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.

Figure 1

Various approaches for HIV vaccine development. The various approaches used in past and present HIV vaccine strategies that are summarized here have been described in detail previously [1-3, 15].

Figure 2

Convergent evolution of SBBC nef/LTR sequences. Comparisons of the genomic structures of the nef/LTR sequences cloned from the earliest available and most recently obtained PBMC samples of D36, C98, C49, C54 and C64 are shown. The genomic structures are compared to wild type HIV (NL4-3). Numbers refer to nucleotide positions in NL4-3. Black boxes represent intact sequence, and gaps represent deletions. Grey blocks represent sequence areas containing alterations of NF-κB and Sp-1 binding sites in the LTR. The dates shown represent the times when PBMC were collected for analysis. PPT, polypurine tract; NRE, negative regulatory unit. This figure has been published previously [29], and is reproduced here with permission from the American society for microbiology.

Figure 3

Longitudinal analysis of T-helper proliferative responses to HIV p24 antigen in SBBC progressors and nonprogressors. T-helper proliferative responses to HIV p24 antigen were determined by [³H]-thymidine incorporation, as described previously [99, 100]. T-helper responses were persistently detectable (stimulation index > 3) in all nonprogressing subjects with below detectable plasma HIV RNA levels (C135, C64, and C49), but absent in all progressors (D36, C98, and C54). Of note, T-helper responses were detectable over a short window in C18, who was a nonprogressing individual with detectable plasma HIV RNA levels.