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HIV Controllers: A Homogeneous Group of HIV-1—Infected Patients with Spontaneous Control of Viral Replication

INSERM E-0109, Faculté de Médecine Paris-Sud, Université Paris XI, Service de Santé Publique, Bicêtre, France.
Clinical Infectious Diseases (Impact Factor: 9.42). 11/2005; 41(7):1053-6. DOI: 10.1086/433188
Source: PubMed

ABSTRACT We identified a total 15 patients who have maintained undetectable plasma HIV RNA loads without antiretroviral treatment for >10 years from cohorts of 1300 and 1551 patients infected with human immunodeficiency virus (HIV). These 15 patients, whom we have referred to as "HIV controllers," are characterized by a low HIV DNA load in peripheral blood mononuclear cells and by a strong HIV-specific immune response.

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    • "EC represent a small percentage within the group of LTNP (0.5–1% of HIV-positive patients) [Deeks and Walker, 2007]. These characteristics make the disease progression in EC individuals extremely rare [Lambotte et al., 2005; Betts et al., 2006]. Although the exact mechanism(s) involved in the host defense against HIV in these groups of infected but progression-resistant persons have not been fully elucidated, several host genetic factors Grant sponsor: Brazilian National Research Council Program CNPq, Brazil; Grant number: 476229/2012-0. "
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    ABSTRACT: Large variation exists in susceptibility to infection with Human Immunodeficiency Virus Type 1 (HIV), and disease progression. These observations demonstrate a role for antiretroviral host factors. Several reports describe α1-antitrypsin (A1AT), the most abundant circulating serine protease inhibitor, as a potent suppressor of HIV infection and replication. We identified the normal (M) and most common deficiency-associated (S and Z) isoforms of the A1AT gene in patients infected with HIV from four multicenter cohorts. The level of disease progression in the patients was characterized and the patients were grouped into as elite controllers (EC), long-term non-progressors (LTNP), or progressors (Prog). No significant difference in the distribution of A1AT alleles was observed in the EC, LTNP, or Prog groups. However, significantly increased prevalence of the A1AT deficiency-associated S allele was observed in HIV-infected patients compared to the prevalence of S A1AT in the general population. These results suggest that deficiency in A1AT may be a risk factor for acquisition of HIV infection, but physiological A1AT concentrations do not affect disease progression after infection occurs. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 01/2014; 86(1). DOI:10.1002/jmv.23759 · 2.22 Impact Factor
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    • "The prevalence of ∆32 heterozygosity in EC appears be statistically higher than in the general population (Pereyra et al., 2010), but not dramatically so, and where reported, the large majority of EC are wild-type for the CCR5 allele (Lambotte et al., 2005; Pereyra et al., 2008). Since Env from EC isolates required more CCR5 and CD4 for entry than env from chronic progressors (Lassen et al., 2009), this suggested the possibility that subtle changes in both env and CCR5 expression in the same patient could together contribute significantly to viral control. "
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    ABSTRACT: Long-term non-progressors (LTNP) were identified after 10-15 years of the epidemic, and have been the subject of intense investigation ever since. In a small minority of cases, infection with nef/3'LTR deleted attenuated viral strains allowed control over viral replication. A common feature of LTNP is the readily detected proliferation of CD4 T-cells in vitro, in response to p24. In some cases, the responding CD4 T-cells have cytotoxic effector function and may target conserved p24 epitopes, similar to the CD8 T-cells described below. LTNP may also carry much lower HIV DNA burden in key CD4 subsets, presumably resulting from lower viral replication during primary infection. Some studies, but not others, suggest that LTNP have CD4 T-cells that are relatively resistant to HIV infection in vitro. One possible mechanism may involve up-regulation of the cell cycle regulator p21/waf in CD4 T-cells from LTNP. Delayed progression in Caucasian LTNP is also partly associated with heterozygosity of the Δ32 CCR5 allele, probably through decreased expression of CCR5 co-receptor on CD4 T-cells. However, in approximately half of Caucasian LTNP, two host genotypes, namely HLA-B57 and HLA-B27, are associated with viral control. Immunodominant CD8 T-cells from these individuals target epitopes in p24 that are highly conserved, and escape mutations have significant fitness costs to the virus. Furthermore, recent studies have suggested that these CD8 T-cells from LTNP, but not from HLA-B27 or HLA-B57 progressors, can cross-react with intermediate escape mutations, preventing full escape via compensatory mutations. Humoral immunity appears to play little part in LTNP subjects, since broadly neutralizing antibodies are rare, even amongst slow progressors. Recent genome-wide comparisons between LTNP and progressors have confirmed the HLA-B57, HLA-B27, and delta32 CCR5 allelic associations, plus indicated a role for HLA-C/KIR interactions, but have not revealed any new genotypes so far. Nevertheless, it is hoped that studying the mechanisms of intracellular restriction factors, such as the recently identified SAMHD1, will lead to a better understanding of non-progression.
    Frontiers in Immunology 04/2013; 4:95. DOI:10.3389/fimmu.2013.00095
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    • "Human leukocytes antigen-B57 and HLA-B27 alleles have been found to be over-represented among EC (Kaslow et al., 1996; Migueles et al., 2000; Kiepiela et al., 2004; Lambotte et al., 2005), and supported by multiple studies showing that HIV-1-specific CD8+ T cells from EC were qualitatively superior (e.g., high proliferative capacity and cytotoxic activity) to those from patients with progressive disease (Migueles et al., 2002; Betts et al., 2006; Addo et al., 2007; Almeida et al., 2007a; Saez-Cirion et al., 2007). "
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    ABSTRACT: The natural course of human immunodeficiency virus (HIV) infection is characterized by high viral load, depletion of immune cells, and immunodeficiency, ultimately leading to acquired immunodeficiency syndrome phase and the occurrence of opportunistic infections and diseases. Since the discovery of HIV in the early 1980s a naturally selected population of infected individuals has been emerged in the last years, characterized by being infected for many years, with viremia constantly below detectable level and poor depletion of immune cells. These individuals are classified as "elite controllers (EC) or suppressors" and do not develop disease in the absence of anti-retroviral therapy. Unveiling host factors and immune responses responsible for the elite status will likely provide clues for the design of therapeutic vaccines and functional cures. Scope of this review was to examine and discuss differences of the cell-mediated immune responses between HIV+ individuals with disease progression and EC.
    Frontiers in Immunology 04/2013; 4:86. DOI:10.3389/fimmu.2013.00086
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