Native but not denatured recombinant human immunodeficiency virus type 1 gp120 generates broad-spectrum neutralizing antibodies in baboons

Abstract

The protection of individuals from human immunodeficiency virus type 1 (HIV-1) infection with an envelope subunit derived from a single isolate will require the presentation of conserved epitopes in gp120. The objective of the studies presented here was to test whether a native recombinant gp120 (rgp120) immunogen would elicit responses to conserved neutralization epitopes that are not present in a denatured recombinant gp120 antigen from the same virus isolate. In a large study of 51 baboons, we have generated heterologous neutralizing activity with native, glycosylated rgp120SF2 but not with denatured, nonglycosylated env 2-3SF2. After repeated exposure to rgp120SF2 formulated with one of several adjuvants, virus isolates from the United States, the Caribbean, and Africa were neutralized. The timing of the immunization regimen and the choice of adjuvant affected the virus neutralization titers both quantitatively and qualitatively. These results suggest that vaccination with native, glycosylated rgp120 from a single virus isolate, HIV-SF2, may elicit a protective immune response effective against geographically and sequentially distinct HIV-1 isolates.

Immunogenicity of HIV-1LAI gp160 and env peptides in squirrel monkey Saimiri sciureus using alumine and experimental adjuvants

“…These results are in agreement with those obtained by other authors who investigated the immunogenicity of different HIVderived peptidic constructs in monkey models, including baboons, macaque, and chimpanzees [16,[18][19][20]. In most of these studies several injections of the immunogen were required in order to achieve antibody titres able to neutralize HIV-1 in vitro [19]. On the other hand, in squirrel monkeys, high titre of serum antibodies above 10 ÿ 6 and neutralizing antibody titres just below 10 ÿ 2 could be reached after two immunizations in some animals.…”

“…Using recombinant gp160 protein in different adjuvant formulations, we showed that high titres of specific antibodies could be induced after only two immunizing doses of the protein, and that these antibodies recognized the protein in Western blot experiments and neutralized the activity of the virus in vitro. These results are in agreement with those obtained by other authors who investigated the immunogenicity of different HIVderived peptidic constructs in monkey models, including baboons, macaque, and chimpanzees [16,[18][19][20]. In most of these studies several injections of the immunogen were required in order to achieve antibody titres able to neutralize HIV-1 in vitro [19].…”

“…These data are in agreement with previous results from our laboratory, where squirrel monkeys were immunized with antigens given together with different adjuvant formulations [17,21]. It is not yet known whether or not the strong adjuvanticity of aluminium hydroxide is specific to squirrel monkeys, compared with baboons [19]. However, alumine was found to be similarly efficient in inducing neutralizing antibody, when using a whole inactivated virus as immunogen in chimpanzees [22].…”

B‐Cell Abnormalities in AIDS: Stable and Clonally‐Restricted Antibody Response in HIV‐1 Infection

“…The existence of both monoclonal and polyclonal serum anti-gpl20 antibodies against conserved epitopes such as the CD4 binding site with broad neutralizing reactivity has been already demonstrated by one of us [32] and others [36,37). Vaccine work in baboons further demonstrates that with an appropriate immunogen and regimen it is possible to broaden the immune response to divergent isolates [38]. Similarly, therapeutic approaches should avoid reinforcing established restricted clonal responses of B-cells producing ineffective antibodies and be able to restore a polyclonal immune response.…”

Increased antibodies against unfolded viral antigens in the elderly after influenza vaccination

“…To investigate the utility of a more direct method of assessing vaccine response, we developed a sandwich ELISA method to separately measure antibodies against native glycoproteins, which are potentially protective, and antibodies against denatured glycoproteins or internal viral proteins ('unfoldons'), 12 which are not protective. [13][14][15][16][17][18] Direct coating of virus onto microtiter plate wells results in virus disruption and denaturing some proportion of surface glycoproteins. Thus, direct virus coating will capture all anti-influenza antibodies against native, denatured, and internal proteins.…”