A model is proposed for validation as an in vitro correlate of protective immunity to HIV-1. While urgently needed to evaluate experimental HIV vaccines, no such correlates presently exists for two fundamental reasons according to the author. First, high levels of specific neutralizing antibodies and cytotoxic T lymphocytes are induced by natural infection but do not prospectively identify individuals who are subsequently protected from virus induced disease. Second, there have been no reports demonstrating pre-existing HIV-1 specific in vitro immunity among prospectively studied, uninfected individuals or cohorts with known repeated exposures to infectious HIV-1. Until groups of protectively immune individuals are identified and studies for in vitro correlates of this immunity, there can be no clear correlates of protective immunity. A simple, highly reproducible, quantifiable in vitro assay of susceptibility or resistance to endogenous and exogenous HIV-1 challenge is described. Among long term asymptomatic and recently infected HIV+ donors, it shows a very strong correlation of resistant phenotype with low plasma viremia which is an accepted prognostic marker of slow disease progression. Overall, approximately 75% of unvaccinated donors or recipients of only envelope based vaccines have PBMCs which consistently support growth of HIV-1 at a challenge dose of 100 TCID50 (as titered in H9 cells). However, induction of stable, CD8+ cell dependent, chemokine independent, in vitro resistance has been demonstrated in an uninfected recipient of the first experimental vaccine inducing strong gag-specific CTL. PBMCs from this volunteer were susceptible, and without CTL activity, prior to the second vaccination. The investigators plan to challenge baseline and post-vaccination PBMCs from participants in trials of the newest generation of experimental HIV vaccines which are expected to induce immune responses qualitatively and quantitatively superior to those induced by vaccines based solely on envelope. The investigators will also examine in vitro resistance of PBMCs from the only cohort of prospectively studied protected individuals who were sex workers in Dakar, Senegal who are HIV-2 positive and are approximately 70% protected from HIV-1 infection compared to their HIV-2 negative appropriately matched co-workers. PBMC cultures from the various groups described will be analyzed for the contribution of CD8+ cells, specific new chosen antibodies and cytokines to the resistant phenotype.
| Castillo, R C; Arango-Jaramillo, S; John, R et al. (2000) Resistance to human immunodeficiency virus type 1 in vitro as a surrogate of vaccine-induced protective immunity. J Infect Dis 181:897-903 |
| Castillo, R C; Arango-Jaramillo, S; John, R et al. (2000) Rapid communication: development of in vitro resistance to macrophage-tropic- and T-cell-line-adapted HIV-1 strains among HIV-positive volunteers treated with highly active antiretroviral therapy. J Acquir Immune Defic Syndr 24:197-202 |
