Alterations in Cholesterol Metabolism Restrict HIV-1 <italic toggle="yes">Trans</italic> Infection in Nonprogressors

ABSTRACT HIV-1-infected nonprogressors (NP) inhibit disease progression for years without antiretroviral therapy. Defining the mechanisms for this resistance to disease progression could be important in determining strategies for controlling HIV-1 infection. Here we show that two types of profession...

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Autores principales:	Giovanna Rappocciolo, Mariel Jais, Paolo Piazza, Todd A. Reinhart, Stella J. Berendam, Laura Garcia-Exposito, Phalguni Gupta, Charles R. Rinaldo
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/81e4fa9071a544f0b23ab381825ea254
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spelling	oai:doaj.org-article:81e4fa9071a544f0b23ab381825ea2542021-11-15T15:47:38ZAlterations in Cholesterol Metabolism Restrict HIV-1 <italic toggle="yes">Trans</italic> Infection in Nonprogressors10.1128/mBio.01031-132150-7511https://doaj.org/article/81e4fa9071a544f0b23ab381825ea2542014-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01031-13https://doaj.org/toc/2150-7511ABSTRACT HIV-1-infected nonprogressors (NP) inhibit disease progression for years without antiretroviral therapy. Defining the mechanisms for this resistance to disease progression could be important in determining strategies for controlling HIV-1 infection. Here we show that two types of professional antigen-presenting cells (APC), i.e., dendritic cells (DC) and B lymphocytes, from NP lacked the ability to mediate HIV-1 trans infection of CD4+ T cells. In contrast, APC from HIV-1-infected progressors (PR) and HIV-1-seronegative donors (SN) were highly effective in mediating HIV-1 trans infection. Direct cis infection of T cells with HIV-1 was comparably efficient among NP, PR, and SN. Lack of HIV-1 trans infection in NP was linked to lower cholesterol levels and an increase in the levels of the reverse cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) in APC but not in T cells. Moreover, trans infection mediated by APC from NP could be restored by reconstitution of cholesterol and by inhibiting ABCA1 by mRNA interference. Importantly, this appears to be an inherited trait, as it was evident in APC obtained from NP prior to their primary HIV-1 infection. The present study demonstrates a new mechanism wherein enhanced lipid metabolism in APC results in remarkable control of HIV-1 trans infection that directly relates to lack of HIV-1 disease progression. IMPORTANCE HIV-1 can be captured by antigen-presenting cells (APC) such as dendritic cells and transferred to CD4 helper T cells, which results in greatly enhanced viral replication by a mechanism termed trans infection. A small percentage of HIV-1-infected persons are able to control disease progression for many years without antiretroviral therapy. In our study, we linked this lack of disease progression to a profound inability of APC from these individuals to trans infect T cells. This effect was due to altered lipid metabolism in their APC, which appears to be an inherited trait. These results provide a basis for therapeutic interventions to control of HIV-1 infection through modulation of cholesterol metabolism.Giovanna RappoccioloMariel JaisPaolo PiazzaTodd A. ReinhartStella J. BerendamLaura Garcia-ExpositoPhalguni GuptaCharles R. RinaldoAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 3 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Giovanna Rappocciolo Mariel Jais Paolo Piazza Todd A. Reinhart Stella J. Berendam Laura Garcia-Exposito Phalguni Gupta Charles R. Rinaldo Alterations in Cholesterol Metabolism Restrict HIV-1 <italic toggle="yes">Trans</italic> Infection in Nonprogressors
description	ABSTRACT HIV-1-infected nonprogressors (NP) inhibit disease progression for years without antiretroviral therapy. Defining the mechanisms for this resistance to disease progression could be important in determining strategies for controlling HIV-1 infection. Here we show that two types of professional antigen-presenting cells (APC), i.e., dendritic cells (DC) and B lymphocytes, from NP lacked the ability to mediate HIV-1 trans infection of CD4+ T cells. In contrast, APC from HIV-1-infected progressors (PR) and HIV-1-seronegative donors (SN) were highly effective in mediating HIV-1 trans infection. Direct cis infection of T cells with HIV-1 was comparably efficient among NP, PR, and SN. Lack of HIV-1 trans infection in NP was linked to lower cholesterol levels and an increase in the levels of the reverse cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) in APC but not in T cells. Moreover, trans infection mediated by APC from NP could be restored by reconstitution of cholesterol and by inhibiting ABCA1 by mRNA interference. Importantly, this appears to be an inherited trait, as it was evident in APC obtained from NP prior to their primary HIV-1 infection. The present study demonstrates a new mechanism wherein enhanced lipid metabolism in APC results in remarkable control of HIV-1 trans infection that directly relates to lack of HIV-1 disease progression. IMPORTANCE HIV-1 can be captured by antigen-presenting cells (APC) such as dendritic cells and transferred to CD4 helper T cells, which results in greatly enhanced viral replication by a mechanism termed trans infection. A small percentage of HIV-1-infected persons are able to control disease progression for many years without antiretroviral therapy. In our study, we linked this lack of disease progression to a profound inability of APC from these individuals to trans infect T cells. This effect was due to altered lipid metabolism in their APC, which appears to be an inherited trait. These results provide a basis for therapeutic interventions to control of HIV-1 infection through modulation of cholesterol metabolism.
format	article
author	Giovanna Rappocciolo Mariel Jais Paolo Piazza Todd A. Reinhart Stella J. Berendam Laura Garcia-Exposito Phalguni Gupta Charles R. Rinaldo
author_facet	Giovanna Rappocciolo Mariel Jais Paolo Piazza Todd A. Reinhart Stella J. Berendam Laura Garcia-Exposito Phalguni Gupta Charles R. Rinaldo
author_sort	Giovanna Rappocciolo
title	Alterations in Cholesterol Metabolism Restrict HIV-1 <italic toggle="yes">Trans</italic> Infection in Nonprogressors
title_short	Alterations in Cholesterol Metabolism Restrict HIV-1 <italic toggle="yes">Trans</italic> Infection in Nonprogressors
title_full	Alterations in Cholesterol Metabolism Restrict HIV-1 <italic toggle="yes">Trans</italic> Infection in Nonprogressors
title_fullStr	Alterations in Cholesterol Metabolism Restrict HIV-1 <italic toggle="yes">Trans</italic> Infection in Nonprogressors
title_full_unstemmed	Alterations in Cholesterol Metabolism Restrict HIV-1 <italic toggle="yes">Trans</italic> Infection in Nonprogressors
title_sort	alterations in cholesterol metabolism restrict hiv-1 <italic toggle="yes">trans</italic> infection in nonprogressors
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/81e4fa9071a544f0b23ab381825ea254
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Alterations in Cholesterol Metabolism Restrict HIV-1 <italic toggle="yes">Trans</italic> Infection in Nonprogressors

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