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Autophagy plays an important role in the containment of HIV-1 in nonprogressor-infected patients

Significance Statement

In this paper, a physiological process playing a key role in eukaryotic cell homeostasis, namely autophagy, has been studied as possible factor counteracting the HIV-1-induced disease. This mechanism is involved in the pathogenesis of the major human diseases such as cancer, neurodegeneration, aging, heart disease, and plays a key function in controlling several infection diseases. Our results highlight the important role of autophagy in counteracting the HIV-1-induced pathogenesis in a special subset of HIV-1-infected patients that spontaneously and durably maintain extremely low virus replication. These individuals, often referred to as long-term non-progressors (LTNP), are able to maintain normal CD4+ T-cell counts for a prolonged period of time and remain asymptomatic without anti-retroviral therapy; some of them, termed elite controllers (EC), shows plasma HIV-RNA values below detectable level (50 copies/ml) persistently. In this study we have shown, for the first time, that in LTNP and EC the resistance to HIV-1-induced pathogenesis is accompanied, in vivo, by a significant increase in the autophagic activity in peripheral blood mononuclear cells (PBMC). In these cells, indeed, viral particles and viral components are trapped inside autophagic vacuoles which are then completely digested in autolysosomes. By contrast, in HIV-1-infected normal progressors, HIV-1 is able to inhibit the late stages of autophagy protecting the virus from the degradation. Among novel therapeutic strategies, the physiological process of autophagy is emerging as an attractive therapeutic target in treatment of several human diseases and aging. In our opinion, these findings could be relevant in the fight against HIV-1 disease, since many autophagy inducers, that are currently under clinical investigation for the treatment of several diseases, might be employed in combination with antiretroviral drugs.

 

Figure Legend

Hypothetical mechanism of HIV-1 removal by autophagy in HIV-1-infected non-progressor patients.

HIV-1 assembles both at the plasma membrane and in intracellular virus-containing compartments (VCCs) of infected cells. The assembled viral particles localized in VCCs as well as some viral components, can be sequestered by autophagosomes where the HIV-1 and its components can get digested in autolysosomes. This protective process is impaired in normal progressors. N, nucleus; m, mitochondrion; VCC, virus containing compartment;  , HIV-1 particles; , viral components. Original magnification of ultrastructural images: 12.000 x; insert 50,000 x.

Autophagy plays an important role in the containment of HIV-1 in nonprogressor-infected patients. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

Nardacci R1, Amendola A1, Ciccosanti F1, Corazzari M2, Esposito V1, Vlassi C1, Taibi C1, Fimia GM3, Del Nonno F1, Ippolito G1,D’Offizi G1, Piacentini M2. Autophagy. 2014 ;10(7):1167-78.

1National Institute for Infectious Diseases; IRCCS “L. Spallanzani”; Rome, Italy.

2National Institute for Infectious Diseases; IRCCS “L. Spallanzani”; Rome, Italy; Department of Biology; University of Rome “Tor Vergata”; Rome, Italy.

3National Institute for Infectious Diseases; IRCCS “L. Spallanzani”; Rome, Italy; Department of Biological and Environmental Sciences and Technologies (DiSTeBA); University of Salento; Lecce, Italy.

Abstract

Recent in vitro studies have suggested that autophagy may play a role in both HIV-1 replication and disease progression. In this study we investigated whether autophagy protects the small proportion of HIV-1 infected individuals who remain clinically stable for years in the absence of antiretroviral therapy, these named long-term nonprogressors (LTNP) and elite controllers (EC). We found that peripheral blood mononuclear cells (PBMC) of the HIV-1 controllers present a significantly higher amount of autophagic vesicles associated with an increased expression of autophagic markers with respect to normal progressors. Of note, ex vivo treatment of PBMC from the HIV-1 controllers with the MTOR inhibitor rapamycin results in a more efficient autophagic response, leading to a reduced viral production. These data lead us to propose that autophagy contributes to limiting viral pathogenesis in HIV-1 controllers by targeting viral components for degradation.

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