Viremic long-term nonprogressive HIV-1 infection is not associated with abnormalities in known Nef functions.
BACKGROUND
A small minority of HIV-1-infected individuals show low levels of immune activation and do not develop immunodeficiency despite high viral loads. Since the accessory viral Nef protein modulates T cell activation and plays a key role in the pathogenesis of AIDS, we investigated whether specific properties of Nef may be associated with this highly unusual clinical outcome of HIV-1 infection.


RESULTS
Comprehensive functional analyses of sequential HIV-1 strains from three viremic long-term non-progressors (VNP) showed that they encode full-length Nef proteins that are capable of modulating CD4, CD28, CD8ß, MHC-I and CD74 cell surface expression. Similar to Nef proteins from HIV-1-infected individuals with progressive infection (P-Nefs) and unlike Nefs from simian immunodeficiency viruses (SIVs) that do not cause chronic immune activation and disease in their natural simian hosts, VNP-Nefs were generally unable to down-modulate TCR-CD3 cell surface expression to block T cell activation and apoptosis. On average, VNP-Nefs suppressed NF-AT activation less effectively than P-Nefs and were slightly less active in enhancing NF-κB activity. Finally, we found that VNP-Nefs increased virion infectivity and enhanced HIV-1 replication and cytopathicity in primary human cells and in ex vivo infected lymphoid tissues.


CONCLUSIONS
Our results show that nef alleles from VNPs and progressors of HIV-1 infection show only modest differences in established functions. Thus, the lack of chronic immune activation and disease progression in HIV-1-infected VNPs is apparently not associated with unusual functional properties of the accessory viral Nef protein.
Anke
A
Heigele
David
D
Camerini
Angélique B
AB
van't Wout
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. frank.kirchhoff@uni-ulm.de.
Frank
F
Kirchhoff
D015703:Antigens, CD / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000821:virology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D014766:Viremia / Q000276:immunology* / Q000821:virology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D015703:Antigens, CD; D015395:Histocompatibility Antigens Class I; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1