Our Science – Robert-Guroff Website
Marjorie Robert-Guroff, Ph.D.
Our laboratory is interested in retroviral pathogenesis and strategies for the diagnosis, treatment, and prevention of retroviral-induced human diseases. HIV and AIDS are our main areas of research.
AIDS Vaccine Development
We are utilizing adenovirus recombinants for delivery of AIDS vaccines. Our studies in chimpanzees have shown that live, replication-competent Ad-HIV recombinants, together with a viral envelope booster immunization, elicit humoral, cellular, and mucosal immune responses, including antibodies capable of neutralizing both lab-adapted and primary viral isolates, antibodies in secretory fluids, and viral-specific cytotoxic T-lymphocytes. Long-lasting protection against syncytial-inducing HIV isolates was demonstrated. Moreover, protection was achieved against a primary, non-syncytium-inducing HIV isolate, representative of the type which is readily transmitted between people. Notably, these advances were achieved using a vaccine based only on the viral envelope. We expect greater vaccine efficacy if multi-component vaccines are employed. These findings have provided the basis for moving ahead into phase I human trials, in which the safety and immunogenicity of Ad-HIV recombinants administered orally or intranasally will be compared. Further studies in chimpanzees will compare the immunogenicity of replication-competent and -incompetent Ad-HIV recombinants, in order that design of next generation vaccine materials can be based in the most appropriate vector.
To further exploit this vaccine approach, an adenovirus type 5 host range mutant (Ad5hr)-SIV recombinant system has been utilized. The full spectrum of immune responses was again seen in rhesus macaques immunized with a host range mutant recombinant carrying the inserted SIV envelope gene, in combination with envelope protein boosting. Moreover, decreased viral burden during the acute phase of pathogenic SIV infection was observed in immunized rhesus macaques. Addition of an Ad5hr-SIVgag recombinant to the priming regimen resulted in improved protection, with reduced viral burdens seen at the set point of infection. Recent results using multi-component Ad5hr-SIV recombinants encoding env/rev, gag, and/or nef, followed by boosting with SIV gp120 or a novel polypeptide (termed a peptomer) mimicking the CD4 binding region of the envelope, showed the best protective efficacy to date. Notably, 39% of macaques immunized with recombinants encoding 3 or more SIV genes and boosted with gp120, or primed with Ad5hr-SIVenv/rev and boosted with the peptomer, exhibited no viremia, or cleared or controlled viremia at the threshold of detection following challenge with the highly pathogenic SIVmac251 isolate. No other approach has achieved this level of protective efficacy to date, except for live attenuated virus, deemed too dangerous for vaccine use.
In further studies using the Ad-recombinant priming/subunit boosting approach, we are improving routes of vaccine administration in order to elicit better mucosal immunity, investigating additional vaccine induced immune responses, such as antibody-dependent cellular cytotoxicity, and evaluating additional combination vaccine regimens using other vectors in combination with the replicating Ad recombinants. Development of additional recombinants encoding regulatory and accessory genes, and envelopes of different HIV clades is underway.
This page was last updated on 2/22/2013.