New Approaches in the Potential Treatment of HIV–acquired Immunodeficiency Disease

Several new studies report progress in the further development of approaches to manipulating the immune response to HIV with the hope of delaying or preventing the loss of immune function leading to AIDS. Although the advent of antiviral therapy has remarkably transformed HIV infection from a fulminant and fatal disease to, in many cases, a long-term chronic disease, the therapy is not perfect. Costs, toxicities, unknown long-term effects, and the emergence of strains resistant to current drug regimens are problematic. The last, a result of the virus's capacity to rapidly mutate, has been anticipated to be a barrier to the effective development of vaccines for HIV, in that such variability leads ultimately to immune surveillance escape. Indeed, a vaccine developed by Merck, V520, was widely publicized last year to have failed, apparently for this reason. Thus, the ability of HIV to evade both humoral and T-cell-mediated destruction is a significant obstacle to the development of effective vaccine strategies. In a study published in Nature, investigators at Harvard used a new vaccine approach and showed efficacy in a rhesus monkey model of AIDS.1Liu J O'Brien KL Lynch DM Simmons NL La Porte A Riggs AM et al.Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys.Nature. 2008; 2008 (e-pub ahead of print 9 November 2008)Google Scholar The trial used a recombinant adenovirus serotype 26 (rAd26) to express simian immunodeficiency virus (SIV) gag proteins in an initial stimulation of the immune system. This differs from the Merck approach, which used recombinant vector based on adenovirus serotype 5 (Ad5). Infection with Ad5 is common in humans, and the authors of the present study surmised that initial immune-mediated clearance of rAd26 would be reduced as compared with an rAd5-based vector. They also incorporated a second exposure (boost) to SIV-1 antigens, this time using an rAd5 backbone. The article demonstrates reduced SIV load in primates vaccinated before SIV challenge in vivo and reduction of AIDS-related mortality in the vaccinated animals with a follow-up of 500 days. The work was done in collaboration with Crucell Holland BV. In a separate study, which addressed the virus's tendency to mutate, investigators at the University of Pennsylvania and Cardiff University in the United Kingdom reported success in engineering T cells with significantly increased T-cell receptor (TCR) affinities for HIV-1.2Varela-Rohena A Molloy PE Dunn SM Li Y Suhoski MM Carroll RG et al.Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor.Nat Med. 2008; 14: 1390-1395Crossref PubMed Scopus (205) Google Scholar Using phage display of a T-cell line from an infected individual, the investigators were able to isolate a TCR gene that encoded a TCR with ~500-fold increased binding to HIV-1 gag peptide. CD8 T cells transfected with this TCR targeted HIV-infected cells and recognized HIV strains that had evaded detection by natural T cells (called “escape variants”). Resulting clones responded robustly to stimulation with higher secretion of cytokines and chemokines, including interleukin-2, suggesting that large numbers of effector T cells could be generated rapidly. In vitro assays using infected T cells showed activity in controlling both natural and mutant HIV spread using effector-to-target ratios ~1,000-fold lower than a wild-type TCR and at ratios that would be attainable in vivo. A clinical trial is planned, according to a news release from the University of Pennsylvania. The technology described is licensed by Adaptimmune. A third approach, reported by investigators at the University of Toronto and the University of California, San Francisco (UCSF), addresses a phenomenon called immune system “exhaustion,” or decreased T-cell functionality, a hallmark of AIDS.3Jones RB Ndhlovu LC Barbour JD Prameet MS Jha AR Long BR et al.Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection.J Exp Med. 2008; 205: 2763-2779Crossref PubMed Scopus (567) Google Scholar Although the mechanism for such exhaustion is not known, the investigators found that the expression of the glycoprotein TIM-3 on CD8+ T cells correlated with viral load and CD38 expression and inversely with CD4 cell numbers (all known to be correlated with AIDS progression and less functional T cells recognizing HIV-1 antigens). Tim-3 expression was upregulated on HIV-1-specific CD8+ T cells. The authors hypothesized and then demonstrated that a pathway associated with Tim-3 resulted in attenuated signaling in CD8+ T cells, including phosphor-ERK, Stat5a, and p38 signaling molecules. Blocking Tim-3 signaling using soluble peptide derived from Tim-3 ligand or an antibody restored proliferative activity to these cells in vitro. One could envision incorporating this approach in vaccine development and in TCR engineering, which requires expansion of HIV-1-directed clones in vitro. According to a press release from UCSF, animal studies are planned. These studies provide hope of more effective approaches, including T-cell-based vaccines, to treating HIV infection and AIDS patients, representing increased understanding of both the basic biology of HIV infection and the evolving technology in the gene transfer field.

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