It is not known whether, to what degree or under what circumstances, cellular and humoral immunity can act cooperatively in clearing or controlling HIV-1 infection. In a vaccine context, the major hurdle has been the inability of candidate vaccines to consistently elicit significant neutralizing antibody titers in contrast to their ability to elicit strong T cell responses. Similarly in established infection, where neutralizing antibody titers are usually very low, we do not know the extent to which cellular and humoral responses may act, or be induced to act, in concert to control infection. ? ? Here we propose to investigate the ability of combined cellular and humoral immunity to protect against HIV infection by providing, prior to viral challenge, a cellular response through vaccination and neutralizing antibodies by passive administration. We refer to this approach as """"""""active T cell/passive antibody."""""""" We propose to evaluate the approach in SIVmac239 challenge of macaques using vaccination protocols already established to elicit vigorous T cell responses to SIV proteins and using an antibody CD4-IgG2 molecule that we have shown is highly effective in neutralizing this generally resistant virus. SIVmac239 is chosen as one of the most appropriate models of HIV-1 infection. CD4-IgG2 is chosen because it behaves in key respects as a conventional monoclonal antibody but has particularly potent activity against SIVmac239. We also propose to further our understanding of the impact of antibodies on ongoing infection in the context of a cellular response in the SIV and SHIV/macaque models by passively transferring neutralizing antibodies to infected animals. ? ? The specific aims are: 1. To evaluate the activity of antibody CD4-IgG2 against SIVmac239 in macaques in protection against mucosal challenge and in an ongoing infection. To evaluate the effects of having specific T cells and neutralizing antibody (CD4-IgG2) present together in macaques prior to challenge with SIVmac239. The neutralizing antibody levels will be chosen to be below those giving sterile protection as determined in Aim 1 and will correspond more to those that cold be achieved through vaccination. 3. To evaluate the effects of anti-HIV-1 neutralizing monoclonal antibodies, singly or as a cocktail, and CD4-IgG2 against an ongoing SHIV162P infection in macaques. This will provide us with the first opportunity to look at the effects of potent human mAbs on established infection in the presence of functional T cells.
| Veazey, Ronald S; Shattock, Robin J; Pope, Melissa et al. (2003) Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med 9:343-6 |
| Mascola, John R; Lewis, Mark G; VanCott, Thomas C et al. (2003) Cellular immunity elicited by human immunodeficiency virus type 1/ simian immunodeficiency virus DNA vaccination does not augment the sterile protection afforded by passive infusion of neutralizing antibodies. J Virol 77:10348-56 |
