GENERATION AND USE OF AN AIDS-INDUCING R5-TROPIC SHIV WITH NOVEL PATHOGENIC PROPERTIES BY SERIAL PASSAGING IN RHESUS MACAQUES We have generated a new pathogenic R5-tropic SHIV following long-term animal-to-animal passage, which bears the env gene from the prototypical macrophage tropic strain, HIV 1Ada. SHIVAD8 is able to sustain plasma viremia in rhesus monkeys for more than 2 years;all 13 inoculated animals experienced marked depletions of CD4+ T lymphocytes. Ten of these monkeys became normal progressors (NPs), generated anti-viral CD8+ T cell responses, and sustained chronic immune activation. These monkeys sustained opportunistic infections involving Mycobacterium avium, Pneumocystis carinii, and Campylobacter coli. In preparation for performing passive transfer and vaccine studies, SHIVAD8 stocks, prepared from animals at the time of euthanasia, have been titrated intra-rectally (IR). As little as 10e3 infectious units administered by this route is capable of consistently initiating a durable infection. RAPID DEVELOPMENT OF GLYCAN-SPECIFIC, BROAD AND POTENT ANTI-HIV 1 GP120 NEUTRALIZING ANTIBODIES IN A SHIV- INFECTED MACAQUE. It is widely believed that the induction of a broadly neutralizing antibody (bNAb) response will be a critical component of a successful vaccine against HIV. A significant fraction of HIV-infected individuals mount bNAb responses, providing support for the notion that such responses could be elicited through vaccination. SIV and SHIV-infection of macaques have been widely used to model aspects of HIV infection but to date only rather limited bNAb responses have been observed in these animal models. In collalboration with Dennis Burton, Scripps Research Institute, we screened plasma from 14 R5-tropic SHIV-infected macaques for broadly neutralizing activity. One macaque displayed extraordinarily potent cross-clade plasma NAb responses against multiple Tier 2 HIV 1 isolates. Neutralization assays performed on plasma samples taken at serial time points from this animal revealed that broad and potent plasma neutralizing activity developed rapidly and coincided with the development of autologous NAb responses. Serum mapping studies were carried out using pseudovirus point mutants and antigen adsorption assays, and indicated that the plasma bNAbs are specific for carbohydrate epitopes critically dependent on the glycan at position 332 of Env gp120. The results described herein provide insight into the development and evolution of broad responses, and may suggest that certain bNAb specificities can be more rapidly induced by immunization than others. This work is in press in the Proceedings of the National Academy of Sciences.
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