Trends in Immunology
ReviewHIV controllers: how do they tame the virus?
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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Cis-regulatory genetic variants in the CCR5 gene and natural HIV-1 control in black South Africans
2019, Clinical ImmunologyCitation Excerpt :A shared defining feature of HIV-1 controllers is a CD4+ T cell count >500 cells/μl of blood. In this study, VCs are defined as having low detectable viral loads (<2000 RNA copies/ml plasma), while rare individuals (<1% of HIV-1 infected individuals in previously studied cohorts [10]) who have undetectable viral loads (<50 RNA copies/ml) after infection with HIV-1 are termed ECs [11]. Individuals who maintain CD4+ T cell counts >500 cells/μl for >7 years without the use of ART, but who do not suppress HIV-1 viral load (generally >10,000 RNA copies/ml), are termed high viral load long-term non-progressors (HVL LTNPs) in this study.
Type i interferons in viral control and immune regulation
2016, Current Opinion in VirologyCitation Excerpt :In contrast, SIV infection in sooty mangabeys and African green monkeys, which develop modest pathology despite equivalent viral loads as macaques, correlate with reduced IFN-I and inflammatory gene expression [83•]. Similar correlations with respect to reduced immune activation exist in HIV infected elite controllers, although whether reduced immune activation follows virus control is uncertain [88,89]. Blockade of PD-1 signaling during chronic SIV infection reduces hyper-immune activation and microbial translocation in rhesus macaques and lower IFN-I signatures in the blood and colon [90].
Pleiotropic Roles of Type 1 Interferons in Antiviral Immune Responses
2016, Advances in ImmunologyCitation Excerpt :In contrast, SIV infection in sooty mangabeys and African green monkeys, which develop modest pathology despite equivalent viral loads as macaques, correlate with reduced IFN-I and inflammatory gene signatures (Bosinger et al., 2009). Similar correlations with respect to reduced immune activation exist in HIV-infected elite controllers, although whether reduced immune activation follows virus control is uncertain (Deeks & Walker, 2007; Saez-Cirion et al., 2007). Blockade of PD-1 signaling during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques and lowers IFN-I signatures in the blood and colon (Dyavar Shetty et al., 2012).
The diffuse infiltrative lymphocytosis syndrome (DILS): A comprehensive review
2015, Journal of AutoimmunityReduction of death receptor 5 expression and apoptosis of CD4+ T cells from HIV controllers
2014, Clinical Immunology