HIV Nef and Vpu protect HIV-infected CD4+ T cells from antibody-mediated cell lysis through down-modulation of CD4 and BST2.
BACKGROUND
HIV proteins Nef and Vpu down-modulate various host factors to evade immune defenses. Indeed, the CD4 receptor is down-regulated by Nef and Vpu, whereas virion-tethering BST2 is depleted by Vpu. Antibody-dependent cell-mediated cytotoxicity (ADCC) is increasingly recognized as a potentially powerful anti-HIV response. Given that epitopes which are specific for ADCC-competent anti-HIV antibodies are transitionally exposed upon CD4-mediated HIV entry, we investigated whether by depleting CD4 and BST2, HIV could negatively affect ADCC function.


RESULTS
Using anti-envelope (Env) Abs A32 and 2G12 to trigger ADCC activity, we find that interactions between CD4 and Env within infected cells expose ADCC-targeted epitopes on cell-surface Env molecules, marking infected T cells for lysis by immune cells. We also provide evidence to show that by cross-linking nascent virions at the plasma membrane, hence increasing cell-surface Env density, BST2 further enhances the efficiency of this antiviral process. The heightened susceptibility of T cells infected with a virus lacking Nef and Vpu to ADCC was recapitulated when plasmas from HIV-infected patients were used as an alternative source of Abs.


CONCLUSIONS
Our data unveil a mechanism by which HIV Nef and Vpu function synergistically to protect infected cells from ADCC and promote viral persistence. These findings also renew the potential practical relevance of ADCC function in vivo.
Tram N Q
TN
Pham
Sabelo
S
Lukhele
Fadi
F
Hajjar
Jean-Pierre
JP
Routy
Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal H2W 1R7, Quebec, Canada. eric.cohen@ircm.qc.ca.
Éric A
ÉA
Cohen
D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology / Q000821:virology*; D002470:Cell Survival; D015536:Down-Regulation; D058851:GPI-Linked Proteins / Q000378:metabolism; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D008954:Models, Biological; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D000074010:Bone Marrow Stromal Antigen 2
D015703:Antigens, CD; D015704:CD4 Antigens; D058851:GPI-Linked Proteins; D015483:HIV Antibodies; D054311:nef Gene Products, Human Immunodeficiency Virus; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2