HIV infection, a defeat of the immune system ? (II)

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The human immunodeficiency virus (HIV) is a lentivirus which, by infecting CD4 T lymphocytes, is responsible for acquired immunodeficiency syndrome (AIDS), characterized by opportunistic infections, encephalopathy and tumors leading, in the absence of treatment, to death within a few years. The biology of the virus, isolated in 1983 and cloned in 1985, is now well understood. Its mode of entry (CD4 membrane receptors and CCR5 or CXCR4 chemokine receptors), the integration of its genetic material into the genome of the infected cell after retrotranscription of viral genomic RNA, the conditions under which these components are produced, virion assembly and production have all been well characterized. The epidemiology of the infection is also well known. To date, 37 million people are infected worldwide, 95% of whom live in poor countries, 50% of whom are women and 9% children. Two million new cases occur every year. To date, just over half of patients are treated with combination antiretroviral chemotherapy, a long way from the WHO's "90/90/90" target: 90% of patients diagnosed, 90% treated and 90% in clinical remission. The ways in which the virus is transmitted via mucous membranes or blood, and the associated risk factors, have also been well determined. During infection, there is a rapid loss of CD4 T lymphocytes, either directly as a result of the lytic effect of viral replication, or indirectly through chronic lymphocyte activation. It is estimated that around¹⁰¹⁰ viral particles are produced (and destroyed by the immune system) every day, explaining the infection's capacity to spread to mucosal lymphoid tissues and secondary lymphoid organs rich in CD4 T cells. The organism seeks to limit the infection by bringing into play multiple immune effectors: factors that restrict the viral cycle through innate immunity, against which the virus has developed "countermeasures"; adaptive B and T responses, particularly cytotoxic ones, which we now know depend on early and intense activation after the onset of infection, as discussed below. This response is essentially inadequate, however, due to several critical factors: a) infection and destruction of cells involved in immune responses, b) high mutation rate of the virus due to the "infidel" nature of reverse transcriptase, which enables it to evade immune responses by selecting mutants. These characteristics also explain the failure to date of attempts to protect the virus by vaccination.

Two major issues currently occupy the field of HIV infection research: i) the concept of the viral reservoir, and ii) the fact that a small number of infected subjects control viral replication even in the absence of treatment: the so-called " elite controllers ".

Antiretroviral treatment considerably reduces viral replication, thereby restoring a pool of CD4 T cells sufficient to control the risk of infection, but spares a reservoir of latently infected cells or cells with a low level of viral replication. Discontinuation of treatment leads to a rapid resumption of viral replication and the reappearance of immune deficiency. It is therefore critical to understand the characteristics of this reservoir in order to target it with new therapeutic strategies. This reservoir comprises around 1 ^CD4/106 T lymphocyte, capable of resuming effective viral replication. The lifespan of this pool is around 44 months, its stability indicating a balance between cell loss and division. It is now known that this pool is established very early in the course of infection, during the transition of T lymphocytes from the effector to memory stage, i.e. after around 6 to 12 days of infection at the stage of maximum expression of the HIV co-receptor CCR5. The capacity for expansion (necessary to maintain the reservoir) is essentially due to the homeostatic or antigen-induced proliferation capacities characteristic of memory T cells. Various strategies have been envisaged to destroy this reservoir, based on activation of viral replication by epigenetic modifiers, followed by targeted immunotherapy with cytotoxic CD8 T cells. While this approach has proved effective in experimental in vitro models, attempts to implement it in vivo (humanized mice) have so far proved unsuccessful, due to the resistance of infected lymphocytes through in vivo selection for resistance to cytotoxic cells. We need to be able to act very early on in the course of infection, by maximizing the cytotoxic immune response during the establishment of the reservoir.

A small fraction of HIV-infected individuals (<1%) continue to control viral replication after discontinuation of antiretroviral therapy, and do so for years or decades. Understanding this control mechanism(s) is of course key to achieving such an effect in all infected subjects! We know that this situation does not reflect differences in infecting viral strains. Controllers " have genetic characteristics (HLA and KIR alleles) which contribute (but are not strictly necessary) to the fact that T immune responses are more intense, more diversified - both in terms of recognized Ag and effector functions - and undoubtedly appear earlier in the course of the infection.

Nevertheless, infection control is not complete in these subjects. A certain degree of viral replication persists within the compartment of T lymphocytes present in the secondary lymphoid organs in the extra-follicular zones. We can therefore speak of compartmentalization of infection control.

Against this backdrop, what new therapeutic strategies should be considered? Immunotherapy and vaccination should aim for rapid and intense generation of polyfunctional cytotoxic T lymphocytes. The use of broad-spectrum neutralizing antibodies - discussed in my lecture a year ago - may represent a form of passive immunotherapy, currently undergoing clinical evolution. Efforts at preventive or therapeutic vaccination have so far failed to produce tangible results, despite the "sophistication" of protocols incorporating the use of several antigens, and the addition of cytokine immunostimulation.

Nevertheless, steady progress in understanding the genetics of the viral reservoir and the effective immune responses of controllers should enable us to meet this challenge more effectively in the coming years.