Viremic non-progression in HIV/SIV infection: A tied game between virus and host

Abstract

High-efficacy antiretroviral treatment (ART) has been a game-changer for HIV/AIDS pandemic, but incomplete CD4⁺ T cell recovery and persistent chronic immune activation still affect HIV-suppressed people. Exceptional cases of HIV infection that naturally exhibit delayed disease progression provide invaluable insights into protective biological mechanisms with potential clinical application. Viremic non-progressors (VNPs) represent an extremely rare population of individuals with HIV, characterized by preservation of the CD4⁺ T cell compartment despite persistent high levels of viral load (>10,000 copies/mL). While only a few studies have investigated the immunovirological characteristics of adult and pediatric VNPs, most of our knowledge about this phenotype stems from its non-human-primate counterpart, the natural simian immunodeficiency virus (SIV) hosts. In this review, we synthesize the insights gained from recent studies of natural SIV hosts and VNPs and evaluate the potential similarities and differences in the mechanisms that underlie the absence of pathogenesis, with special focus on the control of immune activation.

Keywords: HIV pathogenesis; VNP; natural SIV host; pediatric HIV infection; viremic non-progressor.

Graphical abstract

Figure 1

HIV-1 infection profile in standard progressors and viremic non-progressors Chronic HIV-1 infection is characterized by a stable viremia setpoint, which is maintained for years, paralleled by a progressive decline in CD4⁺ T cell counts, which eventually fall below the reference thresholds of 500 cells/μL, 350 cells/μL, and 200 cells/μL. Generally, the magnitude of the viral setpoint during chronic infection is positively associated with the rate of progression to disease, and higher plasma viral loads are associated with faster disease progression. In contrast with the standard progressor profile, VNPs have the surprising capacity to maintain normal CD4⁺ T cell counts (above 500 cells/μL) despite high and persistent levels of viral replication (usually above 10,000 copies/mL).

Figure 2

Host immune factors associated with the non-pathogenic phenotype of natural SIV hosts The immune system of natural SIV hosts and their response to infection show characteristics that may contribute to the absence of pathogenesis: target cell protection from infection, support of alternative cell types to helper functions, preservation of gut immunity, lack of chronic immune activation, preservation of lymphoid tissue structure and functionality, maintenance of CD4⁺ T cell homeostasis, and limited role of SIV-specific adaptive immune responses. LN, lymph node.

Figure 3

Comparison of the main features of viremic non-progression in HIV/SIV infection Natural SIV hosts, pediatric VNPs, and adult VNPs share a common infection profile as a result of different circumstances. In all cases, viruses normally preserve intact pathogenic potential, and the resistance to SIV/HIV pathogenesis is due to protective immune characteristics, some of them preserved across all conditions. However, the extremely low frequency of VNPs, especially among adult populations, and the scarcity of integrative studies on this phenotype have caused many questions to remain unanswered.