RESUMO
Immunodeficiency does not progress for prolonged periods in some HLA B57- and/or B27-positive subjects with human immunodeficiency virus type 1 (HIV) infection, even in the absence of antiretroviral therapy (ART). These "controllers" have fewer HIV provirus-containing peripheral blood mononuclear cells than "non-controller" subjects, but lymphocytes that harbor latent proviruses were not specifically examined in studies to date. Provirus levels in resting memory cells that can serve as latent reservoirs of HIV in blood were compared here between controllers and ART-suppressed non-controllers. APOBEC3G (A3G), a cellular factor that blocks provirus formation at multiple steps if not antagonized by HIV virion infectivity factor (Vif), was also studied. HLA-linked HIV control was associated with less provirus and more A3G protein in resting CD4+ T central memory (Tcm) and effector memory (Tem) lymphocytes (provirus: p = 0.01 for Tcm and p = 0.02 for Tem; A3G: p = 0.02 for Tcm and p = 0.02 for Tem). Resting memory T cells with the highest A3G protein levels (>0.5 RLU per unit of actin) had the lowest levels of provirus (<1,000 copies of DNA per million cells) in vivo (p = 0.03, Fisher's exact test). Using two different experimental approaches, Vif-positive viruses with more A3G were found to have decreased virion infectivity ex vivo. These results raise the hypothesis that HIV control is associated with increased cellular A3G that may be packaged into Vif-positive virions to add that mode of inhibition of provirus formation to previously described adaptive immune mechanisms for HIV control.
Assuntos
Citidina Desaminase/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Memória Imunológica , Provírus/fisiologia , Vírion/fisiologia , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética , Desaminase APOBEC-3G , Imunidade Adaptativa , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Citidina Desaminase/genética , Expressão Gênica , Infecções por HIV/virologia , HIV-1/patogenicidade , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígeno HLA-B27/genética , Antígeno HLA-B27/imunologia , Interações Hospedeiro-Patógeno , Humanos , Provírus/patogenicidade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia , Carga Viral , Vírion/patogenicidade , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismoRESUMO
APOBEC3G (A3G) and APOBEC3F (A3F) reduce Vif-negative HIV-1 provirus formation and cause disabling provirus G-to-A hypermutation in vitro. However, evidence conflicts about whether they negatively impact Vif-positive HIV-1, or only enhance virus genetic diversity, in vivo. We studied peripheral blood mononuclear cells (PBMC) from 19 antiretroviral-naïve, HIV-infected adults: 12 long-term non-progressors (LTNP) and 7 non-controllers (NC). Cells from LTNP had higher A3G and A3F mRNA levels, lower provirus burden, and more A3G-hypermutated positions in provirus sequence than cells from NC. A3G mRNA level was directly associated with its Hypermutation Index (HI) and inversely associated with provirus burden. Plasma HIV-1 RNA levels were inversely associated with A3G expression levels and with HI only among subjects who had HI>1. A3G HI was not associated with provirus burden. These results indicate that A3G deaminase-dependent activity above a threshold level, and its deaminase-independent functions, contribute to decreasing Vif-positive virus replication in vivo.