Trends in Immunology
Volume 28, Issue 12, December 2007, Pages 532-540
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Review
HIV controllers: how do they tame the virus?

https://doi.org/10.1016/j.it.2007.09.002Get rights and content

HIV controllers are rare, chronically HIV-1-infected patients in whom viral replication is undetectable in the absence of antiretroviral treatment. Most such patients are nonetheless infected by replication-competent viruses. An effective, multifunctional HIV-specific CD8+ T-cell response is thought to be central to viral control in these individuals. The mechanisms underlying this spontaneous control of HIV infection and the particular characteristics of the CD8+ T-cell response in HIV controllers are the focus of intensive investigations, because they should help to unravel the pathogenesis of AIDS and to provide new clues for the design of effective vaccine strategies. In this review, we examine recent findings from these studies.

Section snippets

Introducing HIV controllers

As the AIDS pandemic progressed, it became clear that a small number of patients had an unusually mild course of disease. These patients, who represent ∼5% of infected persons 1, 2, were able to maintain high CD4+ T-cell counts for ten or more years in the absence of antiretroviral therapy and were therefore referred to as long-term nonprogressors (LTNPs). Genetic factors [3] and different mechanisms, such as (i) infection by attenuated or defective viruses [4], (ii) high neutralizing antibody

The virus and host cell intrinsic factors

The undetectability of viral markers in HIC plasma and the accompanying very low proviral DNA levels might be explained by infection with attenuated virus or by the occurrence of invalidating mutations during the course of infection. Mutations in Vpr and other viral proteins and, more clearly, deletions in the nef or long terminal repeat (LTR) region of the HIV-1 genome have been associated with LTNP 4, 24, although disease progression has been observed in the long term in some individuals

The immune response

The first line of defense against infections is provided by innate immunity. Although studies focused on innate responses in HICs are not still published, compelling evidence for an important role of NK cell responses in the control of viral load and progression to disease come from epidemiological studies on the polymorphism of the NK killer immunoglobulin-like receptor (KIR) family and their ligands. A protective association between the inhibitory receptor KIR3DL1 (and especially the highly

Characteristics of HIV-specific CD8+ T cells in HICs

Most HICs are characterized by high frequencies of HIV-specific CD8+ T cells 19, 20, 21, 22. However, these frequencies are comparable to those of viremic patients, which suggests that it is not simply the number of IFNγ-secreting HIV-specific CD8+ T cells that accounts for the control of HIV replication in HIC patients. Yet, the high numbers of IFNγ+ HIV-specific CD8+ T cells that are observed in HICs despite the lack of detectable viral antigens are intriguing, because the frequency of these

Potential mechanisms of effective CD8+ T-cell responses in HIV controllers

The activity of virus-specific T cells relies upon an appropriate relationship between the T-cell receptors (TCRs) and their cognate antigenic peptides. TCR usage is dictated by peptide-HLA complexes [59], and it is therefore tempting to think that the overrepresentation of protective HLA alleles (HLA-B57 and -B27) in HICs might be related to the selection of favorable TCRs (Figure 2b). Actually, a conserved and restricted TCR repertoire is found in individuals bearing the HLA-B*5701 allele [60]

Unanswered questions and future directions

Although considerable advances have been made in our understanding of the mechanisms underlying spontaneous control of HIV-1 infection in rare individuals (Box 1, Figure 1), many questions remain. In particular, very little information is available on the acute phase of infection in HICs, who, for obvious reasons, are only identified after several years. This means that it is not clear when, where, and how the infection starts to be controlled. The specific immune response probably plays an

Acknowledgements

The authors thank Jean-François Delfraissy for his insight and support and all of the members of the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) EP36 HIV controllers study group for helpful discussion. We also thank ANRS, Sidaction, and Fondation de France for financial support.

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