamics of type 1 interferons. Another significant particularity of several African NHP species is their ability to downregulate CD4 receptor expression at the surface of their CD4+ T cells when they enter in the memory pool, rendering them resistant to SIV infection [137, 159, 160] Through these mechanisms, natural hosts of SIVs spare specific CD4+ T-cell subsets, which could contribute to the control of inflammation and maintenance of gut integrity, despite high viral replication during chronic nonpathogenic infections. Memory CD4+ T cells were preserved after the early administration of this inhibitor [290]

CONCLUSION

Findings

DATA AVAILABILITY STATEMENT