Pathogenicity and immunogenicity of attenuated, nef-deleted HIV-1 strains in vivo

Abstract

In efforts to develop an effective vaccine, sterilizing immunity to primate lentiviruses has only been achieved by the use of live attenuated viruses carrying major deletions in nef and other accessory genes. Although live attenuated HIV vaccines are unlikely to be developed due to a myriad of safety concerns, opportunities exist to better understand the correlates of immune protection against HIV infection by studying rare cohorts of long-term survivors infected with attenuated, nef-deleted HIV strains such as the Sydney blood bank cohort (SBBC). Here, we review studies of viral evolution, pathogenicity, and immune responses to HIV infection in SBBC members. The studies show that potent, broadly neutralizing anti-HIV antibodies and robust CD8+ T-cell responses to HIV infection were not necessary for long-term control of HIV infection in a subset of SBBC members, and were not sufficient to prevent HIV sequence evolution, augmentation of pathogenicity and eventual progression of HIV infection in another subset. However, a persistent T-helper proliferative response to HIV p24 antigen was associated with long-term control of infection. Together, these results underscore the importance of the host in the eventual outcome of infection. Thus, whilst generating an effective antibody and CD8+ T-cell response are an essential component of vaccines aimed at preventing primary HIV infection, T-helper responses may be important in the generation of an effective therapeutic vaccine aimed at blunting chronic HIV infection.

Human Immunodeficiency Virus Type 1 Nef Incorporation into Virions Does Not Increase Infectivity

“…Soon after its initial description as a negative factor of HIV-1 replication (3,54,63), Nef was shown to be required for optimal HIV and SIV infectivity in vitro and pathogenicity in vivo (4,9,18,28,37,39,40,46,47,71). Several mechanisms have been put forward to explain the gain of infectivity conferred by Nef to HIV-1; however, these mechanisms fail to fit all the experimental systems in which the gain of infectivity can be observed.…”

“…Among these proteins, Nef has proven to play a major role in the progression of infections with simian (SIV) and human (HIV) immunodeficiency viruses toward AIDS in primates (18,28,39,40,46,47,71). Single-round infection assays based on cell-free recombinant viruses also revealed that wild-type (WT) HIV type 1 (HIV-1) and SIV are more infectious than mutants lacking Nef expression (⌬nef viruses) (4,9,37).…”

CD4 downregulation by the HIV-1 protein Nef reveals distinct roles for the γ1 and γ2 subunits of the AP-1 complex in protein trafficking

“…During the early stages of infection, one of the most abundantly produced HIV proteins is Nef, an accessory protein with no enzymatic activity. Nef is a 27-35-kDa myristoylated protein encoded by the HIV-1, HIV-2 and the simian immunodeficiency virus (SIV) genomes, which is crucial for sustaining robust viral production and promoting disease progression to full-blown AIDS (Deacon et al, 1995;Gorry et al, 2007;Gulizia et al, 1997;Kestier et al, 1991;Learmont et al, 1999;Oelrichs et al, 1998).…”

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

“…Nef, an HIV-1 accessory protein, is expressed abundantly in the early stages of the viral life cycle and plays a key role in the progression of infection toward AIDS in primates (13)(14)(15). Among Nef functions, its ability to affect cell surface protein trafficking, including CD4 or MHC I molecules, has been well characterized (16).…”