Report from the Keystone Joint Symposia on HIV Pathogenesis and HIV Vaccines
The lack of efficacy observed with Merck’s HIV vaccine candidate has stirred researchers to intensely scrutinize how the immune system responds to infections and vaccines. From March 27-31, 2008, about 1,000 HIV researchers gathered in Banff, Alberta, Canada, for the Keystone Joint Symposia on HIV Pathogenesis and HIV Vaccines to reveal their newly garnered knowledge.
Three key themes emerged throughout this meeting:
One of the goals of vaccination is to generate memory CD8 T cells that will recognize the offending organism upon encounter, and subsequently multiply and attack the troublemaker. Dr. Rafi Ahmed of Emory University asked “Do different T cell vaccines provoke distinct qualities of memory CD8 T cell responses from the immune system?” To answer the query, his laboratory injected mice with either Lymphocytic chriomemingitis virus (LCMV) or Adenovirus type 5 (Ad5) and Listeria monocytogenes (LM) vectors carrying LCMV antigens and compared the memory CD8 T cell response generated by the three approaches. In blood, CD8 T cell responses to LCMV peaked at nearly 8% of total CD8 T cells on day 8 post-infection but declined to 2.5% within 30 days after infection, as expected. LM vector induced very weak peak immune responses but followed a similar response path. Surprisingly, Ad5 vector was as potent as LCMV in inducing effector CD8 T cells that persisted for a longer period than the other strategies. Disappointingly, less of the Ad5-elicited effector memory cells transformed into memory cells.
A total of 6,000 memory CD8 T cells recognizing LCMV gp33 peptide from the animals that received each regimen were transferred into uninfected mice, which were then challenged with vaccinia virus expressing LCMV gp33 peptide. Cells derived from LCMV or LM immunization expanded quickly in response to the infection but the ability of the Ad5-derived cells to remember the invader was compromised as evidenced by poor proliferation and deficient cytokine (IFNg and IL-2) production among these cells. This study suggests that despite its high immunogenicity use of Ad5 vector may be limited due to its inability to induce long-term immunity.
Dr. Larry Corey of the Fred Hutchinson Cancer Research Center (FHCRC) hinted that the findings in mice may mirror human responses too. Merck’s Ad5-based HIV vaccine may have induced effector T cells, marked by expression of CD45RA and CD57 molecules, incapable of further expansion when challenged with HIV antigens. Monkey studies indicate that this quality of T cells could be attributed specifically to Ad5 vectors, and not to other types of adenoviruses.
Several groups showed that HIV targets and destroys Th17, a specialized group of interleukin-17 (IL-17) secreting CD4 T cells discovered in 2005. Loss of Th17 cells leaves the body susceptible to bacterial, fungal and parasitic infections, which undesirably activate the immune system. In this activated state, CD4 T cells are prime candidates for HIV infection and replication.
Dr. Daniel Douek of the NIAID Vaccine Research Center described the gut, but not blood, of HIV-infected individuals as “the slaughter-house” for annihilation of Th17 cells expressing CCR5 on their surface. Monkeys infected with the disease-causing strain of the monkey HIV cousin, SIVmac 251, also preferentially lost Th17 in their gut, which correlated with raised LPS concentration and a state of generalized immune activation. However African green monkeys and Sooty mangabeys that keep their viral infection in check maintain normal counts of Th17 cells (unpublished data). As Th17 cells regulate innate immune responses, he proposed that preventing immune activation through inhibition of Toll-like receptors may reduce the viral load. Dr. Douek suggests to "watch out for the data" in the next few months.
Salmonella typhimurium is cleared within seven days from the intestine of healthy persons, but proves deadly to many HIV–infected individuals. Dr. Satya Dandekar of University of California, Davis and her colleagues sewed the intestinal loops of SIV- infected monkeys and flooded these loops for a few hours with live Salmonella typhimurium. Healthy animals produced Th17 cells in large quantities to combat the bug, while infected monkeys generated a low-key Th17 response at best. In the diseased monkeys the bacteria spread from the gut into the blood. In separate experiments, using mice lacking IL-17 receptor, the team showed an increased broadcasting of the microbes from the gut implicating that IL-17 deficiency creates holes in the mucosal epithelium (Nat Med. 14, 421, 2008).
Dr. Cristian Apetrei of the Tulane National Primate Research Center cast doubt on the correlation between CD4 T cell loss and disease progression. When infected with SIV, sooty mangabeys remain healthy despite the loss of CD4 T cells and increased viral load. He argued the lack of disease progression observed in sooty mangabeys was due to absence of T cell activation. High level of lipopolysaccharides, a predictor of gut permeability, was detected in blood of SIV-infected rhesus macaques while infected African green monkeys (AGs) showed no signs of immune activation. Administering LPS to the AGs resulted in a burst in viral load as well as T cell activation (detected by expression of DR or Ki67 molecules on T cells).
T regulatory cells (Tregs) lull the immune system from reacting too strongly to HIV, thus clamping down on immune activation. Apetrei’s group found that unlike the rhesus macaques, a large population of T regulatory cells resided in the intestines of AGs as detected by higher levels of FoxP3 and lower amounts of CCR5 expression on CD4 T cells. Depleting Tregs with recombinant interleukin 2/diphtheria toxin conjugate (Ontak) in SIV-infected AGs resulted in transient proliferation of activated CD4 T cells, increased levels of inflammatory cytokines and higher viral load. Apetrei urged the field to consider immune activation, rather than just viral replication, as the target of immune strategies to prevent HIV progression.
HLA molecules on the surface of cells hold pieces of viral peptides as flares for T cells to launch an attack on the infected cell. Evidence now suggests that the type of HLA molecule shapes the progression of HIV infection to disease.
Dr. David Watkins of the University of Wisconsin showed that in macaques HLA Class I alleles, Mamu-B*08 and -B*17, exert greater control on viral replication during the chronic phase of SIV infection. B*08 and B*17 alleles bind to the exact same peptides as human HLA Class I molecules HLA-B*27 and -B*58, respectively. Vaccination of monkeys carrying these “protective” alleles with live attenuated SIVmac239∆3 lacking three SIV genes (Nef, Vpr, LTR) suppressed replication of the challenge virus in the acute phase. Interestingly, in some B*17 monkeys a loss of control over viral load occurred in the chronic phase probably due to recombination between the vaccine and the challenge virus. He emphasized that CD8 vaccines can indeed control viral replication and progression in the absence of neutralizing antibodies, and therefore the CTL approach to vaccination should not be abandoned.
Dr. Bruce Walker of Harvard Medical School stated that some elite controllers (viral load below 50 copies/mL) and viremic controllers (virus copy below 2000/mL) preferentially express HLA-B*57, B*27, B*52 and B*35, but not all individuals who carry these alleles can restrict viral multiplication. So the genetic reason for viral control remains undefined.
In addition to HLA, response to HIV treatment can be predicted by a combined effect of CCR5 gene mutations and CCL3L1 copy number (Nat. Med. 14, 413, 2008). HIV uses CCR5 along with CD4 to infect cells, while CCL3L1 binds to CCR5 and prevents HIV entry. The current HIV therapy standard dictates that drug regimen should be initiated when CD4 T cell falls below 350 cells/mL. Dr. Sunil Ahuja of University of Texas Health Science Center at San Antonio recommended that the time to initiate HIV therapy should be determined by an individual’s genetic makeup.
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Last Updated September 03, 2008