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The recent failure of the Merck HIV candidate vaccine (JW AIDS Clin Care Dec 8 2008) has sent the field back to basics. Researchers are focusing on obtaining a deeper understanding of how the human immune system interacts with HIV. Two new studies provide insights that could inform the development of a vaccine.
Scheid and colleagues examined the basis of the neutralizing antibody response against HIV, one of the holy grails of vaccine development. Such antibodies are not detectable in most HIV-infected patients. In this study, six individuals with low-to-intermediate viral loads who did have neutralizing antibodies were evaluated. Using an HIV envelope glycoprotein “bait,” the investigators selected specific memory B cells from these patients and then cloned and characterized 502 monoclonal antibodies produced by individual cells. The team pinpointed areas of the HIV envelope that are targeted by specific antibodies and found that pools of monoclonal antibodies could neutralize the virus, but only at high concentrations. As an editorialist notes, the study did not identify new broadly neutralizing monoclonal antibodies against HIV, but hope remains that the authors’ novel methodology might do so in the future.
Kawashima and colleagues looked for evidence of HIV evolution in response to the other main arm of the immune system, CD8 cells. The investigators examined viral sequences from 2875 HIV-infected patients drawn from nine cohorts spanning five continents. They determined that the frequency of HIV sequence variants associated with immune escape was correlated with the population prevalence of specific HLA alleles that mediate immune pressure against the virus. This finding suggests that the virus is evolving on a population level to avoid the human immune response.
Scheid JF et al. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 2009 Apr 2; 458:636.
Burton DR and Poignard P. Immune memory downloaded. Nature 2009 Apr 2; 458:584.
Kawashima Y et al. Adaptation of HIV-1 to human leukocyte antigen class I. Nature 2009 Apr 2; 458:641.
Comment
These two studies highlight the promise and the hurdles of HIV vaccine research. Although novel methods of characterizing the human immune response (e.g., Scheid and colleagues’ “bait” strategy) will almost certainly provide new tools to characterize and stimulate antiviral immunity, the virus has the capacity to evolve or “switch” to avoid immune pressure, as Kawashima and colleagues’ study convincingly demonstrates. One hope is that we will eventually be able to identify portions of the virus that cannot escape the immune response. Clearly, advances in our understanding of the interplay between the virus and its human host — of the sort provided by these two studies — will be needed before we can develop an effective HIV vaccine.