Current Opinion in HIV & AIDS:
The T cell in HIV infection and disease: Basic science
Department of Immunology, University Medical Center Utrecht, The Netherlands
Correspondence to Prof. Dr Frank Miedema, Department of Immunology, University Medical Center Utrecht, Lundlaan 6, PO Box 85090, 3508 AB Utrecht, The Netherlands Tel: +31 30 250 7674; fax: +31 30 250 4305; e-mail: F.Miedema@umcutrecht.nl
Abbreviation CTL: cytotoxic T cells.
Since 1984, when it became apparent that the disease that we now know as AIDS was caused by a CD4+ T cell tropic novel human retrovirus, the metaphors used by the research community to describe the pathogenesis of HIV infection have changed at least several times. These shifts in our perception of the effects of HIV on the human T cell system were based on novel experimental evidence that each time changed in a fundamental way the then prevailing ideas.
In the early phase of the AIDS pandemic, our picture was dominated by the concept of viral latency that was based on a vast amount of high-profile research in molecular virology. That work was, however, mainly performed in quite artificial in-vitro systems and pointed to critical roles for gene products coded for by several HIV-specific genes in establishing and maintaining latency and regulating re-activation. In those days, the virus was barely detectable in blood or tissues and the loss of CD4 T cells at that time was thought to be largely due to bystander effects, lysis through cytotoxic T cells (CTL) or ingenious autoimmune-related mechanisms.
With the introduction of better and more sensitive virological, molecular and immunohistological techniques in the early nineties, such as the polymerase chain reaction (PCR) technique, the idea of viral latency became increasingly challenged. Improved culture methods allowed for virus isolation from nearly all asymptomatic seropositives. Infected cells became readily detectable in blood and appeared to be enriched in lymphoid tissues, even in asymptomatically infected individuals [1,2]. Together with reports on high percentages of apoptotic CD4+ and CD8+ T cells already early in infection in blood and tissues, the scene was gradually set for a more dynamic view of the HIV–T cell interaction from 1990 on . Without any doubt, the idea of viral latency was falsified completely by the seminal papers from the laboratories of Ho and Wei [4,5] that for the first time provided a quantitative view of the truly amazing viral production and decay rates. These papers also proposed the idea of high CD4+ T cell death rates caused directly by infection of high numbers of cells. HIV infection was no longer depicted as initially dormant, waiting for a reactivating event, but all of a sudden was compared to a never ceasing and vigorous battle killing large numbers of T cells every day, eventually exhausting the supplies. In these years, viral latency was replaced by clinical latency, which was depicted as an out-of-control fast train, heading for the abyss.
Only 3 years later, based on new experimental findings, the pendulum swung back from high T cell turnover to low-level but chronic activation and insidious interference of HIV with thymic function [6,7]. This generated a host of studies using the newly developed TREC assay to measure thymic output  and more sophisticated in-vivo labeling techniques to estimate T cell production and half-life in relation to T cell depletion and restoration after highly active antiretroviral therapy (HAART). These papers presented compelling evidence that prompted a re-evaluation of the initial idea that increased T cell division was a homeostatic response to the severe T cell loss due to HIV infection. Instead, it appeared that T cell division is part of the systemic immune activation in response to chronic HIV infection – a response that, despite often very low CD4+ T cell numbers, disappears quickly when patients are started on HAART [9,10]. In fact, in a total shift of paradigm, this immune-activation driven T cell proliferation was proposed to be the main driving force for depletion of the naive T cell pool. Together with the recently acquired insight that thymic output in humans is quite limited and not capable of compensating for increased cell death in the periphery, this presented a plausible mechanism for CD4+ T cell depletion .
Concurrently, the initial ideas on impairment of T cell function by HIV infection due to lack of CD4 T help were questioned by findings of high numbers of CTL and even T helper cells  using the novel powerful techniques to directly enumerate HIV-specific T cells, namely HLA class-I tetramer staining and intracellular cytokine staining techniques on the FACS and Elispot assays. It appeared that HIV-specific T cell responses were in fact so abundant that for the first demonstration of the HLA tetramer technology, advantage was taken of the abundance of HIV-specific HLA-A2 restricted CTL in asymptomatic HIV infection . It is now clear that persistent antigenic stimulation, characteristic for HIV infection, reflected by high expression of several markers of immune activation on T cells, affects the number, function and phenotype of HIV specific T cells. Although loss of function with time of HIV infection in patients with high viral load is well documented, evidence for vigorous HLA class-I restricted CTL responses in the asymptomatic phase came from studies on viral escape. In the past 3 years at the patient level, but also at the population level, we are beginning to understand the magnitude and biological effects of CTL editing of the HIV genome . The major impact of protective HLA alleles such as B57 may well be related to forced mutations in otherwise conserved sites that take a toll on viral fitness together with preferential and CTL targeting of highly constraint epitopes. These cost-of-fitness effects are believed to impact the virus early after transmission and it may well be that this is one of the major underlying causes for the relationship between HLA, viral load levels in chronic infection and, even more importantly, viral load set point following clearance of symptoms after acute infection. Viral load set points have been shown to be strongly predictive for rate and rapidity of progression but, recently, it was demonstrated that the level of immune activation, measured by enhanced expression of T cell activation markers such as CD38 in response to viremia, is the dominant driving force for CD4 depletion and progression to AIDS .
The relatively strong cellular immune responses to HIV apparently can, once the infection is established, only temporarily slow down HIV disease progression and in fact have been shown to become gradually lost with progression . Even boosting with therapeutic vaccines or by structured treatment interruptions reportedly does not have durable effects on control of viremia . These new findings, in concert with the effects of HLA-restricted CTL in early infection and the recent data demonstrating immediate and severe depletion of memory CD4+ T cells in the gut during acute SIV and HIV infection , urge us to deeply revisit the biology of HIV transmission. The outcome of the very first interaction between HIV and host immune system sets the clock for the subsequent course of the infection, which warrants a renewed focus of research on the impact of the earliest immune responses mounted by the infected host.
Taking the available data together, it thus seems that our ideas of truly protective immunity cannot be directly derived from studies of T cell function and phenotypes in the natural history of HIV infection. Novel ideas need to be developed concerning vaccine-induced protective immunity. In order to be able to protect from disease, we have to improve on virus-induced immunity in that it has to do better, last longer and act much quicker upon viral challenge. After more than 20 years of research on T cell dynamics and protective immunity, it seems we are in need of, yet again, a new paradigm.
I thank Jose Borghans and Debbie van Baarle for critical reading and suggestions; research support was obtained from the Dutch AIDS Fund (no. 7010), the EU (Eurovac and Theravac) and UMCU/WKZ.
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